AIDS: Part II.

A I D S : P A R T II

ABSTRACT.-- G r e a t sWides h a v e b e e n m a d e in t h e t h e r a p y o f h u m a n i m m u n o d e f i c i e n c y v i r u s (HIV) infection. C u r r e n t l y a p p r o v e d d r u g s i n c l u d e z i d o v u d i n e a n d d i d a n o s i n e . A t h i r d drug, d i d e o x y c y t i d i n e (zalcitibine), h a s r e c e n t l y b e e n filed f o r a p p r o v a l w i t h t h e F o o d a n d D r u g A d m i n i s t r a t i o n . All t h e s e d r u g s w o r k t h r o u g h i n h i b i t i o n o f the r e v e r s e t r a n s c r i p t a s e enz y m e . Z i d o v u d i n e is t h e o n l y d r u g t h a t h a s s h o w n clinical e f f i c a c y a g a i n s t HIV. T r e a t m e n t of p a ~ e n t s w i t h a d v a n c e d HIV d i s e a s e (i.e., a c q u i r e d i m m u n e def i c i e n c y s y n d r o m e [AIDS] o r s y m p t o m a t i c i n f e c t i o n w i t h ( 200 C D 4 + l y m p h o c y t e s p e r mm3), r e s u l t s in a p r o l o n g a t i o n a n d i m p r o v e d quality of life. Z i d o v u d i n e is t h e o n l y a n t i r e t r o v i r a l a g e n t a p p r o v e d f o r t h e treatm e n t of asymptomatlc patients. Early intervention with zidovudine has been s h o w n to delay progression to AIDS w h e n p a t i e n t s ' CD4 + l y m p h o c y t e c o u n t s decline t o less t h a n 500/mm 3, i r r e s p e c t i v e of clinical s i g n s o r s y m p t o m s o f HIV i n f e c t i o n . D i d a n o s i n e is c u r r e n t l y indicated for the t r e a t m e n t of patients with a d v a n c e d HIV d i s e a s e w h o a r e i n t o l e r a n t to o r fsiling z i d o v u d i n e t h e r a p y . T h e m a j o r toxicity o f z i d o v u d i n e is b o n e m a r r o w s u p p r e s s i o n w i t h a n e m i a a n d g r a n u l o c y t o p e n i a ( w h i c h o c c u r s in f r o m 1% t o 45% of patients, d e p e n d i n g o n t h e clinical s t a g e o f d i s e a s e a n d t h e d o s e of t h e drug). D i d a n o s i n e a n d zalcitibine h a v e both b e e n associated with a severe peripheral neurop a t h y , w h i c h is g e n e r a l l y r e v e r s i b l e o n c e s s a t i o n o f t h e d r u g . I n addition, d i d a n o s i n e h a s b e e n i m p l i c a t e d a s a c a u s e of p a n c r e a t i t l s t h a t h a s b e e n fatal in a s m a l l p e r c e n t a g e o f c a s e s . T h e toxicities of d i d a n o s i n e a n d zalcitibine r a n g e f r o m 1% to 10%, d e p e n d i n g o n d o s e , d u r a t i o n of t h e r a p y , a n d t h e p r e s e n c e o f u n d e r l y i n g HIV-related p e r i p h e r a l n e u r o p a t h y o r a p r e v i o u s hist o r y of p a n c r e a t i t i s . T h e clinical h a l l m a r k of HIV i n f e c t i o n is t h e develDM, O c t o b e r 1992

695

o p m e n t of o p p o r t u n i s t i c i n f e c t i o n s a n d m a l i g n a n c i e s , w h i c h a r e a c o n s e q u e n c e of t h e p r o f o u n d i m m u n o deficiency. T h e r i s k o f a n o p p o r t u n i s t i c i n f e c t i o n i n c r e a s e s significantly a s t h e T - h e l p e r l y m p h o c y t e c o u n t d e c l i n e s to l e s s t h a n 20%, o r 200 to 2 5 0 / m m 3. T h e s p e c t r u m of o p p o r t u n i s t i c i n f e c t i o n s r a n g e s f r o m v i r u s e s to p r o t o z o a . P a t i e n t s w i t h a d v a n c e d HIV d i s e a s e a r e a l s o at i n c r e a s e d risk o f i n f e c t i o n w i t h nonopportunistic, community-acquired pathogens. Primary and secondary prophylaxis against the m o s t c o m m o n A I D S - d e f i n i n g o p p o r t u n i s t i c infection, P n e u m o c y s t i s carinii p n e u m o n i a , is n o w r e c o m m e n d e d . S t u d i e s a r e c u r r e n t l y u n d e r w a y to d e t e r m i n e t h e efficacy o f p r o p h y l a x i s a g a i n s t o t h e r o p p o r t u n i s t i c pathogens. Treatment of opportunistic infections associated with AIDS h a s i m p r o v e d significantly o v e r t h e p a s t 5 y e a r s a s n e w d r u g s a n d c o m b i n a t i o n r e g i m e n s of a n f i m i c r o b i a i s h a v e b e e n d e v e l o p e d . T r e a t m e n t of these infections generally requires an induction phase of t h e r a p y , f o l l o w e d b y c h r o n i c lifelong s u p p r e s s i v e t h e r a p y , as is c u r r e n t l y r e c o m m e n d e d f o r t h e treatm e n t of c y t o m e g a l o v i r u s retinitis. O p p o r t u n i s t i c malignancies, principally Kaposi's s a r c o m a and EpsteinB a r r v i r u s - r e l a t e d n o n - H o d g k i n ' s B-cell l y m p h o m a , a r e also s e e n in p a t i e n t s w i t h a d v a n c e d HIV d i s e a s e a n d a r e a direct r e s u l t of t h e p r o f o u n d i m m u n e s u p p r e s sion. The t h e r a p y of t h e n e o p l a s t i c c o m p l i c a t i o n s of AIDS still p r e s e n t s a s i g n i f i c a n t c h a l l e n g e to t h e o n c o l ogist. Significant a d v a n c e s in t h e t r e a t m e n t of HIV infection a n d t h e p r e v e n t i o n a n d t r e a t m e n t of t h e o p p o r t u nistic i n f e c t i o n s a s s o c i a t e d w i t h AIDS h a v e l e d to imp r o v e d survival a n d quality of life for o u r p a t i e n t s . P r e v e n t i o n o f this i n f e c t i o n m u s t still b e o u r u l t i m a t e goal a n d r e m a i n s t h e m o s t f o r m i d a b l e c h a l l e n g e to t h e clinician in t h e 1990s. IN BRIEF THERAPY OF HIV INFECTION

The therapy of h u m a n immunodeficiency virus (HIV) infection is directed at three major strategies: (1) inhibition of viral replication with antiviral agents, (2) restoration of immune function with imm u n e modulating agents, a n d (3) treatment and prophylaxis of op696

DM, O c t o b e r 1992

p o r tu n is tic infections. Vaccines for b o t h t he t r e a t m e n t and prevention of HIV infections are being de ve l ope d but are not e x p e c t e d to be w i d ely available for 5 to 10 years. C ur r ent antiviral t h e r a p y has been p r e d o m i n a n t l y directed at the inhibition of t h e H1V reverse transcriptase e n z y m e . T h e r a p y has been s h o w n to b e beneficial in both e x t e n d i n g the life of patients with a d v a n c e d HW infection (less than 200 T - h e l p e r l y m p h o c y t e s p e r m m 3 with a n a c q u i r e d i m m u n e defic i en cy s y n d r o m e [AIDS]- defining condition) a n d in delaying the p ro g r es s io n to AIDS in people with earlier stages of i m m u n e dysf u n c t i o n (less tha n 500 T-helper l y m p h o c y t e s p e r m m 3 and either a s y m p t o m a t i c or mildly symptomatic). To date, zi dovudi ne in doses of 500 to 600 m g / d a y is the only drug that has s h o w n clinical efficacy in the t r e a t m e n t of HIV-infected patients. The m a j o r toxic effect of z i do v u d in e is reversible bone m a r r o w s u p p r e s s i o n manifested as anemia, granulocytopenia, or both. O t h e r side effects have included h e a d a c h e , nausea, and a myopathy, w h i c h has b e e n described in a p p r o x i m a t e l y 10% of patients on long-term therapy. Resistance of HIV to z i d o v u d i n e has b e e n described in patients with advanced disease w h o have b e e n on t her a py for l onger than 6 m o n t h ++8~The . clinical significance of the resistance is y e t to be defined. The only other d r u g a p p r o v e d for the treatment of HlV infection is didanosine. This drug is similar to zidovudine in its m e c h a n i s m of action and is currently a p p r o v e d for the treatment of individuals with HIV infection w h o are intolerant to or "failing" z i d o v u d i n e therapy. The clinical efficacy of d i d a n o s i n e h a d not been d e m o n s t r a t e d at the time the drug was approved, but the efficacy data/evaluation was to be available b y F eb r u ary 1992. Didanosine is d o s e d accordi ng to weight. Patients weighing less t h a n 50 kg s h o u l d receive 150 mg every 12 hours; those b e t w e e n 50 and 74 kg, 250 mg every 12 hours; and those heavier than 75 kg should receive 375 mg every 12 hours. The bioavailability of the drug is decreased by s t o m a c h acidity and therefore has b e e n f o r m u l a t e d with an i n c o r p o r a t e d buffer. The original drug was f o r m u l a t e d with a citrate/phosphate buffer, w h i c h led to frequeq u e n t d iar r h ea as a side effect. The r e c e n t l y a p p r o v e d folTnulation is a 300-rag ch ewabl e tablet with a different buffer, w h i c h is report ed to d ecr eas e th e incidence of diarrhea. Other m e d i c a t i o n s that require acidity for absorption, s uch as k e t o c o n a z o l e or dapsone, s h o u l d not b e taken concomitantly with didanosi ne. The m aj or toxicities of d i d a n o s i n e are a d o s e - d e p e n d e n t p e r i p h e r a l n e u r o p a t h y a n d an idiosyncratic pancreatitis. Resistance of HIV to didanosine has r ecen tly b e e n reported. The m u t a t i o n in the reverse transcriptase of HIV that leads to this resistance a p p e a r s to reverse zid o v u d i n e resistance. This observation, m a d e so far only in vitro, suggests that c o m b i n a t i o n therapy with z i d o v u d i n e a n d didanosine m a y be advantageous in patients with a d v a n c e d disease. Clinical studies are u n d e r w a y to evaluate t he efficacy of combinations of ziDM, O c t o b e r 1992

697

dovudine with didanosine or dideoxycytidine (ddC) in patients in various stages of HW infection. Dideoxycytidine (zalcitibine) is very similar to didanosine. It is dosed at 0.75 mg orally every 8 hours. The major toxicity is also a dose-dependent peripheral neuropathy. The drug is currently available through an e x p a n d e d access/compassionate plea program. The application to the Food and Drug Administration for approval of the drug was filed October 31, 1991. In at least one head-to-head comparative study with zidovudine in patients with advanced disease, ddC did not appear to be as efficacious as zidovudine. This drug may have the greatest usefulness as combination t h e r a p y with zidovudine or as an alternative to zidovudine in those patients w h o are intolerant of zidovudine. Because of the overlapping toxicity profiles of ddC and didanosine, these two drugs should not be u s e d in combination. Only limited information on resistance of HIV to ddC is available. There has been one report of cross-resistance with didanosine. I m m u n e m o d u l a t i n g agents have been uniformly disappointing as primary therapy for HIV infection. Studies of combinations of immune modulators with antiretroviral agents are underway.

INFECTIOUS COMPLICATIONS OF HIV DISEASE The infectious complications of HIV disease are frequent causes of major morbidity a n d mortality. For the most part, a limited spectrum of infectious diseases predominates. The most c o m m o n opportunistic pathogens causing disease include Pneumocystis cariniL Candida species, cytomegalovirus, Mycobacterium avium complex, Cryptococcus neoformans, Toxoplasma gondii, Cryptosporidium species, Mycobacterium tuberculosis, herpes simplex virus, papovaviruses, and Histoplasma capsulatum. In addition, a b r o a d variety of other bacterial, fungal, a n d protozoan species also contribute to the spectrum of infections a m o n g patients with HIV disease. The overall strategy for the m a n a g e m e n t of the infectious complications of HIV disease includes not only treatment for an individual episode but also primary and secondary prophylaxis. Pneumocystis carinii p n e u m o n i a (PCP) continues to be the most c o m m o n of the opportunistic infections associated with advanced HIV disease, although the epidemiologic patterns have been altered by antiretroviral t h e r a p y a n d the routine use of primary a n d secondary prophylaxis. Disease resulting from PCP only rarely occurs with T-helper lymphocyte counts greater than 20% or 200/mm a. The m o s t c o m m o n disease manifestation is pneumonia, with a diffuse interstitial infiltrate seen on chest radiograph. Atypical manifestations s u c h as localized p u l m o n a r y disease, cavitary disease, or d i s s e m i n a t e d in698


fection have b e e n reported. Diagnosis is based on histologic dem onstration of th e organism in tissues or fluids from the patient. Stand a r d t h e r a p y includes either t r i m e t h o p r i m - s u l f a m e t h o x a z o l e or parenteral pentanlidine. Adjunctive steroids are r e c o m m e n d e d for patients with m o d e r a t e to severe disease. New er therapies include p rimaq u in e- clin dam yc i n, d a p s o n e - t l i m e t h o p r i m , trimetrexate, aerosolized p en tamid i ne, a nd 566C80, an e x p e r i m e n t a l h y d r o x y n a p h t h o q u i n o n e n o w available through an e x p a n d e d access/compassionate plea program. Toxoplasma gondii is another p r o t o z o a n p a t h o g e n that c o m m o n l y causes encephalitis in patients with AIDS. Fever, headache, mental status changes, focal neurologic deficits, and seizures are the most c o m m o n clinical signs and symptoms. Multiple brain lesions with or w i t h o u t e n h a n c e m e n t on c o m p u t e d t o m o g r a p h i c or nlagnetic reson a n c e imaging scans of the brain are the hallmark of the disease. Diagnosis can only be established by brain biopsy, but a presumptive diagnosis c a n be m a d e based on clinical a n d radiologic findings, with a r e s p o n s e to specific toxoplasmosis therapy. T reat m ent of choice is a sulfa agent c om bi ned with p y r i m e t h a m i n e , l ~ r those patients wh o c a n n o t tolerate sulfa drugs, c l i n d a m y c i n has b e e n substituted. Newer oral macrolide antibiotics, clarithromycin, and azithrom y c i n a p p e a r to have good in vitro activity a n d m ay suppl ant the sulfa agents a n d clindamycin in this setting. After a course of therapy, w h i c h generally lasts from 2 to 4 m o n t h s , chronic suppressive t h e r a p y is r e q u i r e d because of a relapse rate of 90%. The most effective m a i n t e n a n c e regimen is yet to be d e t e r m i n e d but includes eit h e r p y r i m e t h a m i n e alone or p y r i m e t h a m i n e c o m b i n e d with one of the above drugs. Cytomegalovirus (CMV) reactivation disease m o s t c o m m o n l y manifests as a sight-threatening cholioretinitis in 15% to 20% of patients with AIDS. Gastrointestinal tract disease, including hepatitis and ulcerative lesions of the esophagus a n d colon, are seen in 5% to 10% of patients. Less c o m m o n disease manifestations include encephalopathy, p o l y r a d i c u l o m y e l o p a t h y or n e u r o p a t h y , pneumonitis, and d i s s e m i n a t e d disease with a wasting s y n d r o m e . Diagnosis is made b a s e d on eith er the typical clinical a p p e a r a n c e of lesions, as in chorioretinitis, or the histologic identification of typical viral inclusions in tissues. CMV disease is treated with either of two intravenous antiviral drugs. Both gancielovir, a n u c l e o s i d e analogue related to acyclovir, an d foscarnet, a p y r o p h o s p h a t e analogue, inhibit viral DNA polymerase. F o u r t e e n to 21 days of i n d u c t i o n t h e r a p y is given with e i t h er of th e drugs, followed by c h r o n i c suppressive t h e r a p y indefinitely b e c a u s e of a high relapse rate, especially for CMV retinitis. The m a j o r toxicity effect of gancielovir is a reversible b o n e m a r r o w supp res s io n manifested by g r a n u l o c y t o p e n i a a n d thrombocytopenia. This p r e c l u d e s use of this drug with z i d o v u d i n e because of the overDM, O c t o b e r 1992

699

lapping toxicity. Significant granulocytopenia may be m a n a g e d by the concomitant administration of granulocyte colony stimulating factors. The major toxic effects of foscarnet are metabolic disturbances and nephrotoxocity. The metabolic disturbances, particularly those related to extracellular shifts of electrolytes, have been implicated in neurotoxicity in a small percentage of patients. Foscarnet can be administered with zidovudine and has d e m o n s t r a t e d in vitro synergy with zidovudine against HlV. Mycobacterial infections, in particular Mycobacterium a v i u m intracellulare complex (MAC) a n d Mycobacterium tuberculosis, are becoming more p r o m i n e n t in the AIDS epidemic. MAC infects up to 40% to 60% of AIDS patients, with 18% to 29% manifesting MAC disease during life. Disease is most c o m m o n l y disseminated but can be localized. Clinical s y m p t o m s m a y mimic those of l y m p h o m a , with hectic fevers, sweats, splenomegaly, lymphadenopathy, weight loss with wasting and diarrhea, a n d anemia or pancytopenia. Diagnosis is based on recovery of the organism from cultures of blood, bone marrow, or other normally sterile tissue such as lymph n o d e or liver. Disseminated MAC is treatable with multidrug regimens, including combinations of amikacin, clofazamine, ethambutol, rifampin, a n d ciprofloxacin. Clarithromycin a n d azithroycin have good in vitro ac o tivity and are being evaluated clinically. As with other opportunistic infections associated with advanced HIV disease, chronic lifelong suppressive therapy is required. The optimal regimens for b o t h treatment and suppression have not been established. Primary prophylaxis against MAC in patients with advanced i m m u n e suppression is currently u n d e r investigation. Disease caused by M. tuberculosis has risen substantially in the last decade in what appears to be a direct relationship to the rise in numbers of cases of AIDS. The clinical manifestations of tuberculosis in people with HIV infection are similar to those w i t h o u t HIV infection. However, atypical presentations and extrapulmonary disease are more c o m m o n a m o n g those coinfected with HIV. The diagnosis of tuberculosis is similar to that in other populations. Treatment is also similar, although the recent reports of up to 20% multidrug-resistant isolates of M. tuberculosis from cities with large populations of patients with AIDS d e m a n d the use of four or five drug regimens until susceptibility testing of the isolate becomes available. Prophylaxis against reactivation of M. tuberculosis in the HlV-infected population is problematic because of the high rate of false-negative purified protein derivative (PPD) skin tests in HIV-infected individuals with T-helper lymphocyte c o u n t s less than 400/mm 3. Patients w i t h HIV infection who have a positive response t o PPD (greater t h a n or equal to 5 m m of induration) should receive isoniazid prophylaxis in a dose of 300 mg/day for 6 to 12 months. Cryptococcus neoformans is the most significant of the fungal 700


p a t h o g e n s infecting p a t i e n t s with AIDS. I n f e c t i o n of the c e n t r a l nerv o u s s y s t e m w i t h a m e n i n g o e n c e p h a l i t i s is t h e m o s t f r e q u e n t clinical m a n i f e s t a t i o n of disease. S y m p t o m s are u s u a l l y insidious in onset a n d i n c l u d e fever, h e a d a c h e , n a u s e a , d i z z i n e s s , s o m n o l e n c e , a n d irritability f o l l o w e d b y i m p a i r e d m e n t a l s t a t u s a n d finally, if untreated, seizures, o b t u n d a t i o n , a n d c o m a . P u l m o n a r y a n d dissemin a t e d d i s e a s e is also r e p o r t e d . Diagnosis is b a s e d o n the d e t e c t i o n of the o r g a n i s m in c u l t u r e or the d e t e c t i o n of c r y p t o c o c c a l antigen in c e r e b r o s p i n a l fluid or blood. T h e r a p y in s e v e r e l y ill p a t i e n t s s h o u l d p r o b a b l y b e initiated w i t h a m p h o t e r i c i n B w i t h o r w i t h o u t the comb i n e d use o f flucytosine. Initial t h e r a p y w i t h p a r e n t e r a l or oral flucon a z o l e m a y b e u s e d in individuals w h o have m i l d e r disease o r lack p o o r p r o g n o s t i c factors. For those w i t h severe d i s e a s e w h o r e s p o n d to initial t h e r a p y , a m p h o t e r i c i n B m a y b e s w i t c h e d to oral fluconazole after 2 to 3 weeks of therapy. C h r o n i c s u p p r e s s i v e t h e r a p y is indicated, a n d fluconazole, 200 to 400 m g p e r day, has b e e n s h o w n to be m o r e effective a n d less toxic t h a n a m p h o t e r i c i n B.

N E O P L A S T I C C O M P L I C A T I O N S OF A I D S

Kaposi's s a r c o m a (KS) is the m o s t c o m m o n o f the n e o p l a s t i c comp l i c a t i o n s of AIDS. Fifteen p e r c e n t to 20% of h o m o s e x u a l m e n with HIV i n f e c t i o n have KS or will d e v e l o p it at s o m e p o i n t d u r i n g their disease c o u r s e . T h e i n c i d e n c e appears, l o w e r a m o n g HIV-infected int r a v e n o u s d r u g users a n d Hispanic individuals, a n d KS is distinctly u n c o m m o n b u t d o e s o c c u r in HIV-infected w o m e n a n d children. T h e clinical m a n i f e s t a t i o n s of KS s p a n t h e s p e c t r u m from localized c u t a n e o u s lesions to w i d e s p r e a d visceral disease. T h e diagnosis of KS is b a s e d o n t h e a p p e a r a n c e of t h e lesions a n d the characteristic h i s t o p a t h o l o g i c c h a n g e s in b i o p s i e d tissue. T r e a t m e n t of KS dep e n d s o n t h e location a n d extent of disease. Local irradiation or intralesional c h e m o t h e r a p y m a y be u s e d in c o s m e t i c a l l y u n a c c e p t a b l e o r strategically l o c a t e d lesions that are c a u s i n g great discomfort. For m o r e extensive or rapidly progressive c u t a n e o u s involvement, comb i n a t i o n c h e m o t h e r a p y is generally r e c o m m e n d e d . C o m b i n a t i o n cytotoxic c h e m o t h e r a p y is usually p o o r l y t o l e r a t e d in t h e s e patients b e c a u s e of p o o r b o n e m a r r o w reserves a n d t h e a d v a n c e d stage of immune suppression. N o n - H o d g k i n ' s l y m p h o m a (NHL) is o c c u r r i n g with i n c r e a s i n g freq u e n c y in t h e HIV-infected p o p u l a t i o n as the survival of p a t i e n t s is p r o l o n g e d b y i m p r o v e d antiretroviral a n d p r o p h y l a c t i c therapies. T h e i n c i d e n c e of this c o m p l i c a t i o n in AIDS p a t i e n t s is e s t i m a t e d to b e 2% to 3%. A r e c e n t s t u d y of p a t i e n t s w i t h a d v a n c e d disease o n z i d o v u d i n e t h e r a p y s h o w e d an a n n u a l i n c i d e n c e of 1.6%. An association a p p e a r s to exist b e t w e e n NHL a n d E p s t e i n - B a r r virus infection. DM, October 1992

701

Prolonged zidovudine t h e r a p y doe s not a p p e a r to be a risk factor for the development of NHL. A n o t h e r factor apparently associated w i t h the increased risk for d e v e l o p m e n t of NHL is a history of KS or CMV disease. Clinical p r e s e n t a t i o n c a n be confined to the central nervous system or can include p e r i p h e r a l involvement. Systemic, or "B," s y m p t o m s with fever a n d weight loss are frequent. T he definitive diagnosis requires biopsy and histologic examination of involved tissue. Central nervous system NHL can be confused clinically and radiographically with o t h e r mass lesions c a u sed by o p p o r t u n i s t i c infections. Appropriate t h e r a p y for NHL requires irradiation and/ or cytotoxic ch emo th e r apy. Favorable initial response rates have b e e n achieved with c o m b i n e d modality therapy, but the durability of t he responses has b e e n short-lived. Consultation with an oncologist is recommended.

70;2


Harold A. Kessler, M.D., is an Associate Professor o f Medicine and Immunology~Microbiology at Rush Medical College~Rush-Presbyterian-St. Luke's Medical Center and Director o f the HIV T r e a t m e n t Program a n d the Coordin a t e d AIDS Resource Center at Rush. He c o m p l e t e d his internal m e d i c i n e residency a n d infectious disease training at Rush, f o l l o w e d by a Research Fellowship in Virology at the L o n d o n School o f Hygiene a n d Tropical Medicine. Dr. Kessler specializes in infectious diseases, with a f o c u s on viral infections. He has b e e n active in the t r e a t m e n t o f patients with HIV infection a n d clinical a n d laboratory research related to HIV s i n c e 1983.

J o s e p h A. Bick, M.D., is an I n s t r u c t o r in Medicine at Rush Medical College~Rush-Presbyterian-St. Luke's Medical Center. He c o m p l e t e d his r e s i d e n c y in internal m e d i c i n e at Rush a n d is currently a Fellow in the Section o f Infectious Disease. Dr. Bick is actively involved in his fellowship in the clinical research p r o g r a m in HIV infection at Rush. DM, O c t o b e r

1992

703

John C. Pottage, Jr., M.D., is an Assistant Professor o f Medicine a n d Immunology~Microbiology at Rush Medical College/Rush-Presbyterian-SL Luke's Medical Center. He is a m e m b e r o f the Section o f Infectious Disease. Dr. Pottage c o m p l e t e d his residency in internal m e d i c i n e a n d clinical fellowship in infectious disease at Rush. He s p e n t a third year o f fellowship in laboratory research on studies related to hepatitis a n d herpes simplex infections. Dr. Pottage focuses his clinical research on the d e v e l o p m e n t o f new therapies f o r HIV infection and, in addition, on opportunistic fungal infections associated with i m m u n o c o m promised patients.

Constance A. Benson, M.D., is an Assistant Professor o f Medicine at Rush Medical College~Rush-Presbyterian-St. Luke's Medical Center and is a m e m b e r o f the Section o f Infectious Disease. She completed her internal medicine residency a n d infectious disease training at Rush. She currently serves as the Medical Director o f the inpatient AIDS care cluster at Rush. Dr. Benson has f o c u s e d her clinical research efforts o n the prophylaxis a n d t r e a t m e n t o f P n e u m o c y s t i s carinii pneumonia, cytomegalovirus retinitis, a n d d i s s e m i n a t e d M y c o b a c t e r i u m a v i u m complex disease associated with advanced HIV infection. 704

DM, October 1992

AIDS: PART

II

THERAPY OF HIV INFECTION

T h e t h e r a p y of h u m a n i m m u n o d e f i c i e n c y virus (HIV) infection involves three m a j o r strategies: (1) inhibition of ongoi ng viral replication with antiviral agents, (2) restoration of i m m u n e function with i m m u n e m o d u l a t i n g agents, and (3) t r e a t m e n t and prophylaxis of o p p o r t u n i s t i c infections. Development of a vaccine to prevent infection in p e r s o n s w ho are exposed to HIV is the best h o p e for controlling HW infection. Vaccines are also being u s e d as i m m u n e modulating agents in p e r s ons already infected with HW. The ni~ost success thus far has b e e n in the d e v e l o p m e n t of antiviral agents a n d in the t r e a t m e n t of opportunistic infections. I m m u n e modulators, as well as vaccines, have met with only limited success. ANTIVIRAL CHEMOTHERAPY

A review of the HIV replication cycle shows several points that can serve as potential targets for antiviral c h e m o t h e r a p y . These include (1) a t t a c h m e n t a n d uncoating, (2) conversion of viral RNA into DNA t h r o u g h reverse transcriptase, (3) t r a n s c r i p t i o n of m e s s e n g e r RNA (mRNA), (4) translation of mRNA into viral proteins, (5) processing a n d assembly of viral proteins, and finally, (6) b u d d i n g and release of the virus t h r o u g h the host cell m e m b r a n e . Additionally, HIV contains several u n u s u a l regulatory genes that influence transcription and translation, w h i c h can also serve as potential targets for antiviral therapy. 2°6 At present, two antiviral agents have b e e n released for general use in the t r e a t m e n t of HW infection, z i d o v u d m e a n d didanosine. Dideoxycytidine will most likely be a p p r o v e d in the near future. All t h r ee of th es e agents are 2', 3'- di deoxynucl eosi des a n d act by inhibiting HIV reverse transcriptase. O t her d i d e o x y n u c l e o s i d e s that are just starting clinical investigation i n c l u d e 3'-deoxy-2',3'-didehyd r o t h y m i d i n e a n d 3'-fluom-3'-deoxythymidine. A s e c o n d g r o u p of agents that inhibit HIV reverse transcriptase are the so-called n o n n u c l e o s i d e reverse transcriptase inhibitors. In-

DM, O c t o b e r 1 9 9 2

705

c l u d ed in this group are the t e t r a h y d r o i m i d a z o b e n z o d i a z e p i n e comp o u n d s , BIRG-587, L-697, 639, a n d L-697, 661. These agents are just beginning clinical trials at this time. Several other target areas exist in w hi c h c o m p o u n d s have b e e n identified and have b e e n s h o w n to have in vitro anti-HIV activity. One promising area of d e v e l o p m e n t is the HIV-protease inhibitors, w hich disrupt the processing a n d assembly of viral proteins. 2°7 Additionally, inhibitors of glycosylation (as a step that o c c u r s duri ng b u d d i n g an d release) 2°8 a nd inhibitors of the regulatory gene p r o d uct, tat, are also in the early stages of development. 2° Because of the pressing n e e d for rapid devel opm ent of antiviral t h e r ap y for HIV infection a nd t he lack of a widely available animal model, studies of antiviral agents rely heavily on discerning antiviral activity as shown by surrogate markers. The most i m p o r t a n t markers that are used at this time i n c l u d e the CD4+ cell count, HIV p24 antigenemia, and quantitative p l a s m a viremia. 4°'m9 Markers that reflect HIV activity, such as s e r u m [~2-microglobulin and s e r u m neopterin, are also evaluated. Clinical variables, w hi ch include weight gain, improvement in the Karnofsky p e r f o r m a n c e status, r e d u c t i o n in the n u m b e r and severity of o p p o r t u n i s t i c infections, a n d mortality ate also closely evaluated. However, as studies are more frequent l y being p e r f o r m e d in a s y m p t o m a t i c a n d mildly symptomatic patients, clinical indicators may take years to s h o w differences. In this section, w e will review the major antiviral agents that are available to clinicians today, as well as agents that are beginning clinical evaluation.

Zidovudine Mechanism of Action.--Zidovudine, or 3'-azido-2',3'-dideoxythymidine (AZT), is an inhibitor of HlV reverse transcriptase. On e n t r y into the cell, zidovudine is c o n v e r t e d into its active form, z i d o v u d i n e triphosphate. This change is m e d i a t e d by host cell kinases located in the cytoplasm. T h e H1V reverse transcriptase is t h o u g h t to be inhibited through two m e c h a n i s m s : (1) zidovudine t r i p h o s p h a t e com petes with thymidine t r i p h o s p h a t e in the formation of proviral DNA, a n d (2) o n ce i n c o r p o r a t e d into the proviral DNA, z i d o v u d i n e triphosphate acts as a chain terminator, a n d DNA replication ceases. Zidovudine inhibits b o t h HIV-1 a n d HlV-2, as well as a w i de variety of animal retroviruses.209' 2 1 0 Pharmacology.--Zidovudine is well absorbed from the gastrointestinal tract, with an oral bioavailability of approxi m at el y 60%. The drug has a half-life of appr oxi m at el y 1.1 hours, a n d 15% to 20% is excreted into the ur i ne u n c h a n g e d . The remaining z i d o v u d i n e is metabolized by the liver by g l u c u r o n i d a t i o n to fomaa 3'-azido-2',3'706

D M , O c t o b e r 1992

dideoxy-5'-glucuronylthymidine, w h i c h is t h e n excreted into the urine. This metabolite has no a n t i - r e v e r s e transcliptase activity.2°9 Zidovudine penetrates into the c e r e b r o s p i n a l fluid at approxim ately 60% of the plasma concentration. The drug is f o u n d in sem e n an d readily crosses the placenta. 21° T h e usual dosage of zidovudine is 100 m g orally every 4 hours, five to six times p e r day. Most patients skip the nighttime sixth dose. Studies are u n d e r way evaluating less frequent dosing of zidovudine, s u c h as 200 mg orally every 8 hours. Although this regimen seems to be widely u s e d at this time, it c a n n o t be r e c o m m e n d e d , p e n d i n g the o u t c o m e of these dose-frequency studies. In pat i ent s receiving hemodialysis, the best dose is probably 100 m g by m o u t h every 8 hours. Z id o v u d in e is also available for i nt r a ve n ous administration. The usual dosage of intravenous zidovudine is 1 to 2 mg/kg infused over 1 h o u r every 4 hours. Continuous infusion of zidovudine has been d es cr ib ed as being useful in children; T M however, its use in adults is investigational. Clinical U s e . - - Z i d o v u d i n e is t he m o s t widely used, well-studied antiviral for the t r e a t m e n t of HW infection. Early studies at the National Institutes of Health s how ed i m p r o v e m e n t in immunologic, virologic, a n d clinical variables in a small g r o u p of patients. 212 This s t u d y led to a larger-scale, pl a c e bo- cont r o l l ed study, in w h i c h survival was clearly improved at 24 weeks with t h e administration of zid o v u d i n e to patients w h o had e x p e r i e n c e d their first episode of P n e u m o c y s t i s carinii p n e u m o n i a . 7 O t he r clinical indicators that were i m p r o v e d b y zidovudine use i n c l u d e d t he f r e q u e n c y of opportunistic infections, Karnofsky p e r f o r m a n c e status, a n d weight. 7 I m m u n o logically, th e CD4+ cell c ount i m p r o v e d temporarily, with a rise of a p p r o x i m a t e l y 80 cells p e r m m 3, peaking at 12 weeks a n d t h e n falling to p r e t r e a t m e n t levels by 24 weeks. Virologically, the level of p24 antigen fell with zidovudine use, a l t h o u g h patients treated with zid o v u d i n e r e m a i n e d culture positive des pi t e z i d o v u d i n e treatment. 7 Based o n the results of the p l a c e b o - c o n t r o l l e d study, zidovudine b e c a m e m o r e widely available t h r o u g h a c o m p a s s i o n a t e plea program. A review of the data from t he s e pa t i ent s s h o w e d improved survival in patients treated with zidovudine, w i t h a 44-week survival rate of 73%. Patients w h o started t h e r a p y w i t hi n 90 days of an epis o d e of P. carinii p n e u m o n i a and w h o h a d h e m o g l o b i n levels greater t h a n 120 g/L and a Karnofsky p e r f o r m a n c e status greater t han 90% derived the m o s t benefit from zidovudine. 213 Once the efficacy of zidovudine was d e m o n s t r a t e d in patients with a d v a n c e d HIV disease, studies w er e b e g u n to define the best d os e of z i d o v u d i n e and at what stage of HIV infection to begin zidovudine. Several studies c o m p a r i n g z i d o v u d i n e in different dosage DM, October 1992

707

r e g i m e n s a n d in p a t i e n t s w h o w e r e less s y m p t o m a t i c w e r e t h e n b e g u n a n d h a v e b e e n r e c e n t l y c o m p l e t e d . T h e first of t h e s e s t u d i e s w a s t h e AIDS Clinical Trial G r o u p (ACTG) s t u d y 002, w h i c h c o m p a r e d high a n d l o w d o s e s of z i d o v u d i n e in t h e s a m e p a t i e n t p o p u lation t h a t was i n c l u d e d in t h e original p l a c e b o c o m p a r a t i v e study. 214 This s t u d y s h o w e d t h a t n o significant difference w a s f o u n d b e t w e e n high- a n d l o w - d o s e z i d o v u d i n e w i t h regard to i n c i d e n c e of o p p o r t u n i s t i c i n f e c t i o n s or C D 4 + cell c o u n t s . However, t h o s e p a tients w h o received l o w - d o s e z i d o v u d i n e h a d a significantly b e t t e r survival rate a n d a d e c r e a s e d i n c i d e n c e of z i d o v u d i n e - r e l a t e d toxicity. O n the basis of this s t u d y , t h e r e c o m m e n d e d d o s a g e for z i d o v u d i n e w a s set at 500 to 600 m g p e r day. 214 T w o large studies, ACTG 016 a n d ACTG 019, e x a m i n e d t h e u s e of z i d o v u d i n e in p a t i e n t s at e a r l i e r stages of HIV infection, s'9 Several d o s a g e r e g i m e n s w e r e also s t u d i e d . ACTG 016 s t u d i e d p a t i e n t s w h o h a d d e v e l o p e d a c q u i r e d i m m u n e d e f i c i e n c y s y n d r o m e (AIDS)r e l a t e d c o m p l e x (ARC) s y m p t o m s , a n d ACTG 019 s t u d i e d p a t i e n t s w h o w e r e a s y m p t o m a t i c . T h e s e s t u d i e s s h o w e d that in p a t i e n t s w h o h a d f e w e r t h a n 500 C D 4 + cells p e r m m 3, t r e a t m e n t w i t h z i d o v u d i n e r e s u l t s in a delay in t h e d e v e l o p m e n t of AIDS-related e v e n t s . No diff e r e n c e s in overall m o r t a l i t y w e r e d e t e c t e d in t h i s g r o u p of p a tients, s'9 Patients w i t h m o r e t h a n 500 C D 4 + cells p e r m m 3 are c o n t i n u i n g to b e s t u d i e d . At p r e s e n t , n o differences b e t w e e n p l a c e b o and zidovudine-treated patients have been detected. M o r e r e c e n t s t u d i e s h a v e s h o w n t h a t a d o s a g e as l o w as 300 m g p e r d a y m a y be effective. O n e s t u d y s h o w e d t h a t in p a t i e n t s t r e a t e d w i t h 300 m g of z i d o v u d i n e p e r day, t h e r e d u c t i o n s in p 2 4 a n t i g e n levels a n d p l a s m a v i r u s titers w e r e similar to t h o s e s e e n in p a t i e n t s t r e a t e d w i t h h i g h e r d o s a g e s of z i d o v u d i n e . 215 It s h o u l d b e n o t e d t h a t this w a s a small s t u d y , a n d s t u d i e s w i t h larger n u m b e r s of p a t i e n t s are o n g o i n g to c o n f i r m t h i s o b s e r v a t i o n . It is p r e m a t u r e at this t i m e to r e c o m m e n d this d o s a g e for initial t h e r a p y with z i d o v u d i n e . D o s ages l o w e r t h a n 300 m g p e r d a y are p r o b a b l y n o t effective a n d c o u l d p o s s i b l y l e a d to a m o r e r a p i d d e v e l o p m e n t of viral r e s i s t a n c e . Recently, two l o n g - t e r m o b s e r v a t i o n a l s t u d i e s h a v e b e e n p u b l i s h e d evaluating t h e efficacy o f z i d o v u d i n e . 21G'217 Both s t u d i e s d e m o n s t r a t e d a survival b e n e f i t a t t r i b u t a b l e to z i d o v u d i n e . In a m u l t i center, p r o s p e c t i v e o b s e r v a t i o n a l s t u d y of p a t i e n t s w i t h l e s s t h a n 250 C D 4 + cells p e r m m 3, t h e 1 8 - m o n t h survival rate w a s 67% .2~ T h ~ o t h e r study, w h i c h e x a m i n e d a g r o u p of p a t i e n t s e n t e r e d into t h e M a r y l a n d H u m a n I m m u n o d e f i c i e n c y Virus I n f o r m a t i o n System, s h o w e d a m e d i a n s u w i v a l of 25 m o n t h s in p a t i e n t s t r e a t e d w i t h zid o v u d i n e . T h e survival b e n e f i t w a s g r e a t e s t in n o n - H i s p a n i c w h i t e s , p e r s o n s y o u n g e r t h a n 45 y e a r s , a n d m e n . 217 Studies s u c h as t h e s e h a v e p o i n t e d out t h a t t h e r e m a y b e d i f f e r e n c e s in t h e v a r i o u s g r o u p s of p e r s o n s infected w i t h HIV. Clearly, m o r e s t u d i e s n e e d to b e d o n e 708

DM,

October 1992

in w o m e n a n d m i n o r i t y g r o u p s to b e s t d e t e l x n i n e t h e o p t i m u m u s e of z i d o v u d i n e . In s u m m a t y , t h e s e s t u d i e s h a v e d e m o n s t r a t e d t h a t in p a t i e n t s w h o h a v e l e s s t h a n 200 C D 4 + cells p e r m m 3, z i d o v u d i n e i m p r o v e s clinical s t a t u s a n d survival a n d d e c r e a s e s the i n c i d e n c e a n d severity of o p p o r t u n i s t i c infections. In p a t i e n t s w i t h C D 4 + cell c o u n t s of 200 to 500 cells p e r m m 3, z i d o v u d i n e c l e a r l y d e l a y s p r o g r e s s i o n to s v m p t o m a t i c d i s e a s e , a l t h o u g h a n overall survival b e n e f i t h a s n o t y e t b e e n d e t e r m i n e d . T h e d o s a g e of z i d o v u d i n e for s t a r t i n g t h e r a p y in all t h e s e g r o u p s is 500 to 600 m g p e r day. F o r p a t i e n t s w i t h m o r e t h a n 500 C D 4 + cells p e r m m 3, n o p r o v e n b e n e f i t of z i d o v u d i n e h a s b e e n f o u n d , a n d it is t h e r e f o r e n o t r e c o m m e n d e d at this time. Z i d o v u d i n e h a s b e e n s h o w n to i m p r o v e m e n t a l s t a t u s in p a t i e n t s w i t h HIV d e m e n t i a . This h a s b e e n d o c u m e n t e d b y n e u r o l o g i c testing, as well as b y p o s i t r o n e m i s s i o n t o m o g r a p h y . 21~'~19 B e c a u s e zid o v u d i n e p e n e t r a t e s into t h e c e r e b r o s p i n a l fluid to a level o n l y 60% of p l a s m a c o n c e n t r a t i o n s , a h i g h e r initial d o s e of z i d o v u d i n e (1,200 rag/day) h a s b e e n r e c o m m e n d e d . T h e b e n e f i c i a l effect of z i d o v u d i n e h a s also b e e n well d e s c r i b e d in p a t i e n t s w i t h HlV-associated t h r o m b o c y t o p e n i a . 22°'221 A doser e l a t e d r e s p o n s e to z i d o v u d i n e , w i t h a n i n c r e a s e in platelets a n d a d e c r e a s e in HIV p24 antigen, is o f t e n s e e n . P a t i e n t s m a y n e e d to b e t r e a t e d w i t h d o s e s of u p to 1,200 r a g / d a y to m a i n t a i n a n a d e q u a t e p l a t e l e t c o u n t . 22°' 221

Toxicity.-- The m o s t c o m m o n s y m p t o m s o f z i d o v u d i n e toxicity e n c o u n t e r e d at t h e start of t h e r a p y a r e n a u s e a , a b d o m i n a l pain, a n d h e a d a c h e s . F o r t h e m o s t part, t h e s e are s h o r t - l i v e d a n d will disapp e a r d e s p i t e c o n t i n u i n g z i d o v u d i n e t h e r a p y . 222 H e m a t o l o g i c toxicity c o n s i s t i n g of a n e m i a a n d l e u k o p e n i a is the m a j o r toxic effect a s s o c i a t e d with z i d o v u d i n e . T h e i n c i d e n c e of this toxicity h a s d e c r e a s e d w i t h the decl~ease in t h e r e c o m m e n d e d dosage of z i d o v u d i n e . T h e m e c h a n i s m of a c t i o n o f h e m a t o l o g i c toxicity r e l a t e s to i n t e r f e r e n c e w i t h t h y m i d i n e m e t a b o l i s m or DNA polym e r a s e in b o n e m a r r o w s t e m cells. 2°a A n e m i a is t h e m o s t c o m m o n toxic effect o f z i d o v u d i n e . In the e a r l y s t u d i e s of z i d o v u d i n e , a n e m i a (defined as a h e m o g l o b i n conc e n t r a t i o n less t h a n 10g/dL) o c c u r r e d in u p to 30% to 40% of t h e p a tients a n d u s u a l l y o c c u r r e d w i t h i n t h e first 8 w e e k s of t h e r a p y . 222 With d o s a g e r e d u c t i o n , as s h o w n in ACTG 002, t h e i n c i d e n c e of anem i a w a s d e c r e a s e d . 214 Additionally, in s t u d i e s o f p a t i e n t s w h o have less a d v a n c e d disease, p a r t i c u l a r l y ACTG 019, t h e i n c i d e n c e of anem i a is as l o w as 1.1% .9 Most p a t i e n t s r e c e i v i n g z i d o v u d i n e have a m a c r o c y t o s i s develop, w i t h m e a n c o r p u s c u l a r v o l u m e values of g r e a t e r t h a n 120 ~ m . ~ For t h e m o s t p a r t , t h e a n e m i a i m p r o v e s w i t h zidovudine discontinuation. DM, O c t o b e r 1992

709

Serum immu nor e a c t i ve e l y t h r o p o i e t i n levels are generally elevated in patients with z i d o v u d i n e - i n d u c e d anemia. 223-2~5 However, in patients wh o have low e r y t h r o p o i e t i n levels (~ 500 IU/L), administration of r eco mb i na nt e r y t h r o p o i e t i n results in i m p r o v e m e n t in t he hematocrit and a d e c r e a s e d transfusion requirement. Patients w i t h erythropoietin levels greater t h a n 500 IU/L do not benefit from rec o mb in an t erythropoietin.22a' z24 Leukopenia o c c u r r e d in a p p r o x i m a t e l y 16% of z i d o v u d i n e recipients in the early studies a nd h a s d e c r e a s e d in i n c i d e n c e with dose red u ctio n and with the use of zidovudine in patients w i t h less advanced disease, zzz Z i d o v u d i n e - i n d u c e d leukopenia is primarily a p r o b lem in patients receiving o t h e r myelotoxic agents s u c h as ganciclovir, interferon alpha, or high-dose t r i m et hopri m -sul fam et hoxazole. Like anemia, z i d o v u d i n e - i n d u c e d leukopenia is generally reversible on discontinuation of zidovudine. Long-term (~1 year) z i d o v u d i n e use has been associated w i t h a m y o p a t h y characterized by m u s c l e wasting and w e a k n e s s in approximately 20% of patients. 2z6-22a Histologic changes are generally nonspecific, with a l y m p h o c y t i c infiltration. Mitochondrial dam age has b e e n described, zza Creatinine p h o s p h o k i n a s e levels are often elevated but correlate poor l y w i t h clinical symptomatology. Other adverse reactions t hat have b e e n described in case report s include nail h y p e r p i g m e n t a t i o n , rash, fever, seizures, a n d confusion. zz6 Overdosage with z i d o v u d i n e has b e e n associated with seizures. 229 Esophageal ul c e r at i ons resulting from an i nt eract i on w i t h esophageal epithelial cells have b e e n described in pat i ent s taking zidovudine without a d e q u a t e fluids in the middle of t he night. 23° Mild to m o d e r a t e elevations in liver transaminases and elevations in alkaline p h o s p h a t e a n d bilirubin levels have also been r e p o r t e d . T M As patients are surviving l o n g e r with antiviral therapy, the incid e n c e of non-Hodgkin's B-cell l y m p h o m a s has increased. W h e t h e r this is related to z i d o v u d i n e u s e or is a reflection of l o n g e r survival is difficult to determine. Publ i s he d reports concerning this issue are inconclusive .232, 233 Resistance.--A c o n c e r n that has arisen from e x p e r i e n c e with zidovudine is the d e v e l o p m e n t of in vitro resistance to z i d o v u d i n e in patients w h o have taken the d r u g for pr ol onged peri ods of time (~6 months). In patients w h o have never received zidovudine, HIV isolates s h o w a uniform susceptibility to zidovudine. T M Sequential isolates from patients taking z i d o v u d i n e s how a gradual stepwise develo p m e n t of in vitro resistance to zidovudine. T M In pat i ent s w h o have less t h a n 100 CD4+ cells p e r m m 3, this resistance develops over 6 to 18 m o n t h s and is p r e s e n t in virtually all patients. In patients w h o have CD4+ cell c o u n t s b e t w e e n 100 a nd 400 cells p e r m m a a n d in those with more t h a n 400 cells per m m 3, resistance develops at a 710


i n c l u d e d in this program had b e c o m e intolerant to zidovudine a n d / o r e x p e r i e n c e d "clinical failure" with zidovudine, w h i c h is defined as the o c c u r r e n c e of multiple o p p o r t u n i s t i c infections and/or p ro g r es s io n to a CD4+ l y m p h o c y t e c o u n t of less t han 50 cells per m m a. This p r o g r a m has identified t he m aj or toxic effects of didanosine, but information concerning the efficacy of d i d a n o s i n e in this patient p o p u l a t i o n has not been published. Several small studies of patients in this program have shown transient i m p r o v e m e n t in clinical indicators a n d little or no i m p r o v e m e n t in virologic and i m m unologic values. 241-244

Toxicity.-- The most c o m m o n adverse effects associated with d i d a n o s i n e are gastrointestinal. Most patients develop mild diarrhea, w h i c h is t h o u g h t to be related to t he c i t r a t e / p h o s p h a t e buffer and is generally self-limited. The most serious gastrointestinal effect is pancreatitis, w h i c h has b e e n seen in a p p r o x i m a t e l y 2% to 3% of patients receiving didanosine. Asymptomatic elevations of the serum amylase a n d lipase are also seen. Death c a u s e d by pancreatitis has occurred, a n d it is clearly i m p o r t a n t to recognize this com pl i cat i on early and begin p r o p e r m a na ge m ent . Although preexisting pancreatitis and cytomegalovirus infection may p r e d i s p o s e the patient to this complication, t h e exact m e c h a n i s m for d i d a n o s i n e - i n d u c e d pancreatitis is u n k n o w n . 2 3 8 - 2 4 4 A n o t h e r serious toxic effect of d i d a n o s i n e is the devel opm ent of p e r i p h e r a l n e u r o p a t h y . This is dose related a n d affects primarily the s e n s o r y nerves. The m os t c o m m o n s y m p t o m s consist of n u m b n e s s a n d tingling in the feet. Loss of the ankle jerk reflex is usually seen on n eu r o lo g ic examination, along with d e c r e a s e d sensation to pinprick a n d vibration. Peripheral n e u r o p a t h y has been r e p o r t e d to occ u r in ap p r o x im at el y 1% of patients t r e a t e d w i t h didanosine and is generally reversible on discontinuation of didanosine. Patients with u n d e r l y i n g p er ipher a l n e u r o p a t h y are m o r e p r e d i s p o s e d to the dev e l o p m e n t of this complication. A n o t h e r neurologic complication that has b e e n r e p o r t e d is seizures. T he exact role of didanosine in the d e v e l o p m e n t of seizures is u n k n o w n . 23s-244 Didanosine does not interfere with b o n e m a r r o w p r e c u r s o r cells, a n d therefore, little hematologic toxicity associated with didanosine has b e e n seen. Anemia and n e u t r o p e n i a have b e e n associated with d i d a n o s i n e in small n u m b e r s of patients. O th er toxicities that have b e e n r e p o r t e d i n c l u d e elevations in t r a n s a m i n a s e levels a nd uric acid levels. Resistance.-- Preliminary information c o n c e r n i n g the developm e n t of resistance to didanosine has r e c e n t l y b e e n published. 245 Several isolates from patients w ho w e r e given d i d a n o s i n e after developing clinical failure with zidovudine w e r e anal yzed for didanosine DM, O c t o b e r 1992

713

sensitivity. After 6 to 12 m o n t h s , resistance to d i d a n o s i n e was detected. Analysis of t he HIV g e n o m e s h o w e d a mutation in the reverse transcriptase region distinct f r o m the mutation sites that confer resistance to dideoxycytidine. T h e ot he r interesting aspect of this m u tation is that it s e e m s to d e c r e a s e the level of resistance to zidovudine, p er h ap s mitigating the effect of one of the m u t a t i o n s associated with zidovudine resistance. Obviously, more detailed studies are n e e d e d to fully evaluate t h e s e findings. 245

Dideoxycytidine Mechanism of Action.-- Like zidovudine and didanosine, 2',3 'o dideoxycytidine (ddC) is an inhibitor of HIV reverse transcriptase. The active form of the drug is ddC triphosphate, w h i c h acts to inhibit reverse transcriptase a n d cause chain termination of the forming DNA strandff °9 Pharmacology.-- The a b s o r p t i o n of ddC from the s t o m a c h is excellent an d is not i n f l u e n c e d b y gastric acidity. The bioavailability of ddC is 87%. The d r u g is rapidly eliminated and has a half-life of 1.2 hours. It is excreted by the kidneys, with approximately 75% of the parent c o m p o u n d being p r e s e n t in the urine. There are no significant metabolites, ddC p e n e t r a t e s into the cerebrospinal fluid at approximately 14% t he pl as m a level. The usual dosage of ddC is 0.75 mg orally every 8 h o u r s , z ° 9 Use of ddC in patients with renal failure has not been studied, a nd dosage r e c o m m e n d a t i o n s c a n n o t be m a d e at this time. Clinical Experience.--Using high doses of ddC in a small g r o u p of patients, i m p r o v e m e n t in the CD4+ cell c o u n t and r e d u c t i o n in p24 antigen were d e m o n s t r a t e d , as well as i m provem ent in clinical indicators. However, severe p e r i p h e r a l n e u r o p a t h y devel oped in virtually all patients, precluding the u s e of ddC at this dose level. 246 Two additional o p e n studies were p e r f o r m e d using l ow er dosage regimens of ddC, w h i c h also resulted in clinical i m p r o v e m e n t , as well as a decrease in circulating p24 antigen levels a n d i m p r o v e m e n t in CD4+ cell c o u n t . 247' 2 4 8 T he i nci dence a n d severity of ddC-related n e u r o p a t h y also declined. 247'248 At present, a large comparative study is ongoing of ddC versus zidovudine in patients w i t h less t h a n 200 CD4+ cells p e r m m 3. This s t udy will help to define the role of ddC m o n o t h e r a p y in these patients. Studies of ddC t r e a t m e n t of patients with higher CD4+ cell c o u n t s are planned. In view of this dos e - r e l a t e d toxicity, a strategy of alternating ddC a n d zidovudine was devised in an effort to decrease ddC toxicity a n d p er h ap s increase antiviral activity by using two drugs. Preliminary data from t he s e studies did s h o w increased antiviral activity, particularly in regimens of m o n t h l y alternating high-dose ddC a n d 714


zidovudine.249, 250 However, n e u r o p a t h y r e m a i n e d a problem. 249' 250 A n o t h e r s t u d y e xam i ne d the c o n c u r r e n t administration of ddC and zidovudine. Th e antiviral efficacy, as m e a s u r e d by CD4÷ cell count elevation, was improved. Several ongoing studies are u n d e r way at this time c o m p a r i n g combination t h e r a p y of ddC and zidovudine (ACTG 155). It appears that the sequential fashion of alternating ddC a n d z i d o v u d i n e is less promising t h a n giving t he drugs concurrently.

Toxicity.-- The major toxic effect of ddC is p e r i p h e r a l neuropathy. It is dose related and is similar to that c a u s e d b y didanosine. At the p r e s e n t dose level, the incidence is a p p r o x i m a t e l y 10%. T hose patients with preexisting n e u r o p a t h y are m o r e p r e d i s p o s e d . As with the n e u r o p a t h y associated with didanosine, ddC-associa~ed neurop a t h y is reversible once ddC is s t o p p e d . It is w o r t h noting that the n e u r o p a t h y m a y c ont i nue to w or s en for several weeks after discontinuation of ddC before gradual i m p r o v e m e n t O c c u r s . 246 250 T h e o t h e r c o m m o n adverse effect associated with ddC is the dev e l o p m e n t of a p h t h o u s ulcerations in the m o u t h . These usually occ u r during t h e first few weeks of therapy, al t hough they m ay occur late in the d d C course. Therapy with ddC is usually no'~ discontinued, a n d th e ulcers resolve in 1 to 3 weeks. Topical steroids sometimes improve this s ym pt om . Fever a n d a m a c u l a r p a p u l a r rash may s ometimes o c c u r in association w i t h a p h t h o u s ulcerations. These s y m p t o m s are self-limited a nd do n o t require ddC discontinuation. Pancreatitis has be e n r e p o r t e d with ddC, a l t h o u g h not to the extent r e p o r t e d with didanosine. Resistance.--Virtually no information c o n c e r n i n g ddC resistance has b e e n p u b l i s h e d o t h e r than the finding of cross-resistance with didanosine.24"~ Other Reverse Transcriptase lnhibitors N u m e r o u s nucleosides have s h o w n anti-HlV activity similar to that of zidovudine. Two di de oxynuc l e os i des that are beginning clinical testing are d e o x y d i d e h y d r o t h y m i d i n e (d4T) a n d fluorodeoxythymidine (FLT). d4T has s how n anti-HIV activity in p h a s e I studies. 2°a Peripheral n e u r o p a t h y has been r e p o r t e d in association with d4T. FLT has b e e n s h o w n to be approximately 10 times m o r e p o t e n t than zid o v u d i n e a n d to have a m or e p r o l o n g e d half-life of 2.5 to 6.3 hours. Importantly, n e i t he r d4T n o r FLT s how s cross-resistance with zidovudine.251 A s e c o n d g r o up of agents that have b e e n s h o w n to have anti-HIV reverse transcriptase activity are the n o n n u c l e o s i d e reverse transcriptase inhibitors. Agents that have b e g u n at least phase I testing i n c l u d e the t e t r a h y d r o i m i d a z o b e n z o d i a z e p i n e (TIBO) c o m p o u n d s , BIRG-587, th e "L" drugs L-697, 639 a n d L-697, 661, a n d the bishetDM, O c t o b e r 1 9 9 2

715

eroarylpiperazine (BHAP) c o m p o u n d s . 252-255 Preliminary data indicate that a rapid in vitro a nd in vivo emergence of resistance of HIV to these c o m p o u n d s exists w h e n they are u s e d alone. Clearly, t h e s e agents will have to be c o m b i n e d with ot he r antiviral agents in an effort to slow the e m e r g e n c e of resistance.

COMBINATION T H E R A P Y

At present, antiviral t h e r a p y of HIV infection generally consists of monotherapy. However, the t r e n d for the future will be combinations of different antiviral agents. The rationale for c o m b i n a t i o n therapy is similar to t ha t d e v e l o p e d for the treatment of bacterial infections: (1) increase t h e r a p e u t i c efficacy by the use of drugs that act by different mechanisms, resulting in synergy; (2) slow t he d e v e l o p m e n t of resistance, again by acting at different sites of action; and (3) red u ce toxicity, possibly by r e d u c i n g the dosage of the drugs. Nu mer o u s co m bi nat i ons have been tried both in vitro and clinically. At present, m o s t of the attention in combination t h e r a p y has b een directed t o w a r d c o m b i n a t i o n of zidovudine with ei t her ddC or didanosine. Both c o m b i n a t i o n s result in in vitro synergy a n d are attractive combinations in view of nonoverlapping toxicity profiles. Small preliminary studies have s h o w n promise with t hese combinations by d emo n st r at i ng a m o r e p r o l o n g e d CD4$ cell c o u n t elevation a n d p24 antigen s u p p r e s s i o n . At present, several large clinical trials are in progress c o m p a r i n g t h e s e combinations. The combination of interferon alpha a n d zidovudine has b e e n u s e d primarily in patients w i t h Kaposi's sarcoma. T h e s e two drugs have a synergistic antiviral effect in vitro, and small studies have s ho wn clinical promise. 256'257 Toxic effects, primarily hematologic (neutropenia) and hepatic, have been observed. Studies to assess the best dosage regimen of z i d o v u d i n e a n d interferon a l p h a are u n d e r way at present, a l t h o u g h the m a x i m u m a m o u n t of interferon al pha that can probably be u s e d w i t h a daily dose of 600 m g of z i d o v u d i n e is b e t w e e n 9 an d 18 million units p e r day. 256' 257 Acyclovir c o m b i n e d with z i d o v u d i n e has also b e e n s t u d i e d because it was f o u n d that these two drugs p r o d u c e d in vitro antiviral synergy. Early clinical studies s h o w e d that the two drugs were tolerated, an d one s t u d y has s h o w n that the combination of acyclovir a nd zidovudine is associated with a decr e ased mortality rate com p a r e d with zidovudine a l o n e . 258-26° The usual dosage of acyclovir in these studies has b e e n 400 to 800 mg by m o u t h five times p e r day c o m b i n e d with 500 to 600 mg of zidovudine. Further studies are underway at present to f u r t h e r define the role of acyclovir c o m b i n e d with zidovudine.

716

DM, October 1992

G U I D E L I N E S FOR A N I T V I R A L T H E R A P Y

At p r e s e n t , antiviral t h e r a p y for HIV i n f e c t i o n is b a s e d o n the C D 4 + cell c o u n t of t h e patient. 26~ T h e u s e o f o t h e r HIV m a r k e r s , s u c h as p 2 4 a n t i g e n e m i a or [32-microglobulinemia levels, are not h e l p f u l a n d are n o t r e c o m m e n d e d for r o u t i n e use. Patients w h o h a v e a C D 4 + cell c o u n t less t h a n 500 cells p e r m m z (as d e t e r m i n e d b y a n a v e r a g e of two or t h r e e d e t e r m i n a t i o n s for 1 to 2 weeks) s h o u l d b e g i n z i d o v u d i n e , 100 m g b y m o u t h e v e r y 4 h o u r s while a w a k e . T h e u s e of o t h e r d o s e f r e q u e n c i e s , s u c h as 200 m g b y m o u t h e v e r y 8 h o u r s , are less well s t u d i e d a n d are n o t r e c o m m e n d e d at this time, e x c e p t in c i r c u m s t a n c e s w h e r e a n e v e r y - 4 - h o u r r e g i m e n is difficult for t h e p a t i e n t to m a i n t a i n . T h e b e g i n n i n g of antiviral t h e r a p y is a m a j o r s t e p for t h e patient, a n d p s y c h o l o g i c p r o b l e m s m a y d e v e l o p . It is i m p o r t a n t to clearly d i s c u s s t h e s i t u a t i o n w i t h the p a t i e n t a n d e m p h a s i z e t h e rationale a n d n e e d for early t h e r a p y . Baseline l a b o r a t o r y s t u d i e s that s h o u l d be o b t a i n e d i n c l u d e a c o m p l e t e b l o o d count, platelet c o u n t , a n d levels of b l o o d u r e a nitrogen, c r e a t i n i n e , a n d liver t r a n s a m i n a s e s . T h e s e s h o u l d b~ r e q u e s t e d b i w e e k l y for t h e first 2 to 3 m o n t h s . If t h e v a l u e s r e m a i n stable, the f r e q u e n c y c a n be r e d u c e d to o n c e e v e r y 2 to 3 m o n t h s . T h e initial p r o b l e m s t h a t the p a t i e n t taking z i d o v u d i n e m a y enc o u n t e r i n c l u d e g a s t r o i n t e s t i n a l d i s t r e s s a n d n a u s e a . For t h e m o s t part, this is self-limited a n d will r e s o l v e in several days. However, if it is severe, m e t o c l o p r a m i d e , 10 m g b y m o u t h e v e r y 6 to 8 h o u r s , can b e given. H e a d a c h e s are also u s u a l l y s e l f - l i m i t e d a n d c a n b e t r e a t e d with analgesics. A n e m i a a n d n e u t r o p e n i a are the m o s t severe toxic effects t h a t m a y d e v e l o p . If t h e h e m o g l o b i n c o n c e n t r a t i o n falls t o less t h a n 8.0 g/dL, z i d o v u d i n e s h o u l d be s t o p p e d for 1 to 2 w e e k s . O n c e the h e m o g l o b i n level h a s r e t u r n e d to m o r e t h a n 10 g/dL, z i d o v u d i n e s h o u l d b e r e s t a r t e d at 100 m g b y m o u t h every 8 h o u r s . If t h e p a t i e n t tolerates this d o s e r e g i m e n , the d o s a g e c a n b e i n c r e a s e d b a c k to 500 m g / d a y after a p p r o x i m a t e l y 1 m o n t h . If a c o n t i n u e d fall of t h e h e m o g l o b i n c o n c e n t r a t i o n is s e e n w i t h r e c h a l l e n g e , z i d o v u d i n e s h o u l d b e h a l t e d a n d t h e p a t i e n t given t r a n s f u s i o n if clinically n e c e s s a r y . If t h e patient c a n t o l e r a t e a n e m i a , h e or s h e s h o u l d be o b s e r v e d until t h e hem o g l o b i n level h a s r e t u r n e d to g r e a t e r t h a n 10 g/dL. A s e a r c h for o t h e r c a u s e s of a n e m i a s h o u l d b e c a r e f u l l y d o n e in all z i d o v u d i n e t r e a t e d p a t i e n t s in w h o m a n e m i a d e v e l o p s , p a r t i c u l a r l y if t h e p a t i e n t h a s less t h a n 200 C D 4 + cells p e r m m 3. N u m e r o u s o p p o r t u n i s t i c inf e c t i o n s c a n c a u s e infiltrative d i s e a s e in the b o n e m a r r o w , w h i c h c a n l e a d to a n e m i a . O n c e it has b e e n d e t e r m i n e d t h a t t h e p a t i e n t c a n n o l o n g e r tolerate z i d o v u d i n e , a n e r y t h r o p o i e t i n level s h o u l d be

DM, O c t o b e r

1992

717

determined. If this is less t h a n 500 IU/L, r e c om bi nant e r y t h r o p o i e t i n can be started in c o n j u n c t i o n with zidovudine. If the e r y t h r o p o i e t i n level is more than 500 IU/L, t he patient s h o u l d be s w i t c h e d to ei t her didanosine or ddC. Dose modification of z i d o v u d i n e is n e e d e d if leukopenia develops. W h en the absolute n e u t r o p h i l c o u n t falls to 750 cells p e r m m a, the dose of zidovudine s h o u l d be r e d u c e d to 300 mg p e r day. If the absolute neutrophil c o u n t falls to less t ha n 500 cells p e r m m 3, zidovudine should be d i s c o n t i n u e d until the absolute n e u t r o p h i l c o u n t rises to 1000 cells p e r m m a. Rechallenge with z i d o v u d i n e can be d o n e in a similar fashion as with anemia. The use of granulocytem a c r o p h a g e colony-stimulating factor (GM-CSF) or granul ocyt e colony-stimulating factor (G-CSF) for t r eat m e n t of leukopenia resulting from zidovudine t h e r a p y is investigational at present. A frequent p r o b l e m with zidovudine treatment is c o n c o m i t a n t ganciclovir use. Most patients c a n n o t tolerate both t h e s e agents because of leukopenia, a n d z i d o v u d i n e is discontinued. Patients are usually switched to d i d a n o s i n e or ddC. Studies are ongoing examining the use of GM-CSF in patients receiving both ganciclovir a n d zidovudine. After long-term use of zidovudine, m y o p a t h y or myositis m a y develop. Dose r e d u c t i o n or d i s c o n t i n u a t i o n is d o n e on a clinical basis. A course of corticosteroids is sometimes given, with variable results. Patients on long-term z i d o v u d i n e t r e a t m e n t who are e x p e r i e n c i n g disease progression p r e s e n t a difficult problem. This is often defi ned as a fall in the CD4+ cell c o u n t to less than 50 cells p e r m m 3 a n d / o r the development of multiple opportunistic infections over a short p er io d of time (usually 6 months). In such patients several t h e r a p e u tic options are available including (1) continuation of zidovudine, (2) substitution of d i d a n o s i n e or ddC for zidovudine, or (3) use of com bination therapy w i t h t he addi t i on of didanosine or ddC to zidovudine. These options are c u r r e n t l y u n d e r study, although m ost investigators probably favor c o m b i n a t i o n t h e r a p y at present. Once a patient has b e e n d e t e r m i n e d to be either z i d o v u d i n e intolerant or a clinical failure, d i d a n o s i n e or ddC should be begun. The initial dose of d i d a n o s i n e is d e t e r m i n e d by t he weight of t he patient. The following dosage regimens are r e c o m m e n d e d : for a patient less than 50 kg, 150 mg orally every 12 hours; for a patient between 50 and 75 kg, 250 mg orally every 12 hours; a n d for a pat i ent heavier th an 75 kg, 375 m g orally every 12 hours. Didanosine m u s t be taken o n an e m p t y s t o m a c h to maximize absorption. Patients s h o u l d not eat for 2 h o u r s before taking the didanosine dose a n d for 1/2 h o u r after the dose. Baseline laboratory tests i n c l u d e a complete blood count, platelet count, an d levels of electrolytes, blood urea nitrogen, creatinine, liver 718

DM,

October 1992

enzymes, uric acid, a n d amylase. D e t e r m i n a t i o n s of lipase a n d triglyceride levels are also suggested. A careful neurologic examination for signs of p er ip her a l n e u r o p a t h y is extremely i m p o r t a n t in patients beginning d i d a n o s i n e therapy. Patients s h o u l d be seen biweekly for the first several m o n t h s and then less often if t h e y are tolerating the medication. Th e initial problems with didanosine are usually the bad taste of the ch ewab le tablet a n d mild diarrhea. T h e u n p l e a s a n t taste can be i m p r o v e d b y breaking up the tablet into w a t e r a n d drinking the resultant solution. The diarrhea is usually self-limited. Pancreatitis is the most severe toxic effect associated with didanosine. Th e patient needs to be i n f o r m e d about t h e . s y m p t o m s a n d s h o u l d be instructed to di s c ont i nue m e d i c a t i o n s and alert his or h e r p h y s ician w h e n t hey occur. It s h o u l d b e n o t e d that pancreatitis can o c c u r rather quickly and can be fatal. Patients with a previous history of pancreatitis should use d i d a n o s i n e very carefully, with close foilow-up. In some patients a s y m p t o m a t i c elevations in s e r u m amylase levels develop. In t he s e patients, didanosine should be d i s c o n t i n u e d , and t hey should be followed until the al~nylase level r e t u r n s to baseline. Didanosine can t h e n be restarted. Peripheral n e u r o p a t h y is also a serious toxic effect associated with didanosine. In phase I studies, it o c c u r r e d in a p p r o x i m a t e l y 16% of patients. T h e patient s h o u l d be i n f o r m e d about early s y m p t o m s of n e u r o p a t h y , w h i c h are tingling a n d n u m b n e s s in the bottoms of the feet after exercise. The loss of the ankle jerk reflex is also an early sign of n e u r o p a t h y a n d m a y herald m o r e severe symptoms. If the pain is mild, the dosage of didanosine s h o u l d be r e d u c e d by one half. Onset of pain requiring analgesics, however, requires didanosine discontinuation. Often, the pain c o n t i n u e s to w o r s e n for 1 to 3 m o r e weeks after didanosine has b e e n d i s c o n t i n u e d . After this period, the p a i n starts to slowly recede. T he t r e a t m e n t for n e u r o p a t h y is analgesics. Once severe n e u r o p a t h y develops in a patient, d i d a n o s i n e a n d ddC s h o u l d not be used. T h e o t h e r option in patients w h o are z i d o v u d i n e intolerant or t r e a t m e n t failures is ddC. The usual dosage of ddC is 0.75 mg by m o u t h every 8 hours. The baseline i n f o r m a t i o n required a n d the follow-up s c h e d u l e for ddC are similar to those for didanosine. ddC is well tolerated from the gastrointestinal standpoint. However, a toxic effect that m a y occur early in t r e a t m e n t is the developm e n t of a p h t h o u s ulcers in the m o u t h . T h e s e are usually self-limited a n d d o not require drug discontinuation, but if severe they can be t r eated with topical steroids. A mild e r y t h e m a t o u s m a c u l o p a p u l a r rash a c c o m p a n i e d by a fever also occurs. It is self-limited a n d does not require d r u g discontinuation. T h e t r e a t m e n t and follow-up reco m m e n d a t i o n s for ddC-related p e r i p h e r a l n e u r o p a t h y are the same as th o s e for didanosine-related p e r i p h e r a l n e u r o p a t h y . DM, O c t o b e r 1992

719

IMMUNOMODULATORS AND VACCINES Efforts to strengthen the i m m u n e system in persons infected with HIV have received a great a m o u n t of interest. However, only a limited amount of success has been achieved. I m m u n e m o d u l a t i n g agents such as isoprinosine a n d ditiocarb sodium have d e m o n strated only limited activity in patients with HIV infection. Interferons have both antiviral and i m m u n e modulating effects that are u n d e r study at present. Newer agents are in the development stage. For i m m u n e modulating agents to be useful, they m u s t be given early in infection. Vaccine development has also met with limited success. Major problems with vaccine development include the frequent m u t a t i o n rate of HIV and lack of a full u n d e r s t a n d i n g of the i m m u n e response to HIV. More than 20 candidate vaccines have been developed a n d are in very early stages of clinical evaluation. Most vaccine preparations are associated with the outer glycoproteins of the virus, gp160 and gp120. Vaccines are being u s e d in both uninfected individuals and infected patients. With infected patients, it is hoped that a vaccine w o u l d act as an i m m u n e modulator. Most early studies with vaccines are performed in patients early in the infection. An improvement in CD4+ cell c o u n t s or a slowin~zin CD4+ cell c o u n t decline is an indicator that is closely followed. Recombinant gp160 has b e e n evaluated in phase I studies in b o t h uninfected and infected individuals. These studies have s h o w n that the vaccine is safe a n d p r o d u c e s a limited i m m u n e response in healthy, uninfected seronegative volunteers. Recently, patients in the early stages of HIV infection (Walter Reed stages 1 a n d 2) were given this vaccine. After a 10-month follow-up, a slower decline in the CD4+ cell count was seen in those who received the vaccine compared with those w h o received a placebo. Larger-scale studies with this vaccine and others are ongoing at this time.z63' 264 INFECTIOUS AND N E O P L A S T I C COMPLICATIONS OF HIV DISEASE

The infectious complications of HIV disease are frequent causes of major morbidity a n d mortality. As the course of the AIDS epidemic proceeds, the treatment and prophylaxis of the most prevalent opportunistic infections c o n t i n u e to evolve. For the most part, a limited spectrum of infectious diseases predominates; however, additional pathogens may emerge as important challenges in the overall treatm e n t of patients with H1V infection. The most c o m m o n opportunistic pathogens causing disease include Pneumocystis carinii, Candida species, cytomegalovirus, Myco720


bacterium avium complex, Cryptococcus neoformans, Toxoplasma gondii, Cryptosporidium species, Mycobacterium tuberculosis, herpes simplex virus, papovaviruses, a n d Histoplasma capsulatum. A broad variety of other bacterial, fungal, a n d protozoan species also contribute to the spectrum of infections a m o n g patients with HIV disease. The following sections will outline the epidemiology, clinical presentation, diagnosis, and m a n a g e m e n t of the most c o m m o n of the infectious complications, with particular attention paid to those that can be expected to surface in the patient population m a n a g e d by the primary care practitioner.

PROTOZOAN INFECTIONS P n e u m o c y s t i s carinii Disease Pneumocystis carinii is currently classified as a protozoan, alt h o u g h m o u n t i n g evidence suggests that it m a y be more appropriately classified as a fungus. Both cystic a n d the extracystic trophozoite forms can be f o u n d in humans. The cystic form is spherical, oval, or cup-shaped, is 4 to 6 p~m in diameter, a n d contains up to eight sporozoites. The trophozoite is a smaller pleomorphic organism with an indefinite cell membrane a n d an eccentrically placed nucleus. P u l m o n a r y disease caused by P. carinii continues to occur at an incidence approaching 65% to 85% of all patients with AIDS at some point during their disease course, although the epidemiologic pattern of disease caused by this organism has b e e n altered by the development of more effective and earlier antiretroviral and prophylactic therapies. 265-267 Disease caused by P. carinii rarely occurs in HIVinfected individuals with CD4+ l y m p h o c y t e c o u n t s of greater than 200 cells per cubic millimeterffL 26s It appears to be more c o m m o n a m o n g HIV-infected m e n than a m o n g HIV-infected women. The organism is ubiquitous in nature, usually acquired during childhood; two thirds of healthy adults have d e m o n s t r a b l e antibody to P. carlnil. 269 Although HIV-infected patients m a y acquire new primary infection, reactivation of latent infection in the presence of progressive i m m u n o s u p p r e s s i o n is the p r e s u m e d pathogenesis of disease. 265-z67 Latent organisms are thought to be harbored within pulmonary alveolar macrophages. The most c o m m o n disease manifestation of P. carinii is pneumonia. In general, patients have acute or s u b a c u t e onset of fever, progressive dyspnea, nonproductive cough, a n d hypoxemia. The degree of h y p o x e m i a may be severe. The m o s t frequent clinical findings on examination are fever, tachypnea, a n d fine inspiratory crackles. Alt h o u g h m o s t patients have diffuse bilateral interstitial infiltrates on chest radiograph, up to 5% of patients m a y have an initially normal DM, October 1992

721

chest radiograph. 265-2~7' 27o Pleural effusions are u n c o m m o n in the absence of other p u l m o n a r y pathogens or malignancies. Rarely, nodular or cavitary lung disease a n d disseminated multiorgan disease involving the choroid layer of the eye, lymph nodes, liver, spleen, bone marrow, central nervous system, a n d other sites may be seen. 265'267'26a'271 Atypical radiographic manifestations s u c h as localized upper lobe infiltrates, n o d u l a r or cavitary disease, or extrap u l m o n a r y disease m a y be seen more often in patients receiving aerosolized prophylaxis regimens. 272' 273 The diagnosis of P. carinii disease is based on the histopathologic demonstration of organisms in tissue or s p u t u m samples stained with cresyl violet, Giemsa, silver stains, or Diff-Quick. Lower respiratory tract samples obtained b y bronchoscopy with bronchoalveolar lavage have a diagnostic yield of 90% to 95% in patients with diffuse interstitial disease. 265-267' 274 The diagnostic yield may be r e d u c e d in the presence of localized or atypical disease or in patients w h o are receiving P. carinii prophylaxis. 273 Although the organisms m a y be demonstrable in i n d u c e d s p u t u m , the organism n u m b e r is lower, and the diagnostic yield, w h i c h ranges from 55% to 90%, is highly d e p e n d e n t on the skill of the respiratory therapist obtaining the specimen and the skill of the cytopathologist examining the stained material. 27~ Transbronchial biopsy or open lung biopsy m a y significantly improve the diagnostic yield of bronchoalveolar lavage or ind u c e d s p u t u m w h e n s u c h samples are negative.273 Serologic testing and culture remain research tools at present and are not sufficiently sensitive to afford routine diagnosis. Diffuse uptake in the lung seen by gallium scanning m a y be a useful ancillary finding, particularly in patients with mild to m o d e r a t e symptoms and an initially normal chest radiograph. Standard therapies include orally or parenterally administered trimethoprim-sulfamethoxazole and parenteral pentamidine.266, 267,276,277 Dosages are listed in Table 7. Reduced dosages of both agents may be effective a n d possibly associated with r e d u c e d toxicity. Adjunctive corticosteroids are currently r e c o m m e n d e d for those patients with m o d e r a t e to severe disease, defined by a r o o m air arterial oxygen pressure less than 70 m m Hg or an alveolararterial oxygen gradient greater than 35 m m Hg.27s-2a° Prednisone, 40 mg by m o u t h every 12 hours (or its intravenous equivalent), is reco m m e n d e d for the first 5 days of therapy, followed by 40 mg once daily for days 6 t h r o u g h 10, a n d 20 mg once daily for days 11 through 21. 27a'2so Steroids s h o u l d be discontinued w h e n therapy for P. carinii p n e u m o n i a is completed. Alternative oral therapeutic regimens for treatment of patients with mild to moderate disease or for those unable to tolerate currently available s t a n d a r d therapies include trimethoprim c o m b i n e d with dapsone, a n d primaquine combined with clindamycin (Table 722

DM, October 1992

7).277, 281 Aerosolized pentamidine given in daily doses of 300 to 600 mg aerosolized over 30 minutes has been used b y some investigators with success both as initial therapy a n d as salvage therapy for patients unable to tolerate standard regimens. 2s2' 283 Trimetrexate has been effective in some instances as salvage t h e r a p y for those patients intolerant of or refi'actory to s t a n d a r d regimens and is available t h r o u g h the National Institutes of Health, National Institute of Allergy and Infectious Diseases. 2s4'2s5 A newly developed hydroxy n a p h t h o q u i n o n e , 566C80, appears active against P. carinii a n d has been effective therapy for a small n u m b e r of patients. It is currently available by request from Bun-oughs Wellcome.2s6 In general, the response to therapy ranges from 60% to 95%, dep e n d i n g on the agent used, the n u m b e r of prior episodes of Pneumocystis p n e u m o n i a previously experienced by the patient, the severity of illness at presentation, the degree of i m m u n o s u p p r e s s i o n of the host, a n d the timing of initiation of t h e r a p y . 265-267 Adverse reaction rates for standard therapeutic regimens of trimethoprimsulfamethoxazole and parenteral p e n t a m i d i n e are reported to range from 20% to 85% of patients receiving these d r u g s . 265-267 B o t h drugs have been associated with skin rashes, drug fever, ~eukopenia, thrombocytopenia, azotemia, and hepatitis. A small proportion of patients receiving trimethoprim-sulfamethoxazole may develop Stevens-Johnson syndrome, which has been fatal w h e n not recognized and appropriately treated. Parenteral p e n t a m i d i n e has been associated with dysglycemic reactions in 5% to 8% of patients and with pancreatitis in approximately 5,% of patients. 265 267 Dapsone has been associated with methemoglobinemia; rarely, hemolysis occurs, particularly among those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.277 Anemia, irrespective of hemolysis, rash, fever, hepatitis, and rarely, neutropenia, have also been associated with dapsone. PIimaquine, too, m a y cause methemoglobinemia and hemolytic anemia, the latter more likely in patients with G6PD deftciency. T M Clindamycin has been a c c o m p a n i e d by nausea, gastrointestinal upset, cholestatic jaundice, diarrhea, a n d pseudomembranous enterocolitis associated with Clostridium difficile overgrowth a n d toxin production. T M Aerosolized p e n t a m i d i n e m a y produce a metallic taste in the m o u t h a n d induce cough or bronchospasm. 2s2'283 Because the drug has minimal systemic absorption w h e n administered by aerosol, other adverse effects associated with it are rare. However, neutropenia, thrombocytopenia, and pancreatitis t h o u g h t to be due to aerosolized p e n t a m i d i n e have been reported.2S2, 283 Trimetrexate can p r o d u c e bone m a r r o w suppression, w h i c h may be alleviated or ameliorated by the concomitant administration of leucovorin. T M 285 Fever, skin rash, hepatitis, and thrombocytopenia have also been reported in association with its use.284' 2sz Skin rash appears to be the chief adverse reaction associDM, O c t o b e r 1992

723

0

Z

L

0

i°

!

-°

e~ o

~ ~-0

~

~.~

o

~ .~!.~

0

Z o

~.°

~

724

'

DM, O c t o b e r

1992

~

~

_

I

.e .~ "~

~.~

L~

~-~.~

~

ee~

'~

~

I

~..~ ~~ ~

"~ ~ ~

~,~.

~ -~ ~

~

~

e,,

~m

.~. ~ .~ ~ V

~,


725

ated with 566C80; o t h e r toxicities and their frequency rem ai n to be established, z86 The suggested d u r a t i o n of acut e t her a py is 14 to 21 days. Relapse rates may be higher in those w h o receive shorter c o u r s e s of therapy, while longer courses m a y be n e c e s s a r y for some a n d a p p e a r to be associated with a s o m e w h a t l ow er relapse rate or l onger d u r a t i o n to first relapse. In the absence of s e c o n d a r y prophylaxis, the overall relapse rate after the first ep i s ode of P. carinii p n e u m o n i a ranges from 26% to 55% within 1 year. za7 Prophylaxis is therefore r e c o m m e n d e d for all patients who have r e c ove r ed from an episode of P. carinii p n e u m o nia. z87 In addition, longitudinal data from the Mul t i cent er AIDS Cohort Study (MACS) of h o m o s e x u a l m e n have s h o w n that individuals with CD4+ l y m p h o c y t e c o u n t s of less than 200 cells p e r m m 3 are at substantial risk for the d e v e l o p m e n t of P. carinii p n e u m o n i a a n d are candidates for prophylaxis, regardless of w h e t h e r they have experienced a previous episode, z87 Agents that have b e e n s h o w n in controlled clinical trials to be effective for the prophyl axi s of P. carinii p n e u m o n i a include oral trimethoprim-sulfamethoxazole, aerosolized p en t am i di ne , a n d oral d a p s o n e (Table 7).zaT-z93 L ow er doses or less f requent dosing schedules may be as effective a n d associated with fewer adverse reactions, zaT-z93 Large comparative trials are u n d e r w ay to establish the m o st effective prophylaxis regimens. Some investigators have suggested that e x t r a p u l m o n a r y pneumocystosis m a y be m o r e c o m m o n among t h o s e receiving inhaled p e n t a m i d i n e or no prophylaxis, z71-273'z94 Systemic p r o p h y laxis with trimethoprim-sulfamethoxazole, one doubl e-st rengt h tablet daily, was recently s h o w n to be m or e effective t h a n aerosolized p e n tamid in e for s e c o n d a r y prophylaxis after a first e p i s o d e of P. carinii p n e u m o n i a , za'~

Toxoplasmosis Toxoplasma gondii is an intracellular protozoan. T h e infectious form, the tachyzoite, invades t he host cell, where it multiplies, e i t h e r forming cysts or lysing the h o s t cell. Tissue cysts m a y cont ai n u p to 3,000 organisms. T h e organisms are worldwide in distribution; cats serve as the p r im a r y host. Acquisition of T. gondii o c c u r s t h r o u g h contact with soil c o n t a m i n a t e d by infectious cat feces or ingestion of infected u n d e r c o o k e d lamb, pork, beef, or u n p a s t e u r i z e d milk. T h e organism may also be t r a n s m i t t e d by placental transfer to a fetus, by blood p r o d u c t transfusion, a n d by organ transplantation. Disease in patients with AIDS is t h o u g h t m os t likely to be due to reactivation of latent infection as a c o n s e q u e n c e of progressive i m m u n o s u p p r e s sion, although p r i m a r y infection can occur. Current estimates are 726


t h a t 30% to 40% of o t h e r w i s e h e a l t h y a d u l t s in t h e United States are seropositive for T. gondii. 296' 297 T o x o p l a s m i c e n c e p h a l i t i s is the m o s t c o m m o n m a n i f e s t a t i o n of t o x o p l a s m o s i s in p a t i e n t s with AIDS. 29s T h e e x a c t i n c i d e n c e of this d i s o r d e r is u n k n o w n , a l t h o u g h c u r r e n t e s t i m a t e s suggest that bet w e e n 10% a n d 20% of HIV-infected individuals will d e v e l o p toxop l a s m i c disease, z98 Fever, h e a d a c h e , m e n t a l s t a t u s changes, focal n e u r o l o g i c deficits, a n d seizures are t h e m o s t c o m m o n clinical s y m p t o m s a n d signs. T h e p r e s e n c e of m u l t i p l e b r a i n lesions, with or w i t h o u t e n h a n c e m e n t w i t h c o n t r a s t materials, o n c o m p u t e d tomog r a p h i c (CT) o r m a g n e t i c r e s o n a n c e i m a g i n g (MRI) scans of t h e brain is t h e h a l l m a r k diagnostic study, zgs-3°l MRI s c a n s m a y be m o r e sensitive for t h e d e t e c t i o n of t o x o p l a s m i c lesions t h a n CT s'cans. 3°°'3°1 C e r e b r o s p i n a l fluid is usually n o r m a l , a l t h o u g h mild elevations of p r o t e i n a n d a m i l d l y m p h o c y t i c p l e o c y t o s i s m a y be seen. 2~8-3°1 Ext r a n e u r o l o g i c disease c a n occur. Sites of e x t r a n e u r o l o g i c localization i n c l u d e l u n g p a r e n c h y m a , c h o r i o r e t i n a , l y m p h o r e t i c u l a r system, a n d occasionally, testicle o r gastrointestinal tract. Tissue cysts m a y also b e f o u n d in m y o c a r d i u m a n d skeletal m u s c l e sites. ~, A definitive diagnosis d e p e n d s o n the d e m o n s t r a t i o n ; 0 f tachyzoites in histologic s p e c i m e n s o b t a i n e d f r o m b i o p s y of involved tissue sites.299 301 O r g a n i s m s r e c o v e r e d f r o m brain, b l o o d , or o t h e r specim e n s c a n b e cultivated in fibroblast t i s s u e c u l t u r e systems. As a cons e q u e n c e of t h e invasive n a t u r e of b r a i n b i o p s y a n d the relative inaccessibility of d e e p lesions, t h e diagnosis o f t o x o p l a s m i c encephalitis is f r e q u e n t l y m a d e i n d i r e c t l y on t h e basis of t h e clinical p r e s e n t a tion, serologic testing, characteristic CT o r MRI b r a i n s c a n findings, a n d t h e r e s p o n s e to a n empiric trial o f t h e r a p y for t o x o p l a s m o sis.3OO, 3ol A l t h o u g h serologic testing is useful for t h e d i a g n o s i s in n o n i m m u n o c o m p r o m i s e d hosts, m a n y p a t i e n t s w i t h HIV infection a n d adv a n c e d i m m u n o s u p p r e s s i o n fail to m o u n t a p p r o p r i a t e serologic res p o n s e s . T o x o p l a s m i c encephalitis is rare a m o n g p a t i e n t s seronegative for T o x o p l a s m a antibodies. Most p a t i e n t s will have d e m o n s t r a ble i m m u n o g l o b u l i n (Ig) G antibody.Z9s, 3oo, 3Ol However, s u c h p a t i e n t s r a r e l y have a rise in IgG a n t i b o d y titer d u r i n g a c u t e infection, a n d d e t e c t i o n of IgM a n t i b o d y is u n u s u a l . Patients w h o are s e e n w i t h t h e clinical p i c t u r e of t o x o p l a s m i c e n c e p h a l i t i s w h o d o n o t have d e t e c t a b l e [gG a n t i b o d y s h o u l d be investigated for o t h e r etiologic c a u s e s for t h e i r illness. T h e c u r r e n t t r e a t m e n t of c h o i c e for t h o s e w h o c a n tolerate sulfa a g e n t s is t h e c o m b i n a t i o n of p y r i m e t h a m i n e w i t h sulfadiazine or triple sulfa derivatives (Table 7).3°2 L e u c o v o r i n is a d d e d for the prevention of or a m e l i o r a t i o n of p y r i m e t h a m i n e - i n d u c e d b o n e m a r r o w s u p p r e s s i o n . In vitro a n d p r e l i m i n a l y clinical d a t a suggest t h a t pyDM, October 1992

727

rimethamine c o m b i n e d with clindamycin in divided d o s e s m ay be a useful alternative regimen. 3°a'a°4 Pyrimethamine alone in h i g h e r doses has been a d v o c a t e d by some. T he new oral m acrol i des azithromycin and c l a r i t h r o m y c i n a p p e a r to have g o o d in vitro activity against T. gondii a n d m a y s uppl a nt the sulfa agents and clindamycin in this setting, a°53o6 Although not available by p r e s c r i p t i o n in the United States, the m a c r ol i de spiramycin has also b e e n u s e d in combination with p y r i m e t h a m i n e in Europe. Last, the n e w hydroxyn a p h t h o q u i n o n e 566C80 has also b e e n s h o w n to be active against T. gondii in vitro an d in animal m o d e l s and m a y be an additional alternative agent, a°7 The r e c o m m e n d e d d u r a t i o n of t h e r a p y is prolonged, from 2 to 4 months, although a clinical r e s p o n s e m a y be seen w i t hi n 2 to 6 weeks for 80% to 90% of patients, with a reduct i on in t he size a n d n u m b e r of brain lesions and i m p r o v e m e n t in clinically evident n e u rologic deficits. 2aa-3°z Relapse rates of greater than 90% have b e e n r e p o r t e d after d i s c o n t i n u a t i o n of therapy, suggesting t he n e e d for longer-term m a i n t e n a n c e t r e a t m ent , a°z The most effective r e g i m e n for main ten an c e has not y e t b e e n established; however, pyrimethamine c o m b i n e d with sulfa agents, p y r i m e t h a m i n e c o m b i n e d with clindamycin, a n d p y r i m e t h a m i n e alone have all b e e n suggested. The availability of t h e n e w macrolide agents a z i t h r o m y c i n a nd clarithromycin m a y e n h a n c e the s p e c t r u m of agents available for m a i n t e n a n c e t h e r a p y of this disease.

Cryptosporidiosis Cryptosporidium

species are coccidian protozoans. Oocysts are the most c o m m o n form d e m o n s t r a b l e in the stool a n d gastrointestinal tracts of infected individuals. The oocysts are 2 to 5 p,m in diameter an d contain f o u r sporozoites. As the oocyst matures, it releases motile sporozoites, t h o u g h t to be the infectious form of the organism. Oocysts m a y sporulate e n d o g e n o u s l y and release s p o r o z o ites as a result of action by digestive enzymes, bile salts, or o t h e r triggers within the gastrointestinal tract. Second-generation m e r o z o ites are able to reinitiate schizogony, with a t r e m e n d o u s potential for reinfecting the host. These organisms are u b i q u i t o u s animal pathogens, with h u m a n s as incidental hosts. Cryptosporidiosis is a c o m m o n cause of selflimited diarrheal s y n d r o m e s w o r l d w i d e in n o n i m m u n o s u p p r e s s e d hosts an d of diarrhea out br eaks in day care settings in the United States. The exact i n c i d e n c e a n d prevalence of this disease in patients with AIDS is c ur r e nt l y u n k n o w n ; geographic locale m a y influence the incidence. Disease a p p e a r s m or e c o m m o n in larger u r b a n areas of the n o r t he a s t a n d s o u t h e a s t United States a n d in the Caribbean; however, s por adi c cases are widespread. The organism can be transmitted from p e r s o n to per s on. 728


Most patients with AIDS and c r y p t o s p o r i d i o s i s have a severe gastrointestinal illness characterized by f r e que nt v o l u m i n o u s watery dia rr h ea ranging in a m o u n t from 2 to 20 L/day, a c c o m p a n i e d by c r a m p y a b d o m i n a l pain, malabsorption, a n d p r o f o u n d weight loss. 3°s-3a° Cryptosporidial cholecystitis has b e e n r e p o r t e d and results in right u p p e r q u a d r a n t abdominal pain, persi st ent n a u s e a and vomiting, a n d cholestasis, with m a r k e d elevations of alkaline phosphatase. T M Radiographic studies d e m o n s t r a t e gallbladder wall thickening an d irregularities of bile ducts. T h e diagnosis of cryptosporidiosis is b a s e d o n the dem onst rat i on of organisms in stool or in small bowel b i o p s y speci m ens stained with a modified acid-fast stain, a°a-31° The organisms can also be histopathologically d e m o n s t r a t e d in the luminal b r u s h b o r d e r of the small intestine. T h e r e is currently no known uniformly effective t h e r a p y for Clyptosporidial disease. A n u m b e r of oral therapies have b e e n used with limited success. 3°a-31° Spiramycin, an oral macrolide agent not c ur r en tly available by prescription in t he United States, has been u s e d with minimal to m o d e r a t e success in earl~ cases of cryptosporidial diarrheal disease. An i n t r a v e n o u s formuYation of this agent is u n d e r investigation in a pr os pect i ve cont rol l ed clinical trial. O th er oral macrolides s uc h as a z i t h r o m y c i n a n d clarithromycin are also • u n d e r investigation. Diclazuril has b e e n u s e d with success in a small n u m b e r of patients and is available t h r o u g h a protocol from Janssen Pharmaceuticals. 3a2 Letrazuril, an analogue of diclazuril, is also c u r r e n t l y u n d e r clinical investigation. Parom om yci n, a nonabsorbable aminoglycoside us ed for t he t r e a t m e n t of amebiasis and giardiasis, has b e e n r e p o r t e d to have limited s u c c e s s in an uncontrolled trial in a small n u m b e r of patients w h e n adm i ni st ered in a dose of 500 mg four times daily. O t h e r agents that have b e e n tried with limited success include difluoromethylornithine, trimetrexate, r e c o m b i n a n t interleukin-2, h y p e r i m m u n e bovine colostrum, and transfer factor. Somatostatin analogues a p p e a r to have some effect in r e d u c i n g fluid a nd electrolyte secretion into t h e bowel l u m e n and r e d u c i n g gut motility, with c o n c o m i t a n t i m p r o v e m e n t in cryptosporidial diarrhea. 313 Adjunctive care w i t h adequat e hydration a n d nutritional s u p p o r t is probably the m ost useful intervention in maintaining patients with severe disease. Parenteral h y d r a t i o n with total p a r e n t e r a l nutrition and c o m p l e t e bowel rest has b e e n associated with m o d e s t clinical i m p r o v e m e n t in small n u m b e r s of patients.

lsosporiasis lsospora belli is a coccidial p r o t o z o a n similar to Cryptosporidium species but larger, w hi ch p r o d u c e s oocysts t hat contain two sporoblasts, allowing distinction from Cryptosporidium organisms, aa4' a15 DM, O c t o b e r 1 9 9 2

729

This particular p r o t o z o a n appears to occur more c o m m o n l y in patients with AIDS w h o c o m e from the Caribbean or southeastern United States. Disease probably occurs in fewer than 1% of patients with AIDS in the United States. a14' a15 Clinical manifestations of disease caused by I. belli are similar to those associated with cryptosporidiosis: chronic profuse watery diarrhea, malabsorption, a n d weight loss. The diagnosis can be m a d e from a microscopic examination of a stool smear stained with a modified acid-fast stain, a14,a15 The treatment of choice is trimethoprim-sulfamethoxazole in higher doses for 10 days, followed by lower d o s e s for an additional 3 weeks (Table 7).314' a15 The relapse rate can be up to 50% within 8 weeks of discontinuation of therapy. Long-term suppressive therapy m a y prevent relapse. Alternative treatments for patients unable to tolerate trimethoprimsulfamethoxazole include metronidazole- and pyrimethaminecontaining regimens. ~14' al5

Other Protozoan Infections Other protozoan diseases r e p o r t e d among HIV-infected patients include disease c a u s e d by Giardia lamblia, which causes a s y n d r o m e of watery diarrhea, malabsorption, and weight loss or wasting similar to that associated with cryptosporidiosis and isosporiasis; disease caused by Leishmania donovani, reported most frequently with localized cutaneous or visceral involvement among patients of Mediterranean origin or with localized rectal disease in patients from other endemic areas; disseminated strongyloidiasis; and disease c a u s e d by Microsporidia, coccidial protozoa associated with myositis, hepatitis, small intestinal disease, or keratoconjunctivitis.a16- az2 VIRAL INFECTIONS Cytomegalovirus Infection Cytomegalovirus (CMV) is a double-stranded DNA, lipid-enveloped virus. It grows slowly in cell culture, is cell associated, and is highly species specific. It p r o d u c e s characteristic intranuclear and cytoplasmic inclusions in tissue. As with all of the herpesviruses, it is capable of establishing a n d maintaining latency and reactivating with r e n e w e d viral replication in the face of profound i m m u n o s u p p r e s sion. The virus is ubiquitous in nature; the prevalence of antibody to CMV in healthy adults ranges from 40% to 100%, d e p e n d i n g on the geographic and s o c i o e c o n o m i c population studied, az3 Virus is transmitted by contact with infected b o d y fluids, through sexual contact, by blood transfusion, b y d o n o r organ contact, and through placental transfer. T M Reactivation m a y be triggered by i m m u n o s u p p r e s s i o n . Other triggers are unknown. 7:]0


Among HIV-infected persons, the m o s t f r e q u e n t clinical manifestation of disease caused by CMV is chorioretinitis.325' 326 Chorioretinitis o c c u r s in 15% to 20% of patients with A I D S . 325' 326 Retinitis m ay be unilateral o r bilateral, c o m m o n l y t h r e a t e n s sight, and may be associated with s y m p t o m s or signs that i n c l u d e floaters, d e c r e a s e d visual acuity, visual field defects, or a s y m p t o m a t i c c h a n g e s on retinal examination. 327 The lesions characteristically a p p e a r as yellow or white retinal exudates, often with f l a m e - s h a p e d hemorrhages. 327 T h e y may be seen only in the p e r i p h e r y in a small p r o p o r t i o n of patients. Most, however, are more centrally l ocat ed and thus sight threatening. Most patients will have CD4+ l y m p h o c y t e counts of less than 100 cells p e r mm 3 at the time of CMV retinitis diagnosis.325 327 Gastrointestinal tract disease c a u s e d by CMV occurs in 5% to 10% of p e r s o n s with AIDS 328, 329 C o m m o n p r e s e n t a t i o n s of gastrointestinal tract involvement include hepatitis; ulcerative disease involving the distal esophagus, w h i c h may c a us e nausea, odynophagia, and weight loss; a n d ulcerative disease of the colon, w h i c h m ay cause diarrhea, often hemorrhagic; and wasting. 323' 32s. 328-330 A ~ d r o m e of papillary stenosis with sclerosing cholangitis, w h i c h m ay p r o d u c e right u p p e r q u a d r a n t abdominal pain, fever, mild elevation of hepatic transaminases, a n d marked elevation of alkaline p h o s p h a t a s e levels, is associated with characteristic cholangiographic abnormalities a n d h as b e e n associated with CMV infection of the biliary tree.311,331,332

Other, less frequent manifestations of CMV disease in patients with AIDS i n c l u d e encephalopathy, p o l y r a d i c u l o m y e l o p a t h y or neuropathy, p n e u m o n i t i s , a nd di s s em i na t e d disease. 325' 326,333,334 CMV a p p e a r s to have a predilection for e p e n d y m a l cells, resulting in a s u b a c u t e e n c e p h a l o p a t h y s y n d r o m e c h a r a c t e r i z e d by fever, mental status changes, seizures, focal neurologic deficits, and/or progressive dementia. 333 Abnormalities of cerebrospinal fluid s u c h as low-grade l y m p h o c y t i c pleocytosis and elevated pr ot e i n c o n c e n t r a t i o n may be seen; however, this s y n d r o m e is often clinically indistinguishable from other, m o r e c o m m o n causes of e n c e p h a l o p a t h y in patients with AIDS. Peripheral n e u r o p a t h y or s e n s o r i m o t o r abnormalities associated with m y e l o p a t h y may also be i n d u c e d by CMV a n d may mimic similar s y n d r o m e s related directly to HIV or to nucleoside antiretroviral therapies. TM Interstitial p n e u m o n i t i s c a u s e d by CMV is u n c o m m o n a m o n g patients with AIDS b u t m a y be seen in those w h o have received corticosteroids or in those with multiorgan disease c a u s e d by CMV.325' 326 A substantial p r o p o r t i o n of patients with AIDS will s h e d CMV in respiratory secretions, and occasionally in u r in e an d blood, in the absence of clinically evident e n d organ disease. This is likely a c o n s e q u e n c e of virus reactivation associated with severe i m m u n o s u p p r e s s i o n . Last, d i s s e m i n a t e d CMV disease DM, October 1992

731

may present with a febrile wasting s y n d r o m e and p e r s i s t e n t viremia in a small n u m b e r of patients. 325' 326 The diagnosis of CMV disease often d e p e n d s on t he recogni t i on of an appropriate clinical s y n d r o m e c o m b i n e d with recovery of the virus in culture, or d e m o n s t r a t i o n of virus in appropriate tissue specimens using i m m u n o c y t o c h e m i c a l stains, m onocl onal a n t i b o d y assays, or in situ hybridization. 325' 326 Serologic testing is n o t helpful in that most patients already have antibodies to CMV a n d those w h o have true primary infection m a y not be capable of m o u n t i n g an appropriate IgM antibody r e s p o n s e . The diagnosis of retinitis is usually b a s ed on the o p ht ha l m ol ogi c a p p e a r a n c e of lesions within the retina an d should be c o n f i r m e d b y an exper i e nced ophthalmologist. 327 There are currently two antiviral agents available for t he t r e a t m e n t of CMV disease: ganciclovir, a gua ni ne nucleoside analogue, a n d foscarnet, a p y r o p h o s p h a t e analogue, both of which inhibit viral DNA polymerase. Both are c u r r e n t l y available only in an intravenous formulation; an oral f or m ul a t i on of ganciclovir is u n d e r investigation. Dosages, which m u s t be a d j u s t e d for bot h drugs in t he p r e s e n c e of renal insufficiency, are o u t l i n e d in Table 7. A 14- to 21-day i n d u c t i o n course is r e c o m m e n d e d . Because relapse or progression of retinitis is c o m m o n and occur s rapidly (within a m edi an of 4 to 8 weeks) in the absence of suppressive therapy, i n d u c t i o n should be followed by a daily m a i n t e n a n c e r e g i m e n as outlined in Table 7.aa5-341 Both drugs ap p ear equally effective for initial and m a i n t e n a n c e t h e r a p y of CMV retinitis; their com pa r at i ve efficacy for treatment of o t h e r m a n ifestations of CMV disease a m o n g patients with AIDS rem ai ns to be determined, although p r e l i m i n a r y data suggest that ganciclovir m a y be of benefit in the t r e a t m e n t of CMV colitis and esophagitis. 342' 343 The major toxic effect associated with ganciclovir is b o n e m a r r o w suppression, resulting in n e u t r o p e n i a in 15% to 25% of patients w i t h AIDS an d t h r o m b o c y t o p e n i a in 5% to 10% of patients. 335-337 Mutagenesis has been associated w i t h the drug in animal studies. Interruption of ganciclovir doses will generally be required for individuals in w h o m a decrease in absolute n e u t r o p h i l count to levels of less t h a n 500 to 750 cells p e r m m 3 develops. For those w h o are too n e u tropenic to begin t h e r a p y or b e c o m e n e u t r o p e n i c on therapy, the adjunctive use of g r a n u l o c y t e colony stimulating factors m a y abrogate this effect. Because synergistically e n h a n c e d h e m a t o p o i e t i c toxicity is often seen w h e n ganciclovir is c o m b i n e d with zidovudine, the use of colony stimulating factors m a y be especially advant ageous w h e n attempting to c o m b i n e zidovudine with ganciclovir therapy.3~, 345 Toxic effects related to foscarnet use include metabolic disturbances of ionized calcium, magnesium, a n d p h o s p h o r u s ; renal insufficiency; anemia; a n d in a small p r o p o r t i o n of patients, n e u r o t o x icity, possibly related to intracellular a n d extracellular shifts of 732


electrolytes. 339-341'343 Foscarnet has been safely combined with zidovudine in the treatment of patients with AIDS without apparent additive b o n e marrow suppression. Foscarnet alone has relatively weak activity against HIV in vitro; the c o m b i n e d use of these two agents m a y afford additive or synergistic antiretroviral activity. Preliminary results of a large clinical trial comparing foscarnet a n d ganciclovir treatment of newly diagnosed CMV retinitis in patients with AIDS suggest a m o d e s t survival benefit for those with normal renal function treated initially with foscarnet. 346 This benefit m a y be related to the antiretroviral activity of foscarnet a n d the ability to c o n t i n u e therapy with zidovudine for those receiving foscarnet.346 CMV retinitis responds to antiviral therapy in 75% to 90% of patients undergoing initial induction treatment. 335-341 The response is generally gauged by the stabilization of existing lesions followed by their eventual regression a n d the inhibition of development of new lesions. The durability of the response during m a i n t e n a n c e therapy ranges from 4 to 8 months. Although some investigators have rep o r t e d significant virologic responses to ganciclovir in l~tients with CMV colitis a n d esophagitis, the clinical response rates may be delayed or reduced, and neither of these agents h a s been uniformly effective in the treatment of gastrointestinal disease caused by CMV.342, 343 The response to therapy of CMV p n e u m o n i t i s in AIDS patients probably parallels that in patients with other underlying i m m u n o s u p p r e s s i v e disorders in that antiviral t h e r a p y may decrease virus load a n d inhibit viral replication but, d e p e n d i n g on the severity of the underlying parenchymal involvement, m a y not have a substantial effect on improvement in lung function. Those patients with milder disease appear to have a more substantial clinical response. The response to therapy of CMV infections of the biliary tract and central nervous system, as well as other manifestations of CMV disease, has not been established.

Herpes Simplex Virus Infection Primary or recurrent m u c o c u t a n e o u s disease caused by herpes simplex virus is a c o m m o n problem a m o n g HIV-infected individuals. Although the clinical manifestations are similar to those seen in persons not coinfected with HIV, m u c o c u t a n e o u s outbreaks may be prolonged a n d may be atypical, resulting in progressively enlarging a n d painful oral, esophageal, genital, or perirectal ulceration. 347-35z Ulcerative disease of the esophagus m a y mimic the clinical presentation of CMV and Candida esophagitis, with fever, nausea, and o d y n o p h a g i a as c o m m o n symptoms. Long-term oral suppressive acyclovir t h e r a p y in low doses may predispose patients with advanced i m m u n o s u p p r e s s i o n to the development of acyclovir-resistant herpetic lesions. 347-zSz AcyclovirDM, O c t o b e r 1992

733

resistant herpes simplex virus disease should be s u s p e c t e d in the instance of enlarging or persistent lesions that are apparently unresponsive to high doses of oral or parenteral acyclovir. Susceptibility testing of such isolates is possible in some reference a n d research laboratories. The diagnosis of herpetic disease is based on clinical presentation, culture of appropriate specimens, or histologic d e m o n s t r a t i o n of herpetic inclusions in tissue biopsies. There is currently no role for serologic testing in the acute diagnosis of herpetic disease in patients with HIV infection. Therapy of m u c o c u t a n e o u s herpes simplex virus disease can be accomplished with oral or parenteral acyclovir (Table 7). Alternatives for patients with acyclovir-resistant disease include prolonged intravenous acyclovir in a total daily dose of 30 mg/kg daily given in divided doses, c o n t i n u o u s infusion acyclovir therapy, or parenteral foscarnet in a dose of 60 mg/kg every 8 hours. 347-352 Although some isolates apparently resistant to acyclovir in vitro retain their susceptibility to vidarabine, this agent has been s h o w n to be m o r e toxic and less effective t h a n foscarnet for clinical treatment. T M Topical trifluridine in a 1% ophthalmic solution applied directly to cutaneous lesions every 8 h o u r s for up to 2 to 4 weeks has been successful in a small n u m b e r of patients refractory to acyclovir therapy. 352 This modality is u n d e r further investigation in a controlled pilot study.

Varicella-Zoster Virus Infection Reactivation of latent varicella-zoster virus (VZV) resulting in single, multidermatomal, or disseminated zoster may be seen in HIVinfected patients. 169' 353-357 Single or multidermatomal zoster m a y precede other clinical manifestations of HIV disease by m o n t h s to years.169, ~53,354 Organ involvement is unusual, but isolated cases of VZV-induced esophagitis and acute retinal necrosis have been anecdotally described. In patients with advanced immunodeficiency, primary disseminated varicella has been seen, particularly among children, accompanied by severe multiorgan system disease that resulted in death. The diagnosis of VZV disease is based on the clinical manifestations and culture of the virus from skin lesions or biopsy material obtained from involved sites. Some have r e c o m m e n d e d serologic testing for HIV in all individuals less than 50 years of age in w h o m zoster infections develop. Although this m a y remain controversial for those who are otherwise h e a l t h y and develop single d e r m a t o m a l zoster, any patient presenting with multidermatomal zoster s h o u l d be tested for HIV. Treatment can generally be accomplished with high-dose oral or parenteral acyclovir (Table 7). Acyclovir-resistant 734

DM, O c t o b e r 1 9 9 2

VZV h a s b e e n r e p o r t e d in a small n u m b e r of p a t i e n t s a n d m a y res p o n d to foscaiTlet. 356' 357

Epstein-Barr Virus Infection Oral hail]y leukoplakia is a n i n t r a o r a l lesion l i n k e d to latent infection w i t h E p s t e i n - B a r r virus (EBV) a n d p o s s i b l y to c o i n f e c t i o n with h u m a n p a p i l l o m a v i r u s (HPV). 353' 3~9 Oral lesions have a w h i t e serpigi n o u s or l i n e a r a p p e a r a n c e , usually o c c u r r i n g along the grooves of the lateral s u r f a c e s of the t o n g u e a n d b u c c a l m u c o s a a n d occasionally s p r e a d i n g to coat the tongue. T h e y m a y b e c o n f u s e d w i t h the a p p e a r a n c e o f p l a q u e s of oral t h r u s h ; h o w e v e r , leukoplakia lesions are a d h e r e n t a n d do n o t scrape off. T h e y are g e n e r a l l y n o n t e n d e r and asymptomatic. T h e d i a g n o s i s is b a s e d o n the a p p e a r a n c e of t h e lesions. Biopsy of t i s s u e w i t h i m m u n o h i s t o c h e m i c a l s t a i n i n g or e l e c t r o n m i c r o s c o p i c e v a l u a t i o n m a y reveal EBV a n d / o r HVP DNA or virions. Regression of t h e lesions h a s b e e n r e p o r t e d w i t h oral acyclovir, oral zidovudine, a n d p a r e n t e r a l ganciclovir. 3~°-362 L e s i o n s m a y also s p o n t a n e o u s l y regress. :~ In a d d i t i o n to oral h a i r y leukoplakia, p a t i e n t s w i t h HIV infection m a y have EBV-associated n o n - H o d g k i n ' s l y m p h o m a develop with a p r e d i l e c t i o n for central n e r v o u s s y s t e m a n d m u l t i o r g a n l y m p h o r e t i c u l a r sites. T h e s e t u m o r s are t h o u g h t , in s o m e instances, to be rel a t e d to m a l i g n a n t t r a n s f o r m a t i o n of l y m p h o i d tissue latently inf e c t e d w i t h EBV. 363' 364 EBV-associated n o n - H o d g k i n ' s l y m p h o m a req u i r e s r a d i a t i o n o r s y s t e m i c cytotoxic c h e m o t h e r a p y a n d d o e s not r e s p o n d to antiviral agents.233' 364, 365

Other Viral Infections O t h e r viruses that c a u s e infections s e e n w i t h i n c r e a s e d f r e q u e n c y o r a s s o c i a t e d w i t h progressive or u n u s u a l m a n i f e s t a t i o n s of disease in p a t i e n t s w i t h H1V infection i n c l u d e HPV, papovavirus, p o x viruses, h u m a n T-cell l y m p h o t r o p h i c viruses I a n d II (HTLV-UII), vaccinia virus, a n d a d e n o v i r u s . H u m a n p a p i l l o m a v i r u s m a y be a s s o c i a t e d with large or m u l t i p l e r e c u r r e n t or r e f r a c t o r y genital o r anal c o n d y l o m a t a . 3G6 T h i s virus has also b e e n l i n k e d w i t h oral hairy leukoplakia. 359 Anogenital intraepithelial d y s p l a s i a or c a r c i n o m a in situ in HIV-infected m e n a n d w o m e n a n d cervical intraepithelial neoplasia, dysplasia, o r c a r c i n o m a in situ in HlV-infected w o m e n have b e e n ass o c i a t e d w i t h HPV coinfection a n d are t h o u g h t to o c c u r w i t h inc r e a s e d f r e q u e n c y in this p o p u l a t i o n . 366-37° Aggressive t h e r a p y using topical, ablative, or laser modalities m a y c i r c u m v e n t the s p r e a d o r m a l i g n a n t t r a n s f o r m a t i o n of HPV lesions. Intralesional o r systemic i n t e r f e r o n a l p h a m a y be useful a d j u n c t i v e t h e r a p y in p a t i e n t s with DM, O c t o b e r 1992

735

condylomata refractory to conventional treatments. All HIV-infected w o m e n should have yearly g~ynecologic examinations a n d Papanicolaou smears; those coinfected with HPV should have these repeated every 6 monthsff~° The JC papovavirus has b e e n etiologically linked to the developm e n t of progressive multifocal leukoencephalopathy.371-374 The incidence of this infection a m o n g patients with AIDS is unclear but appears to be increasing. 372-3~4 Progressive multifocal leukoencephalopathy clinically manifests as an insidious and slowly progressive dementia complex frequently associated with seizures a n d progressive focal neurologic deficits. The diagnosis is based on the characteristic appearance of p a r e n c h y m a l brain lesions involving the white matter on CT or MRI scans a n d the histopathologic d e m o n s t r a t i o n of papovavirus in biopsied brain tissue. Currently no k n o w n effective therapy exists. Pox virus infection p r o d u c e s molluscum contagiosum, w h i c h is characterized by multiple small, umbilicated, p a p u l a r skin eruptions. These may progressively spread and are often refractory to destructive or ablative therapy in patients with advanced i m m u n o s u p pression. 375 A small proportion of HIV-infected patients, particularly those w h o are injecting drug users, m a y be coinfected with HTLV-I/II. 113-115 This m a y be a function of the similar m o d e s of transmission of the two viruses and the entry of HTLV into drug-using populations. Although HTLV-FII has been associated with tropical spastic paraparesis and adult T-cell l e u k e m i a - l y m p h o m a in otherwise healthy individuals latently infected for prolonged periods, the clinical significance of coinfection with HW a n d HTLV-I/II is as yet u n k n o w n . Isolated cases suggesting a relationship between HTLV-FII a n d polymyositis or adult T-cell leukemia-lymphoma have b e e n reported in persons with HIV infection,a76-37a Vaccinia virus has been associated with a fatal disseminated infection after smallpox vaccination in HIV-infected military personnel and after vaccination of HIV-infected patients with i m m u n o g e n s prepared in a vaccinia vector, a79,aa° Last, a small n u m b e r of HIVinfected patients have been reported with ulcerative gastrointestinal disease and interstitial p n e u m o n i t i s caused by adenovirus, aal' 3a2 Therapies for these entities have not been established.

MYCOBACTERIAL INFECTIONS Mycobacterium avium Complex Disease Microorganisms of the Mycobacterium avium-M, intracellulare complex (MAC) are collectively grouped as atypical mycobacteria of Runyon group III. These organisms are n o n c h r o m o g e n s that grow 736

DM, October 1992

optimally in 10 to 21 days after inoculation into specialized radiometric media. They are ubiquitous in the environment, found in soil, water, domestic a n d wild animals, milk, a n d other foodstuffs. Organisms from environmental sources m a y contaminate clinical specim e n s or transiently colonize organ systems. They are thought to be acquired t h r o u g h inhalation or ingestion, based largely on the prevalent finding of MAC in respiratory and gastrointestinal tissues. Currently little evidence exists to suggest person-to-person transmission. The exact incidence of clinical disease c a u s e d by MAC in patients with AIDS is unknown. Published reports suggest that 18% to 29% of HIV-infected patients have MAC disease diagnosed during life, whereas a u t o p s y studies suggest that u p to 40% to 60% will have MAC present in organ tissue at the time of death. 383-387~ Ninety-six percent of infections in patients with AIDS are d u e to M. avium, a83 Disease c a u s e d by MAC can be localized or disseminated.384, ass. 387 A small proportion of persons with AIDS m a y have disease similar to tuberculosis, with fever, weight loss, cough, night sweats, a n d cavitary or nodular p n e u m o n i a . More often, disease is widespread, disseminated to multiple organ systems, a~companied by hectic fevers, sweats, splenomegaly, l y m p h a d e n o p a t h y , weight loss with wasting a n d diarrhea, a n d anemia or pancytopenia.~84, 386,387 Anemia or pancytopenia out of proportion to the degree expected from underlying disease or other therapy is c o m m o n a n d is probably due to bone marrow infiltration. Histologically, large n u m b e r s of acid-fast bacilli are seen infiltrating tissues, with very little a p p a r e n t i m m u n e response. Organs most frequently involved include l y m p h nodes, spleen, liver, a n d gastrointestinal tract. Highgrade bacteremia is common, present in 80% to 90%, and often sustained. Splenomegaly a n d intraabdominal l y m p h a d e n o p a t h y may be associated with chronic abdominal pain. The diagnosis of disseminated MAC disease is based on the recovery of the organism from cultures of blood, b o n e marrow, or other normally sterile tissue, such as liver or l y m p h node. Collection of blood specimens in isolator tubes, c o u p l e d with lysis centrifugation a n d inoculation into radiometric media, is probably the most efficient way of detecting mycobacteremia.388 Acid-fast bacilli demonstrated on stains of tissue specimens in a n d of themselves are nonspecific, because infection caused by M. tuberculosis, M. kansasii, or other atypical mycobacteria may also be associated with positive smears. Culture and appropriate susceptibility testing are necessary for diagnosis a n d planning optimal therapy. No single drug or combination of drugs has b e e n shown to be uniformly successful in eradicating MAC a n d in treating disease in patients with AIDS. 386' a8~,a89-392 High-level resistance of MAC to isoniazid a n d o t h e r standard antimycobacterial agents is common. In DM, O c t o b e r 1992

737

vitro susceptibility data indicate that amikacin, liposome-encapsulated aminoglycosides, clofazimine, rifamycin derivatives, ethambutol, clarithromycin, azithromycin, ciprofloxacin, a n d sparfloxacin are among the limited n u m b e r of agents with substantial in vitro a n d in vivo activity against MAC organisms, although susceptibility to m a n y of these agents is n o t uniform. In recent studies, multiple drug regimens containing three or more of these agents have shown some clinical a n d microbiologic efficacy in the treatment of patients with d i s s e m i n a t e d disease and mycobacteremia (Table 7).3a6,387, 3a9-392 The n e w macrolides clarithromycin a n d azithromycin have been d e m o n s t r a t e d to have marked in vitro actvity against MAC, are orally bioavailable, appear to be well tolerated, a n d are concentrated in tissue and intracellular sites in levels in excess of those required for inhibition of m a n y MAC strains. Preliminary data suggest that these drugs m a y have significant clinical activity; however, the m o s t effective dosages, incidence of emergence of resistance, and other drugs likely to be effective in combination with the macrolides remain to be established in ongoing prospective clinical trials. 39a' 394 Most analyses of t r e a t m e n t efficacy for this disease in patients with AIDS have limited follow-up, largely of less t h a n 12 m o n t h s ' duration. Relapse appears to be common, as does breakthrough mycobacteremia on therapy. The optimal duration of t h e r a p y has not been established, a n d it is likely that most individuals will require some maintenance t r e a t m e n t for life. If amikacin is i n c l u d e d in the treatment regimen, most investigators r e c o m m e n d c o n t i n u a t i o n of the amikacin for 1 to 2 m o n t h s , depending on the tolerance of the patient. Prophylaxis of disease c a u s e d by MAC is currently u n d e r investigation. It has been difficult thus far to identify those patients with AIDS who are most likely to be at increased risk of developing disseminated disease. Retrospective data and small prospective clinical trials suggest that those individuals with CD4+ lymphocyte counts of less than 100 cells per m m 3 and those with other opportunistic infections are likely to be at greater risk a n d may be candidates for prophylactic agents once s u c h become available, aa6' ass Mycobacterium tuberculosis Infection Disease caused by M. tuberculosis has risen substantially in the last decade in w h a t appears to be a direct relationship to the rise in numbers of cases of AIDS.395-39a A disproportionately large n u m b e r of HIV-infected individuals a p p e a r to be coinfected with M. tuberculosis, particularly those w h o are among urban indigent populations or who are injection drug u s e r s . 3 9 5 - 3 9 8 In general, clinical manifestations of tuberculous disease are similar to those in non-HIV-infected individuals and will not be further 738


detailed here. However, atypical p r e s e n t a t i o n s a n d e x t r a p u l m o n a r y disease are m o r e c o m m o n among t hos e coinfected with HIV.387 T h o s e with relatively preserved i m m u n o l o g i c function are more likely to have localized p u l m o n a r y t ube r cul osi s develop, whereas t h o s e with m o r e a dva nc e d i m m u n o s u p p r e s s i o n are m ore likely to have atypical manifestations and e x t r a p u l m o n a r y disease. Th e diagnosis of disease caused by M. tuberculosis d e p e n d s on recovery of th e organism from a p p r o p r i a t e clinical specimens. HIVinfected patients from w h o m clinical s p e c i m e n s d e m o n s t r a t e acidfast bacilli s h o u l d be treated initially with at least three drugs with activity against M. tuberculosis until culture identification can be c o m p l e t e d . C o n t i n u e d t he r apy s h o u l d be g u i d e d by susceptibility testing b e c a u s e outbreaks of disease c a u s e d b y strains of M. tuberculosis resistant to multiple drugs have b e e n r e p o r t e d a m o n g HIVinfected patients from large urban centers. T he suggested duration of t h e r a p y is 12 months; longer d u r a t i o n s a p p e a r to be u n n e c e s s a r y for th o s e with isoniazid-susceptible organisms. Disease c a u s e d by isolates resistant to isoniazid or to multiple drugs m ay require l o n g er t r e a t m e n t courses. All HIV-infected individuals s houl d be skin t e s t e d with intermediate-strength ( 5 - t u b e r c u l i n unit) purified p r o t e i n derivative (PPD) by the M a n t o u x m e t h o d . 396' 397 Skin testing with additional c u t a n e o u s antigens to establish the pr e s ence or absence of anergy shoul d be s i m u l t a n e o u s l y performed. Preferably, s u c h skin testing shoul d be c o m p l e t e d before the d e v e l o p m e n t of a d v a n c e d i m m u n o s u p p r e s sion. Th e p r o p o r t i o n of HIV-infected patients likely to r e s p o n d to cut a n e o u s antigens declines as the de gr ee of i m m u n o s u p p r e s s i o n advances, s u c h that 80% of individuals with CD4~- l y m p h o c y t e counts of less th an 100 cells p e r m m 3 will not r e s p o n d to any c u t a n e o u s antigens. 397 Patients with HIV infection w h o have a positive response to a PPD test, with 5 m m of i ndur a t i on c o n s i d e r e d positive in this setting, s h o u l d receive isoniazid prophylaxis in a dose of 300 mg daily for at least 6 m o n t h s and preferably 12 m o n t h s . 396' 397 Those with HIV infection w ho are anergic a n d w h o are c o n s i d e r e d to be at greater t h a n 10% risk of developing active tuberculosis (injection d r u g users, patients e x p o s e d in jails, t h o s e w h o are immigrants from areas w h e r e tuberculosis is highly endem i c, o r those recently exp o s e d to an active case) should also receive isoniazid prophylaxis. T he mo s t a p p r o p r i a t e prophylaxis regimen for those e x p o s e d to drug-resistant M. tuberculosis has n o t b e e n established.

Other Mycobacterial Infections Mycobacterium kansasii has b e e n associated with outbreaks of m yco b acter ial disease in some ge ogr aphi c locations and sporadic cases elsewhere. 399'4°° Disease c a u s e d by this organism m ay be m o r e c o m m o n am ong HIV-infected injection d r u g users and innerDM, O c t o b e r 1992

739

city populations. The m o s t c o m m o n clinical manifestations are those of p u l m o n a r y or gastrointestinal tract disease, with signs and s y m p t o m s similar to t hos e c a u s e d by M. tuberculosis or o t h e r atypical mycobacteria. M. kansasii isolates are predictably resistant to isoniazid. Effective t h e r a p y requires regimens c o m b i n i n g rifampin a n d ethambutol. Although t h e addition of isoniazid remains cont roversial, some believe its u s e in combination with rifampin a n d ethambutol may prevent o r delay emergence of resistance to rifampin. Sporadic cases of localized or disseminated disease c a u s e d by M. xenopi, M. chelonei, M. fortuitum, M. marinum, M. scrofulaceum, bacille Calmette-Gu6rin, a nd o t h e r atypical mycobacteria have b e e n rep o r t e d in patients with HIV infection. Diagnosis d e p e n d s on appropriate identification of individual species; effective t h e r a p y m u s t be based on results of antimycobacterial susceptibility testing. FUNGAL INFECTIONS Candidiasis Among all Candida species, C. albicans appears to p r e d o m i n a t e in disease entities a m o n g HIV-infected individuals. T h e organisms exist p r e d o m i n a n t l y as unicellular, thin-walled yeast forms that reprod u c e by budding. T h e y g r o w well in routine bl ood culture bottles a n d on agar plates; lysis centrifugation e n h a n c e s recovery. C. albicans organisms are u b i q u i t o u s in nature and are n o r m a l c o m m e n sals of humans, c o m m o n l y f o u n d on skin and in t he gastrointestinal, respiratory, and female genital tracts. Most infections are endogen o u s in origin. Some form of m u c o c u t a n e o u s candidiasis o c c u r s in virtually 100% of HIV-infected patients. M u c o c u t a n e o u s disease t ha t manifests as oral t h r u s h is the m ost c o m m o n form of candidiasis in patients with HIV infection. 4°1' 4o2 It m ay p r eced e a n d is a prognostic indicator of progressi on to AIDS. Chronic or r e c u r r e n t Candida vaginitis is especially c o m m o n a m o n g HIV-infected w o m e n a n d m a y be a m o r e prevalent localization of candidiasis th an o t h e r m u c o c u t a n e o u s sites. 4°2 Candida esophagitis is the initial o p p o r t u n i s t i c infection for approximately 7% of individuals a n d may be m o r e c o m m o n a m ong w o m e n with A I D S . 3 7 ° ' 403 The clinical manifestations of candidiasis are easily recognizable. M u c o c u t a n e o u s oral candidiasis is identified by the p r e s e n c e of glistening white p a t c h e s on t h e oral mucosal and t o n g u e surfaces. These can be s c r a p e d off w i t h a swab or tongue depressor. Less c o m m o n p r es en t a t i ons i n c l u d e erosive changes or c i r c u m s c r i b e d h y p e r e m i c p a t c h e s on the palate. 4°1 Although m o s t patients are asymptomatic, a small p r o p o r t i o n m ay experience m u c o s a l irritation or burning. Candida esophagitis typically p r e s e n t s with fever, odynophagia, a n d d e m o n s t r a b l e ulcers covered with white e x u d a t e 740


in the posterior pharynx and esophagus. Candida esophagitis is not always a c c o m p a n i e d by the presence of oral m u c o c u t a n e o u s candidiasis, nor is it uniformly symptomatic. Candida vaginitis presents with a c r e a m y white vaginal discharge, occasionally adherent to the mucosa, a c c o m p a n i e d by pruritus a n d local tissue irritation. The diagnosis generally depends on the clinical presentation and appearance of the m u c o c u t a n e o u s lesions. A w e t m o u n t of material from involved sites, prepared with potassium hydroxide, will demonstrate b u d d i n g yeast forms on microscopic examination. The organism can be readily cultured from appropriate surfaces a n d histopathologically demonstrated in tissue biopsies. Candida esophagitis m a y be presumptively diagnosed by the presence of ulcerative plaques visible on barium swallow or t h r o u g h visualization and biopsy of plaques by endoscopy. Chronic daily therapy or repeated intermittent courses of treatm e n t with antifungal agents may be required. Topical antifungal t h e r a p y is useful for localized m u c o c u t a n e o u s disease (Table 7). A variety of agents including nystatin, clotrimazole, and other imidazole or triazole derivatives m a y be u s e d orally or i!~travaginally a n d will afford relief in most patients with mild disease. T h o s e who are refractory to topical therapies m a y require systemic administration of antifungal agents. A n u m b e r of these are effective and include oral ketoconazole, fluconazole, a n d itraconazole (Table 7). Gastric acidity is required for the adequate absorption of ketoconazole; concurrent use of antacids or H2-blockers or the concomitant presence of HIV-associated gastropathy with achlorhydria will impair ketoconazole absorption. 4°4 Fluconazole does not d e p e n d on an acidic envir o n m e n t for absorption. Short courses of low doses of amphotericin B are also effective (Table 7).

Cryptococcosis Cryptococcus neoformans is an e n c a p s u l a t e d yeast, similar in size to Candida species, that reproduces by b u d d i n g with narrow-based buds. It is ubiquitous in nature, with a worldwide distribution and no specific geographic localization. Soil or other areas contaminated with pigeon feces or other similarly c o n t a m i n a t e d environments m a y contain large a m o u n t s of the fungus. Circumstantial evidence suggests that infection occurs through inhalation of organisms aerosolized from the soil. Person-to-person transmission has not been d o c u m e n t e d . This particular yeast is s e c o n d only to Candida as the most c o m m o n fungal pathogen in patients with AIDS; its incidence in HIV-infected patients is estimated at 5% to 10% .405,406 Cryptococci have a predilection for the central nervous system in H1V-infected patients with meningoencephalitis as the most frequent clinical manifestation of disease.4°5' 406 The onset is usually inDM, October 1992

741

sidious, with s y m p t o m s of fever, he a da c he , nausea, dizziness, somnolence, or irritability followed by impaired mental status, a n d finally, if untreated, seizures, obtundation, and coma. P u l m o n a r y disease is a less c o m m o n manifestation of cryptococcosis in patients with AIDS and m a y p r e s e n t with the insidious onset of progressive cough, dull chest pain, a n d fever. Chest radiography m a y d e m o n strate a slowly growing d e n s e infiltrate either in t he u p p e r lobes or in segmental p o r t i ons of t he lower lobes. Thick-walled cavitary disease or, rarely, miliary disease m a y be seen. E x t r a p u l m o n a r y or disseminated cryptococcal disease with involvement of skin, bone, adrenal gland, kidney, heart, l y m p h o r e t i c u l a r system, chorioretina, a n d prostate have all b e e n r e por t ed. In particular, the p r o s t a t e a p p e a r s to be a c o m m o n site of relapse and m a y serve as an u n t r e a t e d reservoir for organisms, owing in part to the relatively p o o r p e n e t r a t i o n of prostatic tissue by t h e r a p e u t i c agents. 4°7 The diagnosis of c r y p t o c o c c a l disease is based on the d e t e c t i o n of the organism in c u l t u r e of cerebrospinal fluid, blood, or tissue or t h r o u g h histopathologic d e m o n s t r a t i o n of organisms in clinical specimens. Additional adjunctive studies include India ink smears of cerebrospinal fluid a n d m e a s u r e m e n t of cryptococcal antigen in s e ru m or cerebrospinal f u i d . Cryptococcal antigen is detectable in serum o r cerebrospinal fluid in 90% or m o r e of patients with cryptococcal meningitis.4°5' 406 Initial therapy s h o u l d be g u i d e d by the clinical status of t he patient. In persons with AIDS a n d cryptococcal meningitis w h o have p o o r prognostic indicators, s u c h as altered mental status or coma, positive cryptococcal b l o o d cultures, high serum or cerebrospi nal fluid cryptococcal antigen titers, o t h e r focal neurologic deficits, or advanced i m m u n o s u p p r e s s i o n , parenteral administration of a m p h o tericin B as initial t h e r a p y with or without the c o m b i n e d u s e of flucytosine is generally r e c o m m e n d e d (Table 7).4°a'4o9 Initial t h e r a p y with parenteral or oral fluconazole m a y be used in individuals w h o have milder disease or w h o lack p o o r prognostic factors (Table 7). For those with severe disease w ho r e s p o n d to initial therapy, amphotericin B m a y be s w i t c h e d to oral fluconazole after 2 to 3 weeks of therapy. The r e c o m m e n d e d duration of acute t h e r a p y with fluconazole is 6 to 10 weeks. For t hos e w h o elect to c o n t i n u e a m p h o t e r i cin b, a total dose of 1.5 to 2.0 g s houl d be administered. Some investigators have r e c o m m e n d e d that amphotericin B be c o m b i n e d with flucytosine for the first 2 to 4 weeks of therapy. The dosage of flucytosine should be a d j u s t e d to achieve a level of 50 to 100 p~g/mL 2 h o u r s after the d os e is given (Table 7). This drug is generally p o o r l y tolerated for p r o l o n g e d p e r i o d s by m a n y patients with AIDS b e c a u s e of its b o n e m a r r o w suppressive effect, particularly w h e n it m u s t be c o m b i n e d with o t h e r m a r r o w suppressive agents s u c h as zidovu-

742


dine. Some p u b l i s h e d data suggest that c o m b i n e d t herapy is no m o r e effective and may be less well tolerated t h a n am phot eri ci n B alone.4°a' 4o9 Th e relapse rate, as with other o p p o r t u n i s t i c infections associated with AIDS, is high after initial therapy. 4°s-411 For this reason, maint e n a n c e t h e r a p y is generally r e c o m m e n d e d . Fluconazole has been s h o w n to be m o r e effective and better tolerated t h a n am phot eri ci n B for m a i n t e n a n c e t h e r a p y in this setting; oral daffy doses ranging from 200 to 400 mg have been successful. 41°'4n

Other Systemic Fungal Infections D i s s e m i n a t e d disease caused by Histoplasma capsulatum has been r e p o r t e d in geographically localized clusters a n d sporadic cases a m o n g patients with AIDS.412' 413 This organism is a d i m o r p h i c fungus f o u n d in soil. It is endemic to the central and midwestern Urlited States a n d some tropical a n d subtropical areas of the world. For th e mo s t part, cases in patients with HIV infection are limited to t h o s e w h o reside in or travel to e n d e m i c areas. 412' 41a The clinical pr es e nt a t i on is usually one of insidious or subacute o n s et of fever, weight loss or wasting, a b d o m i n a l pain, hepatosplenomegaly, l y m p h a d e n o p a t h y , diarrhea, h e a d a c h e , and occasionally, cough. Fever m ay be hectic a nd prolonged. 412' 41a Th e diagnosis is m a d e by culture of a p p r o p r i a t e clinical specimens; blood, b o n e marrow, and l y m p h o r e t i c u l a r tissue a p p e a r to have the highest yield. A recently d e v e l o p e d Histoplasma antigen test has b e e n f o u n d to be sensitive a n d specific as a diagnostic test b o t h for detecting the p r e s e n c e of the organism and for following therapy. 414 It is currently available primarily as a research tool. Th e most effective t h e r a p y for d i s s e m i n a t e d histoplasmosis thus far has b e e n a m p h o t e r i c i n B. Daily doses given intravenously to achieve a total dose of 1.5 to 2.0 g over t he course of several weeks are r e c o m m e n d e d . 415 Itraconazole has b e e n s h o w n to be similarly effective in clinical trials, but is not yet available. 41~ As with most o t h e r o p p o r t u n i s t i c pathogens, relapse is c o m m o n and m a i n t e n a n c e t h e r a p y is generally required. 412'4~a K e t o c o n a z o l e has been effective as m a i n t e n a n c e t h e r a p y with the caveat that absorption of the drug m u s t be assured. 412'4~a Amphotericin B has also b e e n u s e d for suppression. 41s Anecdotal reports suggest that fluconazole at higher doses m a y be beneficial both for a c ut e a n d m a i n t e n a n c e treatment, a l t h o u g h failures have occurred. 417 Controlled clinical trials are und e r way. Oth er s p o r adi c or geographically localized fungal infections rep o r t e d in patients with AIDS include coccidioidomycosis, aspergillosis, blastomycosis, and sporotrichosis. Each of t h e s e infections may

DM,October 1992

743

p res en t as a febrile s y n d r o m e with disseminated multiorgan system disease. Coccidioidomycosis is m o r e c o m m o n in the s o u t h w e s t e r n United States, is often associated with meningitis or o t h e r central nervous system manifestations, a nd appears to r e s p o n d initially to parenteral a m p h o t e r i c i n B a n d to itraconazole.416' 418 Aspergillosis presents chiefly with p u l m o n a r y disease; dyspnea, cough, a n d fever a p p ear to be the m os t f r e que nt s y m p t o m s and are relatively insidious in onset. 419 U p p e r lobe cavitary disease, nodules, pleural-based lesions, and diffuse infiltrates are radiographic manifestations of disease. 419 Therapy with a m p h o t e r i c i n B or itraconazole m ay be successful if instituted early.419 Amphotericin B and o t h e r imidazole or triazole derivatives a p p e a r also to be effective in the t h e r a p y of blastomycosis and spor ot r i chos i s in the small n u m b e r of HlV-infected patients treated.

BACTERIAL INFECTIONS Recurrent bacterial infections are c o m m o n a m o n g p e r s o n s with HIV disease. Bacterial infections seen with increased f r e q u e n c y include those c a u s e d by Staphylococcus species, Streptococcus pneumoniae, Haemophilus influenzae, Campylobacter species, a n d Salmonella species. 42°-424 Bacterial infections in this p o p u l a t i o n in general a p p e a r to be associated w i t h a high incidence of bacteremia, freq u en t relapses or r e c u r r e n c e s , a nd often, multiorgan system involvement. Syndromes of m i xe d bacterial origin such as sinusitis a n d pelvic inflammatory disease are also problematic. Organisms associated with u n u s u al manifestations but not necessarily seen with i n c r e a s e d fr eq u en cy include Afipia felis, Nocardia, Listeria, Legionella, a n d Shigella species. 4zS-4a° Bacteremic infections c a u s e d by Staphylococcus aureus a p p e a r most c o m m o n a m o n g t hos e with indwelling catheters a n d skin a n d soft-tissue infections; metastatic foci of infection in bone, muscle, lung, a n d joints are not infrequent. C o m m u n i t y - a c q u i r e d p n e u m o nia, with or w i t h o u t b a c t e r e m i a or metastatic foci of infection, is most often the p r e s e n t i n g s y n d r o m e associated with S. pneumoniae a n d H. influenzae. Salmonella and Campylobacter infections m o s t frequently involve a n d / o r manifest initially in the gastrointestinal tract; as with o t h e r bacterial species, metastatic foci of infection after b a c t e r e m i a are c o m m o n . Acute, recurrent, a n d c h r o n i c sinusitis occurs with a p p a r e n t increased frequency a m o n g HIVinfected patients. Small studies evaluating the microbial cause sug L gest that the s p e c t r u m of bacterial pa t hoge ns is similar to that seen in n o n - H I V - i n f e c t e d patients. Although pelvic inflammatory disease does not ap p ear to o c c u r w i t h increased frequency a m o n g w o m e n

744


a n d m a y r e m a i n as ym pt om a t i c unless lesions e r o d e mucosal surfaces a n d b l e e d or their enlarging bulk creates obstructive changes. Infiltrative KS within the gastrointestinal m u c o s a m ay cause diarrhea, malabsorption, a n d wasting. The diagnosis of KS is ba s ed on the a p p e a r a n c e of the lesions and t h e characteristic histopathologic c h a n g e s in b i o p s i e d tissue. Cutan e o u s a n d m u c o s a l lesions of epithelioid bacillary angiomatosis, linked to the cat-scratch bacillus, m a y m i mi c t h e gross a p p e a r a n c e of KS lesions; t h e y can be histologically distinguished. Although diss e m i n a t e d cat-scratch disease is less c o m m o n t h a n KS, it m a y be p r u d e n t to establish the diagnosis of KS b y bi opsy rat her t h a n dep e n d i n g o n t h e physical a p p e a r a n c e of lesions. Visceral disease detection generally requires biopsy confirmation; p u l m o n a r y disease m a y b e particularly difficult to diagnose in that sam pl es obtained by b r o n c h o a l v e o l a r lavage m ay not cont ai n a b n o r m a l cells. Transbronchial, o p e n lung, or pleural biopsy m a y be necessary. T r e a t m e n t of KS d e p e n d s on the location and extent of disease. 437 Isolated c u t a n e o u s disease m a y require no t h e r a p y if lesions are few, n ot rapidly progressive, and not cosmetically obvious. F/~r large lesions or t h o s e strategically located in an area of discomfort or cosmetic c o n c e r n , local irradiation m a y diminish t h e size a n d appearance. For m o r e extensive or rapidly progressive c u t a n e o u s disease, systemic in ter f e r on alpha or single-agent cytotoxic c h e m o t h e r a p y m a y be beneficial. 437 Interferon al pha doses s h o w n to be effective alone range f r o m 10 million to 20 million units/day. 2s6' 2s7,437,438 The overall t u m o r r e s p o n s e rate ranges from 40% to 60%, d e p e n d i n g on t h e u n d e r l y i n g i m m u n e status of the patient; t h o s e with CD4+ lymp h o c y t e c o u n t s of greater t han 400 cells p e r m m ~ at the initiation of t h e r a p y are likely to have m or e substantial and durable res p o n s e s Y 6' a57' 437' 438 Zidovudine or antiretroviral t h e r a p y alone d o es n o t a p p e a r to influence the p r o g r e s s i o n of KS.a57 The combination of z i d o v u d i n e with interferon alpha m a y afford not only treatm e n t of KS b u t the potential c o m b i n e d synergistic antiretroviral effect of b o t h drugs, a56' 257 Interferon al pha doses of 5 million to 10 million u n its /d a y c o m b i n e d with a total daily d o s e of 600 mg of zid o v u d i n e a p p e a r e d to be relatively well tolerated a n d associated with substantial a n t i t u m o r effect in one study. 256 Cytotoxic agents u s e d as single-drug t h e r a p y include a d r i a m y c i n a n d the vinca alkaloids vincristine a n d vinblastine. Doses m u s t be individualized; res p o n s e rates vary with doses, extent of disease, a n d underlying host status. The effective use of these agents generally requires the expertise of an oncologist. Side effects of local irradiation are usually limited to local tissue e d ema, inflammation, a n d / o r necrosis. Major toxicities of systemic interferon a l p h a include a flulike s y n d r o m e of fever, myalgia, and fatigue; hepatotoxicity; and m y e l o s u p p r e s s i o n . Additive myelosupDM,

October 1992

747

pression is the m a j o r adverse effect w h e n interferon alpha a n d zidovudine are c o m b i n e d . M yel os uppr es s i on and cardiotoxicity are dose-limiting toxicities of adriamycin, particularly w h e n hi gher dosage or p r o lo n g ed t h e r a p y is used. Peripheral n e u r o p a t h y associated with vinca alkaloids makes their use predictably difficult in combination with d i d a n o s i n e or o t h e r similar antil~troviral agents. For those with visceral o r extensive or rapidly progressive c u t a n e ous involvement, c o m b i n a t i o n c h e m o t h e r a p y is generally r e c o m m e n d e d . 439 However, the myelosuppressive effect of multiple cytotoxic agents often p r e c l u d e s c o n t i n u a t i o n of zidovudine, a n d chem o th er ap eu tic doses are often limited by the p o o r b o n e m a r r o w reserve of patients with a d v a n c e d HIV-related i m m u n o s u p p r e s s i o n . Lower doses of multiple agents have b e e n c o m b i n e d with beneficial effect, but long-term survival and durability of the t u m o r r e s p o n s e remain limited. 43"~

Non-Hodgkin's Lymphoma Non-Hodgkin's l y m p h o m a (NHL) is a neoplastic c o m p l i c a t i o n of H1V infection th a t is o c c u r r i n g with increasing f r e q u e n c y as sut'cival of patients with HIV disease is p r o l o n g e d by i m p r o v e d antiretroviral a n d prophylactic therapies. 233 Although NHL is m o s t likely to o c c u r in patients with a d v a n c e d HIV disease, it may be t h e initial AIDSdefining illness o r HlV-related event in those with h i g h e r CD4+ lymp h o c y t e counts. T he i n c i d e n c e is not well delineated; estimates range from 2% to 3% .233 According to data from a prospect i ve longitudinal study, pat i ent s receiving zidovudine t h e r a p y h a d an a n n u a l incidence of NHL of 1.6% p e r y e a r of follow-up.Z33 Some investigators have suggested that NHL, particularly primary central nervous syst e m lymphoma, m a y be a c o n s e q u e n c e of malignant t r a n s f o r m a t i o n of EBV-infected lymphocytes.44° In a s t udy by Moore et al.,2aa p e r i p h eral NHL o c c u r r e d m o r e f r equent l y am ong patients with oral hairy leukoplakia, a n o t h e r EBV-associated lesion, suggesting that EBV coinfection m a y influence d e v e l o p m e n t of NHL o u t s i d e the central nervous system as well. O t h e r factors apparently associated w i t h an increased risk of d e v e l o p m e n t of NHL among HIV-infected patients in that study i n c l u d e d previous KS and CMV infection, z3a Prolonged zidovudine use did n o t a p p e a r to be associated with the o c c u r r e n c e of NHL; the a p p a r e n t increase in incidence was p r o b a b l y d u e to prolonged survival related to z i d o v u d i n e use and o t h e r cofactors. The clinical p r e s e n t a t i o n of NHL d e p e n d s on t he site of involvement. Central n e r v o u s s ys t e m localization remains a c o m m o n prim ar y site.233' 363 365,441 S y m p t o m s of headache, focal neurologic deficits, an d seizures p r e d o m i n a t e . A single, space-occupyi ng m ass is the most frequent finding o n brain imaging studies. Without histologic confirmation, s u c h lesions are difficult to distinguish from 748

DM, October 1992

o t h e r mass lesions caus e d by oppor t uni s t i c infections such as toxoplasmosis, progressive multifocal l e u k o e n c e p h a l o p a t h y , or central n e r v o u s s y s tem tuberculosis. Involvement of l y m p h o i d tissue outside t h e central nervous system has b e c o m e increasingly m ore common. Gastrointestinal mass lesions, splenic disease, bone m a r r o w infiltration, a n d pe r i pher a l nodal disease m a y p r o d u c e diarrhea, abd o m i n a l pain, weight loss, splenomegaly, p a n c y t o p e n i a , and enlarging n o d al masses, respectively. Rarely, intraoral or other m u c o c u t a n e o u s enlarging ulcers have b e e n an initial manifestation of NHL in this population. Systemic, or "B," s y m p t o m s with fever and weight loss are frequent. Laboratory abnormalities reflect the site(s) of involvement; anemia or p a n c y t o p e n i a a n d elevated serunl lactate d e h y d r o g e n a s e levels are c o m m o n a m o n g those with bone m arrow infiltration or high t u m o r burden. The definitive diagnosis of NHL, as with m a n y ot her HIV-related disorders, requires biopsy a n d histologic e x a m i n a t i o n of involved tissue. Histologically, these are often high-grade, immunoblastic or large B-cell, aggressive tumors. The diagnosis of p r i m a r y central nervous system NHL m a y be difficult in that lesions m a y notvbe immediately accessible to biopsy pr ocedur e s . A practical m a n a g e m e n t s c h e m a for clinically stable patients m a y be to treat empirically for toxoplasmosis or for ot her opportunistic infections if adjunctive data s u p p o r t s u ch alternative diagnoses, for 2 to 4 weeks, followed by rep eat brain imaging. If the lesion(s) increases or n e w lesions are seen at the e n d of this period, the need for b i o p s y is m o r e imperative. Appropriate t h e r a p y for NHL require~ radiation, cytotoxic chemotherapy, or t h e combination of both. C ons u l t at i on with an oncologist is r e c o m m e n d e d . The choice of agents, doses used, a n d duration of t h e r a p y d e p e n d s on the t u m o r type, site of involvement, and underlying host factors. Combinations of m e t h o t r e x a t e , adriamycin, cyclop h o s p h a m i d e , vincristine, prednisone, a n d b l e o m y c i n (MACOP-B) a n d of c y c l o p h o s p h a m i d e , vincristine, m e t h o t r e x a t e , etoposide, and cytarabine (COMET-A), as well as o t h e r s t a n d a r d c h e m o t h e r a p e u t i c regimens, have been associated with favorable initial r e s p o n s e rates. T h e durability of responses and the influence of t h e r a p y on overall survival r emain arguable. 363-3~5 For pat i ent s with advanced HW disease, the durability of the t u m o r r e s p o n s e a p p e a r s to be short-lived, a n d p o o r m a r r o w reserve often limits the tolerability of therapy.

Other Neoplastic Diseases Oth er malignancies that are r e p o r t e d a m o n g pat i ent s with HIV infection include EBV-associated Burkitt's l y m p h o m a ; malignant melanoma; p e r i p h e r a l T-cell lymphoma; c a r c i n o m a of the anus, rectum, cervix, or genital tract, presumably related in p a r t to concom i t ant HPV or to o t h e r sexually transmitted cofactors; and Hodgkin's DM, O c t o b e r 1992

749

disease.a67-a70, 442-446 B u r k i t t ' s l y m p h o m a , m a l i g n a n t m e l a n o m a , a n d T-cell l y m p h o m a s are r a r e n e o p l a s m s a m o n g H I V - i n f e c t e d i n d i v i d u a l s a n d will n o t b e f u r t h e r c h a r a c t e r i z e d h e r e . T h e c l i n i c a l m a n ifestations, d i a g n o s i s , a n d t r e a t m e n t of c a r c i n o m a a s s o c i a t e d w i t h HPV h a v e b e e n t o u c h e d o n in e a r l i e r s e c t i o n s . M a l i g n a n c i e s of t h e a n a l o r genital t r a c t f o r t u n a t e l y r e m a i n relatively u n c o m m o n , w i t h t h e p o s s i b l e e x c e p t i o n of c e r v i c a l d y s p l a s i a a n d i n t r a e p i t h e l i a l n e o p l a s i a a m o n g H I V - i n f e c t e d w o m e n . 36s-37° W h e n s u c h m a l i g n a n c i e s d o o c c u r , t h e y o f t e n n e c e s s i t a t e c o m b i n e d m o d a l i t y t h e r a p i e s , inc l u d i n g ablative, s u r g i c a l , a n d / o r s y s t e m i c c h e m o t h e r a p e u t i c i n t e r v e n t i o n , d e p e n d i n g o n t h e site, t u m o r type, a n d h o s t f a c t o r s . W h e t h e r H o d g k i n ' s d i s e a s e is s e e n m o r e f r e q u e n t l y a m o n g HIVi n f e c t e d i n d i v i d u a l s r e m a i n s c o n t r o v e r s i a l . 446 A m o n g H I V - i n f e c t e d p e r s o n s in w h o m H o d g k i n ' s d i s e a s e d e v e l o p s , t h e c l i n i c a l p r e s e n t a t i o n a p p e a r s to b e o n e of a d v a n c e d n e o p l a s t i c d i s e a s e , m i x e d c e l l u l a r i t y h i s t o l o g i c a l l y , a f a v o r a b l e initial c l i n i c a l a n d t u m o r r e s p o n s e to c o m b i n a t i o n c h e m o t h e r a p y w i t h p o o r d u r a b i l i t y a n d o v e r a l l survival, a n d a t e n d e n c y t o o c c u r in a g e r a n g e s o u t s i d e t h o s e m o s t f r e q u e n t l y a s s o c i a t e d w i t h H o d g k i n ' s d i s e a s e in u n i n f e c t e d p e r s o n s . 446 REFERENCES*

206. DeVita VT Jr, Broder S, Fauci AS, et al: Developmental therapeutics and the acquired immunodeficiency syndrome. Ann Intern Med 1987; 106'.568-581. 207. McQuade TJ, Tomasselli AG, Lin L, et al: A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-1 like particle maturation. Science 1990; 247:454-456. 208. Pottage JC, Farrington K, Spear G, et al: Comparative in vitro anti-HIV activity of four new aminosugar derivatives, in 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington DC, American Society for Microbiology, 1990, abstract 506, p 185. 209. Yarchoan R, Mitsuya H, Myers CE, Broder S: Clinical pharmacology of 3'azido-2',3'-dideoxythymidine (zidovudine) and related didoxynucleotides. N Engl J Med 1989; 321:726-738. 210. Broder S, Mitsuya H, Yarchoan R, Pavlakis GN: Antiretroviral therapy in AIDS. Ann Intern Med 1990; 113:604-618. 211. Pizzo PA, Eddy J, Falloon J, et al: Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988; 319:889- 896. 212. Yarchoan R, Weinhold KJ, Lyerly HK, et al: Administration of 3'-azido-3'deoxythymidine, an inhibitor of HTLV-III/LAVreplication, to patients with AIDS and AIDS-related complex. Lancet 1986; 1:575-580. 213. Creagh-Kirk T, Doi P, Andrews E, et al: Survival experience among patients with AIDS receiving zidovudine: Follow up of patients in a compassionate plea program. JAMA 1988; 260:3009-3015. 214. Fischl MA, Parker CB, Pettinelli C, et al: A randomized controlled trial of a *References 1 through 205 appear in Part I of this article in the September 1992 issue of Disease-a-Month. 750

DM, October 1992

215.

216.

217.

218.

219.

22~.

221.

222.

223. 224.

225.

226. 227. 228. 229. 230. 231. 232.

r e d u c e d daily d o s e of zidovudine in p a t i e n t s with t h e a c q u i r e d i m m u n o deficiency s y n d r o m e . N Engl J M e d 1990; 323:1009-1014. Collier AC, Bozzette S, C o o m b s RW, et al: A pilot s t u d y of low dose zidovud i n e in h u m a n i m m u n o d e f i c i e n c y virus infection. N Engl J M e d 1990; 323:1015-1021. M o o r e RD, Creagh-Kirk T, Kernly J, et al: L o n g - t e r m safety and efficacy of z i d o v u d i n e in patients w i t h a d v a n c e d h u m a n i m m u n o d e f i c i e n c y virus disease. A r c h I n t e r n M e d 1991; 151:981-986. M o o r e RD, Hildago J, Sugland B, C h a i s s o n RE: Z i d o v u d i n e and the natural history of t h e a c q u i r e d i m m u n o d e f i c i e n c y s y n d r o m e . N Engl J M e d 1991; 324:1412-1416. Schmitt FA, Bigley JW, McKinnis R, et al: N e u r o p s y c h o l o g i c a l o u t c o m e of z i d o v u d i n e (AZT) t r e a t m e n t of patients w i t h AIDS a n d AIDS-related complex. N Engl J M e d 1988; 319:1573-1578. Yarchoan R, Berg G, Brouwers P: R e s p o n s e of h u m a n i m m u n o d e f i c i e n c y virus-associated neurological disease to 3 ' - a z i d o - 3 ' d e o x y t h y m i d i n e . Lancet 1987; 1:132-137. Pottage JC, B e n s o n CA, Spear JB, et al: T r e a t m e n t of h u m a n i m m u n o d e f i c i e n c y virus-related t h r o m b o c y t o p e n i a w i t h z i d o v u d i n e . JAMA 1988; 260:3045 - 3048. Swiss G r o u p for Clinical Studies on A c q u i r e d I m m u n o d e f i c i e n c y S y n d r o m e (AIDS): Z i d o v u d i n e for the t r e a t m e n t of t h r o m b o c y t o p e n i a associated with h u m a n i m m u n o d e f i c i e n c y virus (HIV): A p r o s p e c t i v e study. A n n Intern M e d 1988; 109:718-721. R i c h m a n DD, Fischl MA, Grieco MH, et al: T h e toxicity of a z i d o t h y m i d i n e (AZT) in t h e t r e a t m e n t of patients w i t h AIDS a n d AIDS-related c o m p l e x (ARC): A double-blind, p l a c e b o - c o n t r o l l e d trial. N Engl J M e d 1987; 317:192-197. Spivak JL, Barnes DC, Fuchs E, Q u i n n TC: S e r u m i m m u n o r e a c t i v e el~ythropoietin in HIV infected patients. JAMA 1989; 261:3104-3107. Fischl M, Galpin JE, Levine JD: R e c o m b i n a n t h u m a n erythropoietin for patients w i t h AIDS treated with z i d o v u d i n e . N Engl J M e d 1990; 322:1488 - 1493. Walker RE, Parker RI, Kovacs J, et al: A n e m i a a n d erythropoiesis in patients w i t h the a c q u i r e d i m m u n o d e f i c i e n c y s y n d r o m e (AIDS) a n d Kaposi's sarc o m a t r e a t e d with zidovudine. A n n I n t e r M e d 1988; 108:372-376. Rachlis AR: Zidovudine (retrovir) u p d a t e . Can M e d A s s o c J 1990; 143:1177-1185. Gertner E, T h u r n JR, Williams D, et al: Z i d o v u d i n e associated myopathy. A m J M e d 1989; 86:814-818. Dalakas MC, |lla |, P e z e s h k p o u r GH, et al: M i t o c h o n d r i a l m y o p a t h y caused by l o n g - t e r m z i d o v u d i n e therapy. N Engl J M e d 1990; 322:1098-1105. Spear JD, Kessler HA, Nusinoff-Lehrman S, d e M i r a n d a P: Z i d o v u d i n e overdosage. A n n Intern M e d 1988; 109:76-77. E d w a r d s P, T u r n e r J, Gold J, C o o p e r DA: E s o p h a g e a l ulceration i n d u c e d by z i d o v u d i n e . A n n Intern M e d 1990; 112:65-66. D u b i n G, Braffman MN: Zidovudine i n d u c e d hepatotoxicity. A n n Intern M e d 1989; 110:85-86. Pluda JM, Yarchoan R, Jaffe E, et al: D e v e l o p m e n t of non-Hodgkin's lymp h o m a in a c o h o r t of patients with severe h u m a n i m m u n o d e f i c i e n c y virus (HIV) infection on long-term antiretroviral therapy. A n n Intern M e d 1990; 113:276-282.

DM, October 1992

751

233. Moore RD, Kessler H, R i c h m a n DD, et al: Non-Hodgkin's l y m p h o m a in patients with a d v a n c e d HIV infection treated with z i d o v u d i n e . JAMA 1991; 265:2208- 2211. 234. Larder BA, Darby G, R i c h m a n DD: HlV with r e d u c e d sensitivity to zidovudine (AZT) isolated d u r i n g p r o l o n g e d therapy. Science 1989; 243:17311734. 235. Richman DD, Grimes JM, Lagakos SW: Effect of stage of disease a n d d r u g dose on z i d o v u d i n e susceptibilities on isolates of h u m a n i m m u n o d e f i ciency virus. J Acquir I m m u n e Defic Syndr 1990; 3:743-746. 236. Larder BA, K e m p SD: Multiple m u t a t i o n s in HIV-1 reverse transcriptase confer high level resistance to zidovudine. Science 1989; 246:1155-1158. 237. Larder BA, C h e s e b r o B, R i c h m a n DD: Susceptibilities of z i d o v u d i n e s u s c e p tible and resistant h u m a n i m m u n o d e f i c i e n c y virus isolates to antiviral agents d e t e r m i n e d b y u s i n g a quantitative plaque r e d u c t i o n assay. Antimicrob Agents Chemother 1990; 34:436-441. 238. Yarchoan R, Pluda JM, T h o m a s RV, et al: Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related c o m p l e x . Lancet 1990; 336:526-529. 239. Lambert JS, Seidlin M, R e i c h m a n RC, et al: 2 ' , 3 ' - d i d e o x y i n o s i n e (ddI) in patients with t h e a c q u i r e d i m m u n o d e f i c i e n c y s y n d r o m e or AIDS-related c o m p l e x - - A p h a s e I trial. N Engl J Med 1990; 322:1333-1340. 240. Cooley TP, K u n c h e s LM, S a u n d e r s CA, et al: Once daily a d m i n i s t r a t i o n of 2',3'-dideoxyinosine (ddI) in patients with t h e acquired i m m u n o d e f i c i e n c y s y n d r o m e or AIDS-related c o m p l e x - - r e s u l t s of a p h a s e I trial. N Engl J Med 1990; 322:134-145. 241. Pottage JC, B e n s o n CA, Sha BE, et al: Experience w i t h d i d a n o s i n e in patients with a d v a n c e d AIDS a n d

AIDS: Part I.

Antithrombotic drugs: part II.

Religio Psycho-Medici. Part II.

Indian Medicinal Plants (Part II).

Whodunit (and why). Part II.

Standards in neurosonology. Part II.

Part II: Certain Analytical Discriminations.

Pediatric pain management (Part II).

Medicaments: aids to success in endodontics. Part 2. Clinical recommendations.

Diffuse Cystic Lung Disease. Part II.

Attachment fixation of the overdenture: part II.

From Volume to Value . . . Part II.

Bioharness(™) Multivariable Monitoring Device: Part. II: Reliability.

Overactive bladder - 18 years - Part II.

Special Issue about Natural Resources--part II.

Information systems. Part II: the medical record.

Cutaneous porphyrias part II: treatment strategies.

Polymorphic ventricular tachycardia--part II: the channelopathies.

Split cord malformation: Part II: Clinical syndrome.

Hereditary ovarian cancer. Pedigree studies, Part II.

Biosimilars in Dermatology: Current Situation (Part II).

Advancing the activity cliff concept, part II.

Eponyms in cardiothoracic radiology--part II: vascular.

Replantation and reconstructive microvascular surgery. Part II.

AIDS: Part II.

Follow Us

Suggest Documents

AIDS: Part I.

Antithrombotic drugs: part II.

Religio Psycho-Medici. Part II.

Indian Medicinal Plants (Part II).

Whodunit (and why). Part II.

Standards in neurosonology. Part II.

Part II: Certain Analytical Discriminations.

Pediatric pain management (Part II).

Medicaments: aids to success in endodontics. Part 2. Clinical recommendations.

Diffuse Cystic Lung Disease. Part II.

Attachment fixation of the overdenture: part II.

From Volume to Value . . . Part II.

Bioharness(™) Multivariable Monitoring Device: Part. II: Reliability.

Overactive bladder - 18 years - Part II.

Special Issue about Natural Resources--part II.

Information systems. Part II: the medical record.

Cutaneous porphyrias part II: treatment strategies.

Polymorphic ventricular tachycardia--part II: the channelopathies.

Split cord malformation: Part II: Clinical syndrome.

Hereditary ovarian cancer. Pedigree studies, Part II.

Biosimilars in Dermatology: Current Situation (Part II).

Advancing the activity cliff concept, part II.

Eponyms in cardiothoracic radiology--part II: vascular.

Replantation and reconstructive microvascular surgery. Part II.

AIDS: Part II.

Recommend Documents

Follow Us