Antiviral therapy of HIV infection.

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Annu. Rev. Med. 1991. 42:69-90

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ANTIVIRAL THERAPY OF

Annu. Rev. Med. 1991.42:69-90. Downloaded from www.annualreviews.org Access provided by University of Prince Edward Island on 02/07/15. For personal use only.

HIV INFECTION! Douglas D. Richman, M.D.

Departments of Pathology and Medicine. University of California, San Diego; and Infectious Diseases (1IIF), San Diego Veterans Administration Medical Center, San Diego, California 92161 KEY WORDS:

acquired immunodeficiency

syndrome,

chemotherapy, human

immunodeficiency virus, zidovudine (AZT)

ABSTRACT In only five years, antiretroviral therapy progressed from promising in vitro results with a newly recognized virus (HIV) to the standard practice of primary care applicable to hundreds of thousands of patients. With AZT (zidovudine) we have learned that we can prolong survival, reduce morbidity, and delay the progression of asymptomatic infection to disease. We have also learned that doses of AZT lower than those used in the original studies are as effective but less toxic. Additional compounds are under evaluation and more are needed to provide regimens, probably as combinations of drugs, that can be administered chronically with more efficacy, less toxicity, and diminished likelihood to select for drug-resistant virus. INTRODUCTION

In only five years, antiretroviral chemotherapy progressed from promising in vitro results with a newly recognized virus to the standard practice of primary care applicable to hundreds of thousands of patients. This remarkable progress resulted from several systematic, multicenter clinical investigations of zidovudine (3'-azido, 3'-deoxythymidine, AZT), the first useful and licensed antiretroviral drug. This review concentrates on AZT I

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because it has rapidly become a part of the standard of practice of primary care for large numbers of individuals and because it has taught us lessons about the chemotherapy of human immunodeficiency virus (HIV) infec tion that will be generally applicable. Other promising candidate drugs, which we hope will improve the real but limited progress already made with AZT, are then reviewed, with coverage limited to compounds already administered to humans or soon scheduled for phase I study. AZT

In Vitro

AZT is a dideoxynucleoside analogue of thymidine in which the 3' hydroxyl (-OH) is replaced by an azido (-N 3) group. The cellular pharma cology, mechanism of action, and toxicology of AZT have been reviewed in detail (1, 2). Briefly, cellular thymidine kinase converts AZT into its 5' monophosphate (3). Cellular thymidylate kinase then converts the mono phosphate into the diphosphate, which is further converted by cellular enzymes to the triphosphate (AZT-TP) (3). AZT-TP, as an analogue of thymidine triphosphate, inhibits the reverse transcriptase of human immunodeficiency virus type I (HI V-I) and other lentiviruses (4). The mechanism by which AZT-TP inhibits viral replication has not been precisely delineated. Two mechanisms have been proposed: (a) the competitive inhibition of reverse transcriptase, and (b) the termination of viral DNA chain elongation mediated by the prevention of 3'-5' phos phodiester bond formation (3, 5). Mitsuya et al (4) first demonstrated inhibition of replication of HIV-1 in cell lines and peripheral blood mono nuclear cells at concentrations of < I ,uM that were 100�fold lower than those that produced cellular toxicity (I). This selectivity has been attributed to the lower susceptibilities of cellular DNA polymerase IY. and f3 to AZT TP than the viral polymerase (5). Phase I

AZT was first administered to patients in 1985, within only six months of the demonstration of its efficacy in vitro. In a phase I dose escalation study in 19 adults with severe HIV infection, AZT was rapidly absorbed from the gastrointestinal tract, with mean peak serum levels attained at approxi mately one hour (6). Approximately 60% of ingested drug is bioavailable because of first-passage glucuronidation by the liver (7). This glucuron idated metabolite has no apparent toxicity or antiviral activity and like AZT is excreted almost exclusively by the kidneys with a half-life of approximately one hour. The mean peak concentration in an adult admin istered 100 mg is approximately 1-3 ,uM. In patients with impaired renal

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function, the half-life of AZT is only slightly prolonged because of rapid hepatic glucuronidation (7a). The glucuronide of AZT (GAZT) does accumulate in patients with reduced creatinine clearance (7a). The toxicity of chronically elevated levels of GAZT is unknown. AZT penetrates well into the CSF, with CSF-to-plasma ratios of 50-100% at least four hours after the first dose (7).


Efficacy Based upon these pharmacokinetic data and the encouraging observations in the original phase I study subjects, a phase II randomized, double-blind, placebo-controlled study was initiated: 282 patients either with a first episode of Pneumocystis carinii pneumonia diagnosed within 120 days or with advanced AIDS-related complex were randomly assigned to receive either placebo or 250 mg of AZT by mouth every four hours (8). The study was terminated prematurely after a median duration on study of only 16 weeks because 19 placebo recipients and only one AZT recipient had died (P < 0.001). In addition to prolonging survival, AZT therapy reduced the frequency and severity of opportunistic infections, improved body weight, prevented deterioration of Karnofsky performance score, increased peri pheral CD4 lymphocyte counts, and reversed skin test anergy in many patients. Of note, the rates of opportunistic infections in the AZT and placebo groups did not begin to diverge until after 6 to 8 weeks of therapy. The drug did not reduce the isolation rates of HIV from peripheral blood mononuclear cells; however, viral p24 antigenemia as measured by ELISA was significantly reduced by AZT therapy (8). The administration of AZT has been associated with the anecdotal reports of significant neurological improvement (9, 10). These observations are supported by the analysis of the neuropsychological assessments of the subjects participating in the placebo-controlled study (11). AZT partially reversed and delayed further deterioration of cognitive dysfunction, utiliz ing tests of memory and attention, for example. No improvement was seen in measures of affective symptoms. Thrombocytopenia may be another specific complication of HIV infec tion to respond to the administration of AZT. Although AZT is toxic to cells of the erythroid and granulocytic series slight mean increases were observed in platelet counts in the phase II study (12). Several case reports have appeared describing significant improvements of thrombocytopenia associated with the administration of AZT (13, 14). A prospective, placebo controlled, blinded crossover study of 10 patients with severe thrombo cytopenia documented an impressive impact of AZT on this condition (15). Neither the mechanism of the thrombocytopenia nor how AZT reverses it has been elucidated.

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Toxicity

Although significant clinical benefit has been documented with AZT, seri ous adverse clinical reactions also occur, particularly bone marrow sup pression (12). In the phase II, placebo-controlled trial, nausea, myalgia, insomnia, and severe headaches were reported more frequently by recipi ents of AZT; macrocytosis developed within weeks in most of the AZT group. Anemia with hemoglobin levels below 7.5 grams per deciliter developed in 24% of AZT recipients and 4% of placebo recipients (P < 0.001). These patients require more transfusions with packed red blood cells. Macrocytosis developed within weeks in most of the AZT group. Of note, not all patients with macrocytosis developed anemia and not all episodes of anemia were macrocytic. Erythropoietin levels tend to rise in the presence of red cell hypoplasia (16). Neutropenia ( < 500 cells per cubic millimeter) occurred in 15% of AZT recipients, as compared with 2% of placebo recipients (P < 0.001). Subjects who entered the study with low CD4 1ymphocyte counts, low serum vitamin B l2 levels, anemia, or low neutrophil counts were more likely to have hematologic side effects. Prolonged marrow failure has been associated with AZT administration (17). Although marrow toxicity with AZT is 'more likely when the under lying disease is more severe, no absolute predictors of susceptibility to toxic side effects are available (12). Moreover the underlying mechanism of marrow insufficiency in HIV infection remains obscure. An apparent increased association of hematologic toxicity with acet aminophen administration (12) is not based upon a pharmacokinetic inter action and may not hold up with further scrutiny (18). No other drug interactions were noted in the phase II study (12). The serum half-life of AZT can be prolonged by administering probenecid (19, 20). Ganciclovir (DHPG) has significant additive toxicity with AZT on granulocytes to the extent that the two drugs usually cannot be safely co-administered at standard doses (21). This toxicity cannot be accounted for by phar macokinetic interaction; neither drug affects the excretion of the other (21). A myositis-like syndrome-characterized by parathesias, myaglias, muscle edema, muscle wasting, and elevations of serum lactate dehydro genase and creatine phosphokinase levels-has also been associated with prolonged AZT administration (22). This myopathy, which is often diffi cult to distinguish from HIV-associated myopathy, appears to result from mitochondrial toxicity (23). The monitoring of the phase II study patients suggested continued benefit with prolonged therapy (24). Survival rates of patients treated with AZT were higher than might have been expected from previous experience with similar patients. Patients continued to experience episodes of oppor-


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tunistic infections; however,these infections were either of decreased sever ity or were more responsive to conventional therapy. Hematologic toxicities continued to be the major laboratory abnormality associa ted with drug administration; however, new or more frequent toxicity was not observed with more prolonged therapy (24). Progressive bone marrow suppression did not appear to be associated with prolonged administration.

Use for Earlier Stages of Infection and Lower Dose Epidemiologic data suggest that the widespread administration of AZT to certain populations in the United States in 1986 and 1987 was associated with a discernible improvement in survival rates in these populations (25). The encouraging epidemiologic data regarding the survival benefits of the use of AZT coincided with the availability of the results of three large multicentered trials of the AIDS Clinical Treatment Groups (ACTG) of the National Institute of Allergy and Infectious Diseases. These studies have yielded data with important implications, not only for the use of AZT but for antiretroviral chemotherapy in general. Two important impli cations involve the application of therapy to patients with HIV infection before significant disease develops and the principle that efficacy does not i continue to accrue as the dose of drugs is escalated. ACTG study 016 demonstrated that patients with 200 to 500 CD4 lymphocytes and one or two symptoms of AIDS-related complex were less likely to experience disease progression if they were administered the originally licensed dose of 200 mg orally every four hours than if they were given a placebo (26). The probability of disease progression in the placebo recipients was inversely related to the CD4 T-lymphocyte count at entry into the study. In the subjects with more than 500 CD4 cells the prob ability of progression during the two-year observation period was so small that no benefit of therapy could be discerned. In the subjects with fewer than 500 CD4 cells, however, the risk of progression was reduced by just over 50% regardless of the probability of progression at entry based upon such predictors of risk as CD4 cell count, symptoms, or HIV p24 antigenemia. Serious anemia and neutropenia occurred in 5% and 4% of AZT recipi ents respectively. These levels of toxicity were significantly lower than those described in subjects with more advanced stages of infection, an indication that underlying HIV disease diminishes the margin of tolerance for many drug toxicities. ACTG study 019 was conducted in asymptomatic subjects seropositive for HIV (27). This study reinforced the conclusions that AZT delayed the


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progression of disease with acceptable levels of toxicity in patients infected with HIV infection and fewer than 500 CD4 1ymphocytes. No benefit was discernible in the population with more than 500 CD4 lymphocytes for the almost two years of observation, and that component of the study is continuing. ACTG study 019 also examined the issue of drug dose. Subjects were randomized to a placebo arm, a high dose AZT arm of 300 mg orally every four hours while awake (equivalent to the total daily dose of 1500 mg in the original phase II study), or a low dose of 100 mg five times daily. The subjects in both the high and low dose arms experienced rates of progression that were reduced compared to the placebo recipients, an outcome mirroring the benefits observed in the ACTG 016 study. The hematologic toxicity of the low dose (500 mg daily) was barely higher than that seen in the placebo recipients, while the toxicity of the higher dose resembled that seen with the 1200 mg dose in the ACTG 016 study. Two major conclusions were thus generated by ACTG study 019. First, AZT can delay the progression to disease in asymptomatic patients with fewer than 500 CD4 cells. Second, toxicity, but not benefit, increases with increas ing daily dose of AZT. ACTG study 002 reinforced these conclusions regarding dose in patients

with AIDS (28). A total of 524 patients who had experienced one episode of Pneumocystis carinii pneumonia were randomized to either 250 mg orally every four hours or 200 mg every four hours for one month followed by 100 mg every four hours. The recipients of the lower dose fared at least as well with less toxicity than the recipients of the higher dose, which resembled the regimen in the original phase II placebo-controlled study. ACTG studies 002 and 019 thus indicate that the chemotherapy of HIV might not reflect the same paradigm developed for oncologic chemo therapy, in which benefit is thought to accrue until the maximally tolerated dose is approached. Both ACTG 002 and 019 revealed that AZT has been administered in doses that were too high and that less toxicity and perhaps longer and more sustained therapy will bc possible in the future with little if any loss of efficacy, with only 500 to 600 mg daily. This lower dosage will also benefit combination drug regimens. Toxicity Management

Although suppression of p24 antigcncmia has not been proven to correlate with clinical outcome, the return of p24 antigenemia within a week or two of significant reduction or withdrawal of AZT therapy would argue that AZT should be conceived of as a suppressive regimen (29). This problem raises the issue of the proper management of drug toxicity. Adverse reac tions, including nausea, insomnia, and headaches, occur in many patients taking AZT. Most endure these symptoms because of the potential benefit



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and find that the reactions subside with time. Occasionally a patient will find the symptoms intolerable and elect to discontinue. The management of hematologic toxicity is a more frequent problem. Many physicians treat anemia alone with packed red blood cell trans fusions while maintaining the therapy with AZT. In the future much anemia may be ameliorated, but not resolved, with erythropoietin therapy (30). Some patients can be sustained in this manner for long periods; for others anemia is the harbinger of granulocytopenia. If transfusions or erythropoietin are required, dose reduction to 100 mg every eight hours is indicated. Granulocytopenia requires dose reduction. Once again, there are no data to argue a best method for dose reduction. The magnitude of fall from baseline and the rate of fall influencc modification. One guideline is to reduce the dose to 100 mg every eight hours if the neutrophil count falls below 800 cells/mm 3 and to discontinue the drug at 400 to 500 neutrophils. If a patient requires withdrawal of AZT on two or three occasions then the potential harm, effort, and cost of further attempts to administer AZT should be avoided. Similarly, if the patient develops a serious opportunistic infection for which the treatment can improve the quality and duration of life (for example, ganciclovir for serious CMV retinitis or pyrimethamine for toxoplasmosis), then AZT should be discontinued rather than delay or interfere with indicated treatment. The need for alternative therapies is made urgently apparent by the patient intolerant of AZT.

Resistance The emergence of AZT resistance in patients with AIDS or AIDS-related complex (ARC) raises new considerations in the use of the drug and for the design of new drug regimens (31). Little variation in AZT sensitivity was seen in isolates from patients never treated with AZT. No reduction in sensitivity was documented during the first six months of treatment. After six months, most isolates replicate in the presence of higher con centrations of AZT. Many isolates show more than 100-fold increases in resistance and replicate at drug concentrations not attainable with normal doses of drug. Mutations in four amino acid residues of the reverse trans criptase gene of HIV have to date been associated with AZT resistance, and the progressive accumulation of mutations is associated with the stepwise increase in degrees of resistance (32). Although the emergence of resistance has not yet been demonstrated to be linked to diminished drug efficacy, this is a reasonable concern (33). It is encouraging that AZT-resistant isolates retain their susceptibilities to most other agents. To date, only nucleosides with 3' -azido moieties, for example, 3'-azido, 3'-deoxyuridine (AZdU) and 3'-azido, 3'-deoxyguano-


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sine, have been shown to have diminished inhibitory activity against AZT resistant isolates. Cross-resistance has not yet been observed to other nucleosides and compounds of other classes with antiretroviral activity (34). The study of isolates from patients on prolonged AZT therapy was extended to subjects at earlier stages of disease, specifically subjects for ACTa studies 016 and 019. Such patients developed resistance at sig nificantly slower rates than occur in patients with AIDS or advanced AIDS-related complex (35). The likelihood that resistant virus will emerge under the selective pressure of prolonged therapy increases as the CD4 lymphocyte count falls. The emergence of resistance is a function of mutation rate and replication rate. It is becoming increasingly apparent that the level of virus replication ("virus load") increases as the immune status diminishes (36, 37). It is also encouraging that the lower dose regimens utilized in ACTa studies 002 and 019 did not select for resistant virus more readily than the higher dose regimens (35). The likelihood that resistance will develop after one year of therapy in a patient with AIDS or advanced ARC is 90%. In contrast, isolates from a patient with 200 to 500 CD4 lymphocytes and few or no symptoms show a 30% likelihood of measurably diminished susceptibility to AZT. The clinical significance of drug resistance may depend upon the quantitative reduction of sensitivity. If greater than a 100-fold reduction in sus ceptibility to AZT is looked for, it is found within 12 months for one third of the isolates from the higher risk patients, but it has not yet been detected within that period in the lower risk patients (35). OTHER NUCLEOSIDES

AZT has changed the natural history of HIV infection and its study has established several valuable principles for antiretroviral drug development and use. Nevertheless, AZT intolerance, suboptimal efficacy as demon strated by the inability of the drug to sterilize the blood or to prevent progression of disease, and the emergence of resistance calling for com bination chemotherapy all point to the need for additional and better drugs. Many other dideoxynucleoside analogues with antiretroviral activity have been described (1, 2). Dideoxycytosine (ddC) and dideoxy inosine (ddI) are in multicenter phase II efficacy trials and are the most likely compounds to join AZT as approved drugs in the near future. Dideoxycytosine

In phase I studies, dideoxycytosine (ddC) decreased circulating p24 anti genemia and induced elevations of CD4 cell counts similar to those seen


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with AZT (38, 39). The development of the drug has been delayed, however, by the need to identify a dosing regimen with suitably low rates of peripheral neuropathy. Single-dose pharmacokinetics have been reported with doses spanning the current oral dose of 0.75 mg every 8 hours (39a). The peak concentration of ddC was roughly proportional to the administered dose and a peak concentration of 0.5 ,uM was observed after a I -hour infusion of 0.06 mg/kg. The plasma half-life was approxi mately 1-2 hours, with renal clearance accounting for drug elimination. Oral bioavailability was 70-80%. Concentrations of drug in the cere brospinal fluid were 9-37% of the concurrent plasma levels 2-3.5 hours after an intravenous infusion (38). No evidence of metabolism of ddC has been noted. At relatively high doses it produced a moderate dermatitis and mucositis in the first few weeks of therapy and, more importantly, a severe peripheral neuropathy in the second or third month of therapy (38). A study with a larger dose range documented that, at 0.06 and 0.03 mg/kg orally every four hours, a diffuse erythematous rash and aphthous stomatitis occurred in the first weeks on drug but these symptoms resolved without interruption of therapy (39). Hematologic toxicity was notably rare. Peripheral sensory neuropathy occurred in all patients at these doses, between the 4th and 14th week; it improved slowly in most patients after discontinuation of ddC, with ARC patients tending to show a greater reduction than AIDS patients. Serum p24 antigen fell and CD4 cell numbers rose in most patients during therapy. At dose levels of 0.01 and 0.005 mg/kg orally every four hours, skin rash and aphthous stomatitis were mild or absent. Peripheral neuropathy occurred by week 12-14 in all patients receiving 0.01 mg/kg orally every four hours. The regimen of 0.01 mg/kg every eight hours appeared to provide the best balance of impact on p24 antigen and CD4 cell counts with the least toxicity, and this regimen is being evaluated in the phase II studies (40). Because ddC and AZT have relatively nonoverlapping toxicity profiles, alternating regimens of AZT and ddC were evaluated in a pilot study (38) and in larger systematic studies for use both as primary antiretroviral therapy (41) and for patients intolerant to AZT alone (42). In addition, combination regimens of AZT and ddC arc under study to assess the possibilities of increased efficacy, reduced toxicity, and delayed emergence of drug resistance (43). Dideoxyinosine

Dideoxyinosine (ddI) has been evaluated in several phase I trials (44-46). Because ddI is subject to acid-mediated hydrolysis of the glycosidic bond, it must be administered with a buffer to attain 20-50% oral bioavailability.


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The plasma half-life of ddI is 1 to 2 hours; however, the half-life of the antivirally active, intracellular compound dideoxyadenosine triphosphate is 12-24 hours (47). The phase I studies thus evaluated the drug in once or twice-daily regimens. Regimens of 375 to 750 mg orally twice daily produced relatively low levels of toxicity and encouraging responses in CD4 cell counts and p24 antigenemia. Higher doses of ddI were associated with unacceptably high frequencies of pancreatitis and peripheral neuropathy. This dose range is being utilized in three ACTG phase II studies, as well as in a large expanded distribution program by the pharmaceutical sponsor. CANDIDATE NONNUCLEOSIDE DRUGS

A large number of compounds have been proposed for the therapy of HIV. Many proved unsuccessful when evaluated systematically. These include suramin (48-51), HPA-23 (52-54a), AL 721 (55), ansamycin (rifa butin) (56, 57), fusidic acid (58-60), and dextran sulfate (61 64). A number of lessons have been relearned with these compounds. For example, pharmacokinetic studies showing that dex tran sulfate is not orally bioavail able (65) would have rendered the need for difficult and expensive phase II studies unnecessary (66). Systematic data regarding other highly touted compounds, like ribavirin (67, 68), peptide T (69-71), and compound Q, GLQ 223 (72), have not been published. Nevertheless, a large number of other candidate compounds with promising potency and selectivity in vitro are becoming available for clinical study.

Recombinant CD4 The first step in the interaction of HIV and the host cell is binding of the virion glycoprotein gp120 and the host cell receptor CD4. CD4 is a glycoprotein with a hydrophobic, membrane-anchoring amino acid sequence at the carboxy terminus and a gp120 binding side at the amino terminus (73-75). The construction by recombinant DNA technology of expression vectors that encode and express a CD4 polypeptide truncated between these two sites results in a soluble secreted polypeptide that inhibits HIV-l infectivity at approximately 10 Itg/ml (76-80). Phase I studies of two different preparations of recombinant soluble CD4 have been completed (81, 82). Although remarkably free from toxicity, these preparations also have not produced a convincing effect on surrogate markers like p24 antigenemia or CD4 lymphocyte counts. The highest serum concentrations attained just approach the levels that inhibit HIV replication in vitro. Another possible explanation for lack of dis cernible activity in the phase I study is the observation that clinical isolates


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of HIV may be 10- to 100-fold less susceptible to inhibition by soluble CD4 in vitro than are the laboratory strains like HTLV-IIIB and LAV-I originally used to assess these products (82a). At any rate, the adminis tration of larger amounts of soluble CD4 will probably not be practical. The only remaining promise for these compounds is that they might display synergy in vivo with AZT, for example, as they do in vitro (83). A chimeric molecule containing the amino terminal binding site of CD4 and the Fc end of IgG heavy chain appears to retain the gp120 affinity of the former and the prolonged serum half-life and several other charac teristics of the latter (84, 8S). A similar approach utilizing the Fc portion of IgM to yield a pentameric molecule has also been generated (86). Phase I clinical studies of the CD4-IgG molecule, both alone and in combination with AZT, were initiated in 1990. If surrogate markers of efficacy were to be favorably affected, this molecule would hold promise because high serum levels could be attained with once- or twice-weekly parenteral administration. Nonnucleoside Reverse Transcriptase Inhibitors

Reverse transcriptase inhibitors that are not nucleosides have been identi fied with sufficient potencies and selectivity in vitro to hold promise as candidate compounds. Tetrahydro-imidazol[4,S l -jk] [1,4]-benzodiazepin2(1H)-one and -thione (TIBO) is a benzodiazapine derivative that inhibits HIV-l and its transcriptase but not HIV-2 (87). These compounds are probably allosteric inhibitors of the enzyme that do not bind in the nucleo side or pyrophosphate binding sites. One or more compounds of this class are expected to enter phase I trials in 1990. Foscarnet (phosphonoformate, PFA) is a pyrophosphatc analogue that inhibits directly a broad range of DNA polymerases and to a certain extent influenza virus RNA polymerase (88). The compound has been most extensively examined for use for herpesvirus infections. Foscarnet was shown to inhibit the reverse transcriptase activity of all animal retroviruses examined with cell-free assays (89). One of the first retroviruses shown to be inhibited in culture by foscarnet was the sheep lentivirus, visna (90). The drug inhibits the replication of HIV-l in several assay systems at concentrations of 100 J-lM or less, levels that are readily attainable clinically (91, 92). Studies of foscarnet in patients with AIDS suggest that this drug, like AZT and ddC, may have antiretroviral activity as measured by suppression of p24 antigenemia (93-9S), but it does not reduce the ability to isolate virus from peripheral blood cells by culture (94). Foscarnet has been administered at 120 to 180 mg per day divided into two or three l-2-hour infusions for up to four weeks or as a continuous infusion at O.lS mg/kg/min for up to 21 days. The clinical experience in


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patients infected with HIV suggests the drug is relatively well tolerated; however, reversible renal dysfunction, thrombophlebitis at the infusion site, headaches, and anemia are associated with administration of foscarnet (93, 94). Further evaluation of this compound is warranted; however, it is not orally bioavailable, and must be administered intravenously, which limits its utility. Foscarnet is poorly soluble, and large doses are required because of its relatively low potency (96). Systemic therapy thus requires large doses of intravenous solution. Because of the great inconvenience of administration and the side effects of foscarnet, it will probably be of little use in the therapy of HIV, but it may find a role as a secondary drug for CMV disease. Tat Inhibitors

The tat gene (trans activator of transcription) expresses one or more polypeptides essential for virus replication (97, 98). A class of compounds have been identified that inhibited a tat-dependent transcription assay in vitro and HIV replication in cell culture. A candidate drug of this class is expected to enter phase I trials in late 1990. -

Compounds that Inhibit Posttranslational Modification

Retroviral polypeptides are translated as polyproteins that are cleaved posttranslationally by a viral protease. Many proteins also undergo glyco sylation, phosphorylation, or myristoylation by host enzymes. These types of posttranslational modifications have been approached as targets of antiviral therapy. PROTEASE INHIBITORS The protease of HIV-1 and other retroviruses cleaves viral polypeptides at well-defined sites (99-104). Synthetic peptides of as few as six amino acids including pepstatin A can completely inhibit virus-specific proteolysis (105-107). Several groups have identified transi tion-state analogues of the phenylalanine-proline scissile bond, a substrate of the HIV-1 protease but not of host aspartate proteases (108-110). At least one of these compounds, which has activity in vitro at less than 1 IlM, is scheduled for phase I trials in 1990.

The inhibition of glycosylation of the en GLYCOSYLATION INHIBITORS velope glycoproteins could be expected to affect viral budding, release, binding, or penetration by fusion, all functions presumably mediated by the env products. Castanospermine is an alkaloid isolated from the seeds of an Australian chestnut tree, Castanospermum australe, that inhibits (X1,6-g1ucosidase (111). It is relatively toxic in mice (112). Several amino sugars, termed nojirimycin analogues, inhibit enzymes that trim N-linked

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glycan structures, and these compounds at concentrations of I to 10 jig/ml inhibit syncytium formation by HIV (113-115). At these concentrations glycosylation of envelope products is inhibited, which thus impairs their function (I ll, 113, 114). Whether compounds that inhibit host cell enzymes can effectively inhibit retroviral replication with acceptable toxicity in vivo remains to be determined. N-butyl-deoxynojirimycin entered phase I clinical trials in 1989.

Hypericin Hypericin and pseudohypericin are aromatic polycyclic diones extracted from the Saint Johnswort plant of the Hypericum family (116). These have antiviral activity against Friend murine leukemia virus in vitro and in vivo (116, 117). In cell culture these compounds appear both to inhibit virion maturation and to inactivate virion infectivity (117). Purified hypericin entered preclinical evaluation in early 1990 and was expected to enter phase I trials by the end of the year.

Interferons Most of the experience with interferons in patients with AIDS has been gained in open trials for the treatment of Kaposi sarcoma. These trials used recombinant interferon-a or purified interferon-a prepared from lymphoblastoid cells (118-124). Tumor regression is seen in a minority of patients, with a greater likelihood of response in patients with higher CD4 lymphocyte counts. The dose-limiting toxicities of interferon (fever, chills, weakness, fatigue, anorexia, headache, myalgias, arthralgias, leukopenia, and elevations of aminotransferase) occur in a large proportion of patients. It should be remembered that dose-limiting toxicity in oncologic practice may occur at higher doses than would be tolerated for the suppression of chronic HIV infection. The data regarding the use of interferon for the treatment of HIV infection, rather than its malignant complications, are much more limited. Interferons-a, (3, and y all inhibit the replication of HIV in vitro, both in T lymphoid cells (125-129) and in primary human macrophages (130). In addition, recombinant interferon-a synergistically inhibits HIV replication in vitro with two drugs that have antiretroviral activity in vivo, AZT (131) and foscarnet (132). A randomized, double-blind, placebo-controlled trial of recombinant human interferon-a 2a in patients with AIDS was initiated before AIDS had been recognized as a retroviral disease (133). Random ization of 67 subjects to placebo, 3 million units or 36 million units three times weekly for 12 weeks, failed to demonstrate significant differences in tolerance, laboratory endpoints (p24, CD4 cell counts), or clinical status.

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The power of this study to detect a clinically relevant difference among its various study arms was inadequate because of the small number of subjects and their heterogeneity. In more recent studies, administration of inter feron- rx did appear to reduce p24 antigenemia, improve CD4 cell counts, and produce dose-limiting toxicity (122, 123, 134-137).


Immunomodulating Compounds

A large number of biological response modifiers and "immuno modulating" compounds have been proposed for the therapy of HIV infection. Some of these are well-characterized compounds; some have been systematically evaluated in clinical trials. None has yet been shown effective. No efficacy was shown in small, open trials of cyclosporin (138), levamisole (139), thymopentin (140, 141), and transplantations of thymic tissue (142). Investigators administering transfer factor (not further characterized) or cyclosporin were encouraged by their trials, but viral markers were not tested (138,143). Lithium carbonate appeared ineffective and toxic (144). Other candidate immunomodulating compounds include AS 101 (ammonium trichloro[dioxyethylene-O,O'- ]tellurite) (145), DTC (diethyl dithiocarbamate, Imuthiol), Imreg- l , disulfiram, isoprinosine (146), thymostimulin (TP- l ) (147), and methionine-enkephalin. Critical inter pretation of thc merits of such compounds requires information about their composition and purity, well-designed systematic studies, scrutiny of the primary data, and statistical analysis. To evaluate conclusions of benefit (or the lack of it) for a disease with the impact of AIDS, this information must be available accurately and expeditiously. Reports of controlled trials of DTC and isoprinosine claimed clinical benefit but no impact on p24 antigenemia (148, 149). These studies merit confirmation. SUMMARY

A great deal has been learned in a short period of time about the chemo therapy of HIV infection. Although the accomplishments have been remarkable, the limitations of the currently available chemotherapy and the magnitude of the epidemic impart a sense of urgency to accomplish yet more at an accelerated pace. In addition to what we have learned about AZT and how to use it, other promising candidate drugs are under investigation. Such drugs will be necessary to identify combination regi mens that can be administered for prolonged periods and that will confer greater efficacy, less toxicity, and lower likelihood of selecting for drug resistant virus.


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