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Chemotherapy and immunity in opportunistic parasitic infections in AIDS A. ZUMLA 1 and S. L. CROFT 2 1

Center for Infectious Diseases, University of Texas, Health Science Center at Houston, School of Medicine and Public Health, Houston, 6431 Fannin, Texas, USA 2 Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT SUMMARY

Parasitic diseases are endemic in parts of the tropics, but there is no convincing evidence that their prevalence or incidence is increasing due to the HIV epidemic. Available scientific data on parasitic infections in patients with the Acquired Immunodeficiency Syndrome (AIDS) suggests a predominance of Pneumocystis carinii, Toxoplasma gondii and Cryptosporidium spp. For reasons which are unclear, parasitic infections such as Plasmodium falciparum, Strongyloides stercoralis and Entamoeba histolytica, where cell-mediated immune responses are also thought to be significant, do not appear to be opportunists of importance. It is being increasingly recognized that chemotherapy for parasitic diseases has a hostdependent component, although scientific data on this subject remain scanty. The management of opportunistic parasitic infections in patients infected with HIV is dogged by failures and relapses, aptly illustrating the notion of the relationship between chemotherapy and the immune response. This review discusses the immunity and chemotherapy of opportunistic parasite infections in patients infected with the Human Immunodeficiency Virus (HIV). Key words: AIDS, Blastocystis, Cryptosporidium, Entamoeba, Giardia, Isospora, Leishmania, Pneumocystis, Toxoplasma.

INTRODUCTION

In the decade of struggle against the Human Immunodeficiency Virus (HIV) several advances have been made in the diagnosis, treatment and prevention of infectious complications in AIDS patients (Gold, 1987; Harawi & O'Hara, 1990). Infections taking advantage of T-cell and B-cell defects are common in patients with HIV infection. Parasitic opportunistic infections, to which AIDS patients are susceptible, comprise only a minority of the large number of parasites capable of causing human disease. Parasites which have exploited the immunological defect in AIDS patients are listed under Table 1. It is those parasites which have an intracellular habitat that are most troublesome (Wong, 1984; Lockwood & Weber, 1989). For reasons not yet known, there is a marked geographical variation in the incidence of parasitic infections in AIDS patients. Most clinical studies have been concentrated on the three parasites which commonly infect AIDS patients in the west: Toxo-

Sarcoptes,

1991; Piper et al. 1991). However, evidence pointing to the interaction between chemotherapy and immunity in parasitic infections in AIDS patients is only indirect, arising from the clinical observations that reactivation and relapse of these infections, despite appropriate chemotherapy, correlates with decline in cell-mediated immunity. Case study reports and reviews of Leishmania spp infections in AIDS patients (Zumla, 1989; Peters et al. 1990) illustrate that immunosuppression is the underlying cause of failure of therapy and the high mortality in AIDS patients with leishmaniasis. THE

IMMUNE DEFECTS IN AIDS

Although a profound loss in cell-mediated immunity is central to the immune defect in AIDS, nearly every arm of the immune response is affected (Koenig & Fauci, 1988). The human immunodeficiency virus can infect T-helper lymphocytes, monocytes, macrophages, B-lymphocytes and CNS microglial cells via the cell-surface CD4 molecule. A plasma gondii, Pneumocystis carinii and Cryptosteady decline in cell-mediated immunity occurs as a sporidium spp. They are a major burden in the result of the progressive depletion of CD4+ lymphocytes due to a direct cytopathic effect, CD8+ Tmanagement of AIDS patients, and frequent relapses after treatment have necessitated the development of cell lysis of cells expressing viral proteins, and primary and secondary prophylaxis regimes. additional pathogenetic mechanisms which are currently being defined (Editorial, 1992). HIV infection The relationship between chemotherapy and imof monocytes or macrophages may result in chemomunity in experimental parasitic infections is increastactic defects and altered lymphokine release (Koenig ingly being denned (Brindley & Sher, 1987, 1990; & Fauci, 1988). A small percentage of B lymphocytes Doenhoeff et al. 1991; Iwobi, Doenhoff & Neal, Parasitology (1992), 10S, S93-S101 Copyright © 1992 Cambridge University Press PAR S

A. Zumla and S. L. Croft Table 1. Opportunistic parasites in AIDS patients Pneumocystis carinii Toxoplasma gondii Cryptosporidium spp. Microsporidia spp. Enterocytozoon bienusi Encephalitozoon hellem Isospora belli Leishmania infantum Strongyloides stercoralis Sarcoptes scabiei

express the CD4 antigen, and B-cell dysfunction is part of the immune dysfunction found in AIDS. It is apparent from clinical and epidemiological evidence that the immunoparesis in patients with AIDS predisposes them to infection with only a select group of parasites (Lockwood & Weber, 1989; Zumla & James, 1991) (Table 1).

Pneumocystis carinii Pneumocystis carinii pneumonia (PCP) continues to be the commonest opportunistic infection in AIDS patients in industrial countries and is consequential upon depressed cell-mediated immunity (Wofsy, 1990; Abouya et al. 1992). Untreated and with persistence of impaired immunity, PCP is invariably fatal. In Europe and the USA, PCP is the most common life-threatening opportunistic infection in AIDS patients, and it is thought that most AIDS patients in the West at some stage will develop PCP. P. carinii was the first parasite to be identified in AIDS patients. Previously it was classified as a coccidian protozoan, although on the basis of recent evidence it has been classified as an ascomycete fungus (Edman et al. 1988). The infection is most likely acquired in early life by inhalation resulting in asymptomatic infection, remaining in a latent or controlled form until immunosuppression intervenes. It is not clear whether PCP is due to reactivation of this latent infection or due to reinfection. It causes a chronic interstitial pneumonia and the alveoli become distended with a foamy, amorphous material resulting in a honeycomb of very fine-walled cystic spaces in which the parasite may be seen. The interstitial infiltrate consists of lymphocytes, eosinophils, macrophages and a large number of plasma cells. Cell-mediated immune responses appear crucial in containing P. carinii. It is probable that HIV-infected macrophages are functionally abnormal, allowing unchecked multiplication of trophozoites in the absence of helper lymphocytes. PCP is a feature of African AIDS patients treated in Europe (Katlama et al. 1984; Blaser & Cohn, 1986), but appears to be less common in Africa

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(Abouya et al. 1992) than it is in Europe and America. PCP occurs in the Caribbean and Brazil, with a similar frequency in the West (Blaser & Cohn, 1986). Since the diagnosis can be made with more certainty by invasive procedures, the lack of appropriate diagnostic facilities may partly account for some of the difference. However, several questions arise. Are the differences in geographical variation in incidence of PCP in AIDS patients due to variation in prevalence of the parasite in the environment, or are there geographically differing susceptibilities to PCP ? The introduction of the polymerase chain reaction (PCR) for detecting Pneumocystis in sputum will enable better definition of the problem. Griffin & Lucas (1982), in an experiment designed to determine the presence of P. carinii in Kenya, exposed immunosuppressed mice to the atmosphere, and five months later killed them and examined their lungs for histological evidence of PCP. The failure of the mice to contract even light infections suggested a geographically decreased prevalence of the parasite. It is possible that patients with AIDS in the tropics succumb to other more virulent infections before the degree of immunosuppression needed to permit reactivation of P. carinii is attained (Blaser & Cohn, 1986). A 'hierarchy of reactivation' of latent infections in AIDS patients may occur (Lucas, 1988); a relatively low threshold for reactivation of tuberculosis and toxoplasmosis compared to P. carinii. As cell-mediated immunity is progressively compromised, more virulent opportunistic or reactivated pathogens proliferate, and induce lesions earlier than the less virulent pathogens such as atypical mycobacteria, fungi and pneumocystis. Cohort studies of HIV-infected persons have demonstrated that the risk of PCP is low until the CD4 cell count drops below 200/mm3 or the total lymphocyte population declines to below 20% (Masur et al. 1989; Phair et al. 1990). There may also be differences in susceptibility between persons of different ethnic origins. The treatment, and primary and secondary prophylaxis, of PCP have been the subject of intense study (reviewed by Clement & Sande, 1990; Wofsy, 1990; Meduri & Stein, 1992). Widely supported regimens for the initial treatment of PCP include trimethoprim-sulphamethoxazole (TMP-SMZ), intravenous pentamidine isethionate and trimethoprimdapsone. There are no clear guidelines regarding therapy for PCP when the patient fails to respond or is intolerant of the regimes. Clindamycin and primaquine are showing promise. Trimetrexate with leucovorin rescue has been used, although rates of relapse have been high. Several other agents such as piritrexin, eflornithine and the hydroxynaphthoquinone, atovaquone (566C80) are currently under investigation. Treatment should be followed by lifelong secondary prophylaxis. Recommendations for primary PCP prophylaxis from the Centers for Disease Control (CDC, 1989) state that prophylaxis

Chemotherapy and immunity in AIDS

should be initiated in HIV-positive individuals with CD4 counts of < 200/mm3 or 20 % of total lymphocytes. TMP-SMZ, dapsone, pyrimethamine-sulphadoxine and inhaled aerosolized pentamidine have been used for PCP prophylaxis with varying degrees of success (Wofsy, 1990). Toxoplasma gondii Central Nervous System (CNS) toxoplasmosis is the most commonly recognized CNS infection in AIDS patients in the West. Toxoplasmosis is a worldwide zoonosis caused by the obligate intracellular protozoan parasite Toxoplasma gondii (reviewed by Cook, 1990; Jackson & Hutchison, 1989; Clement & Sande, 1990). The prevalence of chronic (latent) infection among adults in the USA and Europe shows a marked geographical variation, with 90 % infected in Paris and approximately 50 % in the USA (McCabe & Remington, 1988), 6% in Zambia and 34% in Uganda (Griffin & Williams, 1983; Zumla et al. 1991). Toxoplasma infections can present in a variety of ways. Although the parasite is known to have a predilection for the central nervous system in AIDS patients, it can affect the lungs, eyes, testicles, heart and gut. The infection is normally mild or asymptomatic, with the parasite persisting as encysted bradyzoites in a dormant state. Cell-mediated immunity appears to be important in containing the parasite. Immunocompetent chronically infected mice treated with monoclonal antibodies against either the cell-surface protein of CD4 T lymphocytes (Vollmer et al. 1987) or interferon-y (Susuki, Conley & Remington, 1989) developed widespread acute encephalitis similar to that observed in AIDS patients. In chronic mouse infections cyst rupture is normally rare, and followed by the formation of microglial and inflammatory nodules with macrophages engulfing released cystozoites and limiting proliferation (Ferguson, Hutchison & Petterson, 1989). Studies of monocyte-derived macrophages from patients with AIDS show a decreased ability to kill T. gondii (Eales, Moshtael & Pinching, 1989). While infection of humans by T. gondii is common, relatively few normal persons develop clinically significant disease. However, T. gondii can cause serious disease in persons with congenital infection and in the immunocompromised. It is now increasingly being recognized as an important cause of morbidity and mortality among individuals infected with HIV (Luft, Conley & Remington, 1983; Wong, 1984; Cook, 1990). In the USA and Europe, about 30 % of HIV-positive patients with positive toxoplasma serology will at some stage develop cerebral toxoplasmosis (McCabe & Remington, 1988). It may be that cerebral toxoplasmosis in AIDS patients in Africa is underdiagnosed (Lucas et al. 1988; Canning, 1990). Chronically infected asymptomatic patients harbouring T. gondii infection showing

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elevation of anti- Toxoplasma IgG antibody appear to be important risk groups for reactivation of cerebral toxoplasmosis should immunosuppression intervene. Experience from New York (Gold, 1987) shows that positive IgG serology for Toxoplasma infection is present in about 20 % of AIDS patients, of whom 30% had developed CNS toxoplasmosis. Thus the risk of reactivation of the parasite in patients seropositive for Toxoplasma in AIDS patients is extraordinarily high, and is increased in patients with CD4+ cell counts below 100/mm 3 (Luft et al. 1984). The prognosis of Toxoplasma encephalitis is poor despite treatment, and this poor outcome cannot be entirely ascribed to lack of potent anti- Toxoplasma drugs. The standard regimen of pyrimethaminesulphadiazine with folinic acid rescue is highly effective against the tachyzoites of T. gondii. These drugs act synergistically, since pyrimethamine inhibits dihydrofolate reductase while sulphadiazine inhibits dihydropteroate synthetase in the folate pathway. In AIDS patients, recurrence of the disease is invariable if the drugs are withdrawn, and lifelong secondary prophylaxis is the rule. Prolonged use of these drugs may result in a high incidence of bone marrow suppression and severe cutaneous skin reactions which preclude their use. Clindamycin, trimetrexate and spiramycin have all been used with varying degreees of success. Recently the macrolide, azithromycin, and the hydroxynaphthoquinone, atovaquone, have shown promising experimental activity (Araujo et al. 1988, 1992). As interferon-y is an important mediator in host immunity to toxoplasmosis, combination therapy of rMu IFN-y with pyrimethamine and clindamycin (Israelski & Remington, 1990), and azithromycin (Araujo & Remington, 1991) have been explored; 75 mg/kg per d azithromycin and 2 mg rMu IFN-y per d for 10 d gave mice a 40 % protection against lethal T. gondii compared to a 10% and a 0% protection afforded respectively by azithromycin or IFN-y alone. This approach indicates an attractive and logical way forward. Cryptosporidium spp. In the light of the AIDS epidemic, Cryptosporidium changed from a medical curiosity to an important and widespread enteropathogen of humans (reviewed by Current, 1989; Ma, 1990). Cryptosporidia are small (2—6 /tm) coccidian parasites which invade and replicate within the epithelial cells lining the digestive and respiratory organs of vertebrates, while also being extra-cytoplasmic. The life cycle is complex (Current, 1989; Ma, 1990), involving several stages of development. The most common clinical presentation in AIDS patients is a profuse, watery diarrhoea. Cryptosporidia are not confined to the gut in AIDS patients. Acute 7-2

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cholecystitis, sclerosing cholangitis and respiratory tract infections have been described. The immune status of the host is the major factor determining the severity and duration of infection following oral exposure to Cryptosporidium parvum oocysts. Although there is speculation that lack of IgA and IgM may lead to failure of the host to clear the parasite in gut infections (Ma, 1990), in respiratory cryptosporidiosis the organisms have been found inside macrophages (Ma et al. 1984), and cellular immune mechanisms may be of importance in their clearance. In juvenile cryptosporidiosis an antibodydependent, cell-mediated cytotoxic effect has been implicated (Laxer et al. 1990). Experimental studies have also shown the importance of T cells, as mice treated with anti-CD4, anti-CD8 or anti-IFN-y monoclonal antibodies develop more severe infections (Ungar et al. 1991). There is currently no effective therapy for human cryptosporidiosis. To date, over 80 different treatments have been tried unsuccessfully against this parasite in immunosuppressed individuals. No controlled studies have been published, and all therapeutic information is based on isolated reports (Blanshard, 1992). Since effective therapy is not available, it is not possible to discuss drug-immune interaction. However, immunological intervention may be an important approach to the control of cryptosporidiosis. In a study of 8 AIDS patients with prolonged cryptosporidiosis, a marked improvement in gut symptoms in 5 patients followed the oral administration of a dialysed extract prepared from the lymph node cells of calves immune to C. parvum (Louie et al. 1987). In another study 6 out of 7 patients showed clinical improvement compared with only 1 out of 7 treated with leucocyte extract from non-immune calves (Saxon & Weinstein, 1987). A second approach has developed from observations that antibodies in colostrum reduce cryptosporidiosis in breast-fed infants. Hyperimmune colostrum from cows vaccinated with cryptosporidial antigen has been used to treat immunosuppressed and AIDS patients (Saxon & Weinstein, 1987; Ungar et al. 1990). Treatment of patients with IL-2 had limited success (Connolly et al. 1989).

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helium in the epithelial cells of the cornea (Canning & Hollister, 1991). E. bienusi appears to be found only in humans and is the most important of the microsporidia in AIDS cases, infecting and disrupting enterocytes and probably causing 30% of diarrhoea in patients where no other cause was diagnosed (Cali & Owen, 1990; Orenstein et al. 1990). Little is known about the immune response to microsporidia, although antibody responses to E. cuniculi have been reported and used in serodiagnosis (Hollister & Canning, 1987). There is no established treatment for microsporidial infections in humans. Six E. bienusi/HIV-infected men responded to treatment with albendazole (Blanshard et al. 1992), and itraconazole cured a case of E. helium (Yee et al. 1991). A marked reduction in diarrhoea occurred within 2d in 10 out of 13 patients with microsporidiosis treated with metronidazole (Eeftinck Schattenkerk et al. 1991). The improvement in symptoms was not associated with a parasitological cure. Isospora belli Only one species of Isospora, Isospora belli, is pathogenic for man. With the advent of the AIDS epidemic, /. belli has been increasingly diagnosed (Ma, 1990). It causes diarrhoea and malabsorption similar to cryptosporidium, and chronic infection lasts for years. The human immune responses to /. belli have not yet been defined. Unlike cryptosporidium, Isospora responds to antimicrobial treatment. Immunocompetent patients usually respond well to anti-Isospora treatment, and quinacrine, metronidazole and pyrimethamine-sulphadiazine have been used successfully. Trimethoprim-sulphamethoxazole 4 times daily for 10 d given to 15 Haitian patients with AIDS resulted in cessation of diarrhoea within two days (DeHovitz et al. 1986). However, recurrence of infection after initial clearance following treatment of Isospora belli in AIDS patients is frequent. Suppression after therapy has been achieved with either trimethoprim-sulphamethoxazole (160mg/800mg 3 times weekly) or with 500 mg sulphadoxine and 25 mg pyrimethamine weekly.

Microsporidia spp. Microsporidia are obligate intracellular protozoa that have been widely described in invertebrates and vertebrates. Transmission is by spores, and host cell invasion is characterized by the polar filament, which is used to inject parasite sporoplasm into the host cell. Parasites of four genera have been identified in humans (Cali, 1991), of which only three species from two genera have been clearly diagnosed in AIDS patients: Encephalitozoon cuniculi, known to invade many cell types; Enterocytozoon bienusi in the enterocytes of the intestine; and Encephalitozoon

Leishmania spp. Although leishmaniasis has a worldwide distribution, with annual figures of 100000 for visceral leishmaniasis (VL) and 300000 for cutaneous leishmaniasis (CL) (Ashford, Desjeux & de Raadt, 1992), the majority of cases of double infections of leishmaniasis and HIV so far reported have been VL/HIV-1 from Spain, Italy and France. In this context it must be noted that the Mediterranean basin, along with Brazil and Kenya, is an endemic area for VL where it is estimated that subclinical

Chemotherapy and immunity in AIDS

cases outnumber clinical cases by 5:1 and that VL may be an opportunistic infection (WHO, 1990). Also, leishmaniasis is primarily a zoonotic disease found in rural areas, whereas HIV/AIDS is concentrated in urban areas. In immunocompetent patients, acute visceral leishmaniasis is characterized by hepatosplenomegaly, thrombocytopenia, anaemia, a rise in y-globulin, a specific suppression of the T-cell response to leishmania antigen (Ho et al. 1983) and a reduced production of IL-2 and IFN-y (Carvalho et al. 1985). The immunopathological picture in VL/HIV double infections is different, and reviews of over 60 cases, predominantly from the Mediterranean, have described varying degrees of depression of the CD4:CD8 ratio, a reduction in anti-leishmanial antibodies (34% of cases compared to 95 % of immunocompetent cases) and dissemination of parasites to the skin, lung and gastrointestinal tract (Montalban et al. 1989; Peters et al. 1990; Altes et al. 1991). More recently in Italy, low-virulence L. infantum, which normally causes cutaneous leishmaniasis, was reported to disseminate to the viscera. In most cases treatment of leishmaniasis has started with the recommended pentavalent antimonials, either sodium stibogluconate (Pentostam) or meglumine antimonate (Glucantime) (WHO, 1990; Herwaldt & Berman, 1992). In a review of 48 cases (Peters et al. 1990), 10 failed to respond to antimonial treatment and relapse occurred in 14, a 48% failure rate. In the 10 cases of antimonial failure, secondline treatments with allopurinol, pentamidine, amphotericin B, ketoconazole and paramomycin were tried, but the outcome was rarely improved. The later survey of Altes et al. (1991), including 57 patients with VL and HIV-1 who were treated with antimonials, reported no response in 11 cases and partial response in 20 cases, a 54 % failure rate. The idea that an immune response is required for the activity of antimonials against VL is not new (Schmidt & Peters, 1938) and it is also well established that cases of diffuse cutaneous leishmaniasis, where cell-mediated immunity is also lacking, are unresponsive to antimonials. However, the dependency upon the immune response is relative, as pentavalent antimonials are active against intracellular Leishmania amastigotes in non-activated macrophages in vitro, but are more active against amastigotes in activated macrophages (Haidaris & Bonventre, 1983). Additionally, antimonials are more than 90 % effective in the treatment of nonHIV L. donovani-infected patients who have a specific suppressed T-cell response. In a series of studies Murray et al. (1988, 1989, 1991) examined some aspects of this complex relationship, showing that IFN-y stimulated macrophages accumulated Sb v more than non-stimulated macrophages, and that although the in vivo efficacy of pentavalent antimonials was T-cell dependent, IFN-y and IL-2

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had some effect, but were not major mediators in the response. This approach has been extended to the clinic, and Badaro et al. (1990), successfully cured 6 of 8 patients, who had not responded to antimonials alone, with a combination of rIFN-y and Glucantime. Amphotericin B does not depend upon macrophage activation for its anti-leishmanial activity (Haidaris & Bonventre, 1983), and the development of three amphotericin B-lipid complexes, which have low toxicity to mammals and which can target the drug to macrophages, offers possible improved therapy for VL. A liposome formulation, AmBiSome (Vestar Inc.) was effective in curing a case of VL resistant to other drug treatments (Davidson et al. 1991), and has recently been used to treat three VL/HIV cases (R. Davidson, personal communication). Other protozoa

Although CD4 cells have a role in the immunoregulation of Trypanosoma cruzi infections, other Tcell subsets are probably as important (Tarleton, 1991). So far, only four cases of double infection with HIV in Chagas' reported in humans have been reported (Ferriera et al. 1991), all of which show CNS involvement. There were no descriptions of therapeutic treatments. No link between HIV and human African trypanosomiasis has been demonstrated (Louis et al. 1991). Similarly, no clear association has been demonstrated between HIV and Plasmodium falciparum infection. Although some studies have suggested an interaction (Volsky, Yin Tang & Stevenson, 1986) most, including two longitudinal studies (Colebunders et al. 1990; Greenberg et al. 1991), have not. A recent review by Butcher (1992) summarizing surveys on malaria and HIV, comments that 'HIV thus appears to have less effect on falciparum malaria than does pregnancy'. Entamoeba histolytica, Giardia lamblia and Blastocystis hominis have been identified in up to 15 % of AIDS patients (Guerrant & Bobak, 1991). No relationship between infection of these parasites and HIV immunosuppression has been described, and the higher infection levels in certain human populations probably relate to sexual practices. T-cellmediated immunity is thought to be an important defence against invasive amoebiasis (Salata & Ravdin, 1986). However, AIDS patients colonized with Entamoeba histolytica cysts do not show any higher incidence of invasive amoebiasis (Reed, Wessel & Davis, 1991). Several large series of homosexual men have revealed colonization by non-pathogenic Entamoeba histolytica that do not cause symptoms even in the severely immunocompromised AIDS patients (Allason-Jones et al. 1986, 1988). The paucity of reported cases of invasive amoebiasis from developing countries with a high prevalence of AIDS

A. Zumla and S, L. Croft

suggest that the immune defect in AIDS does not seem to favour amoebic invasion.

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necessary to eradicate the infection, although the response to scabicides appears better in patients with AIDS (Moss & Salisbury, 1991).

Helminths Helminths do not appear to be important opportunists in patients infected with HIV. There is some controversy as to whether Strongyloides stercoralis is an opportunist of importance in patients infected with HIV. Stronglyloides stercoralis hyperinfection syndrome is a well-documented feature in immunosuppressed patients (Longworth & Weller, 1986). Petithory & Derouin (1987) suggested that HIV infection is a predisposing factor for severe strongyloidiasis. However, although there have been isolated case reports of disseminated strongyloidiasis in AIDS patients in the USA and Europe (VieyraHerrera et al. 1988; Armignacco et al. 1989), observations from the tropics do not suggest that this parasite is a prominent opportunist. While it was thought that impaired cell-mediated immune responses due to immunosuppression, malignancy, miliary tuberculosis, malnutrition and leprosy were primarily responsible for hyperinfection, strongyloidiasis has been reported in patients with selective hypogammaglobulinaemia and intact T-cell function. The relative contributions of cell-mediated and humoral immunity in protection against Strongyloides are not known. An important protective role may be played by local immune responses at gut mucosal level. The under-representation of the hyperinfection syndrome among opportunistic infections linked to AIDS may be due to the relative unimportance of cell-mediated immunity in the control of the parasite (Genta, 1984). Concomitant, persistent or relapsing bacterial sepsis can occur in disseminated strongyloidiasis. Relapsing sepsis has been attributed to persistence of larvae in extraintestinal sites despite adequate treatment. Therapy with thiabendazole is usually given for 10 d, but at present the preferred length of treatment for infection in patients with AIDS is not known. Sarcoptes scabiei Depression of cell-mediated and humoral immune responses can result in extensive and severe infection with the mite Sarcoptes scabiei, leading to high ectoparasite densities and, in the clinical condition, Norwegian or crusted scabies. Although there have been scanty case reports of such disease in AIDS patients (Moss & Salisbury, 1991; Ran & Baird, 1987), it appears not to be a major problem in AIDS patients. The clinical manifestations of scabies appear significantly altered by HIV infection (Donabedian & Khazan, 1992) and difficulties in diagnosis may arise. In ordinary scabies, one application of gamma-benzene hexachloride eradicates 90 % of live mites (Rook, 1986). In Norwegian scabies, repeated application of scabicide for several months may be

CONCLUSION

The increased relapse rate following treatment means that improved drug treatment is required for opportunistic parasitic infections in AIDS. Further studies are required to support the suggestion that one of the main problems in the treatment of opportunistic parasitic infections in AIDS is due to lack of an effective host immune response. Many of the problems in treatment are also due to the toxicity of available compounds. Effective in vitro and in vivo models are required for drug testing of P. carinii, Cryptosporidium and the Microsporidia. Attention should also be paid to the drug-immune response interaction, as preliminary studies combining interferon-y with some anti-protozoals have shown promise. REFERENCES ABOUYA, Y. L., BEAUMEL, A., LUCAS, S., DAGO-AKRIBI, A., COULIBALY, G., N'DHATZ, M., KONAN, J. B., YAPI, A. & DECOCK, K. M. (1992). Pneumocystis carinii pneumonia.

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