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AIDS Care: Psychological and Sociomedical Aspects of AIDS/HIV Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/caic20

Current treatment of opportunistic infections in HIV disease E. K. Bagdades

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Department of Thoracic Medicine, The Royal Free Hospital , London, UK Published online: 25 Sep 2007.

To cite this article: E. K. Bagdades (1991) Current treatment of opportunistic infections in HIV disease, AIDS Care: Psychological and Socio-medical Aspects of AIDS/HIV, 3:4, 461-466, DOI: 10.1080/09540129108251610 To link to this article: http://dx.doi.org/10.1080/09540129108251610

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AIDS CARE, VOL. 3, NO. 4, 1991

Current treatment of opportunistic infections in HIV disease E. K. BAGDADES Downloaded by [New York University] at 05:25 12 February 2015

Department of Thoracic Medicine, The Royal Free Hospital, London, UK

The development of progressive and severe immunosuppression is the hallmark of HIV infection. The diminished host defenses allow the development of pathological states by a variety of opportunistic organisms which along with malignancies are the major causes of mortality and morbidity in AIDS patients. In addition some of these organisms may play a further role, acting as ‘cofactors’ in the complex pathogenesis of HIV disease. The treatment and prevention of these infections has, therefore, attracted extensive and continuing study. The author presents an update on the management of the most important and commonest of these infections. The majority of references in the text correspond to material from the Seventh International Conference on AIDS which was held in Florence in June. Other important recently published work is also referred to. Pneumocystis carinii pneumonia (PCP)

PCP has been the commonest AIDS defining illness. Initial mortality rates were of the order of 20% or above but these have dramatically improved to about 5% over the last few years even for patients with severe hypoxia at presentation. Treatment of the acute pneumonitis is usually with Co-trimoxazole 120 mg/kg/day

oral or intravenous. Success rates with this regimen are slightly higher than with intravenous Pentamidine 4 mg/kg/day. Inhaled Pentamidine has also been used in treatment but is an inferior alternative in severe disease. Fever, neutropenia and allergic reactions are common with Co-trimoxazole but discontinuation of therapy is only necessary in severe cases. Intravenous Pentamidine is potentially nephrotoxic. It can also cause abnormalities in glucose metabolism, hypotension, cardiac arrhythmias etc. Regimens which decrease the dose of Pentamidine after a few days at 4 mg/kg/day have been safer and probably equally effective (WB2192, WB2214). Two studies published last year showed that patients presenting with severe hypoxia benefit from the addition of Prednisolone 80 mg/day (Bozzette, 1990) or Methylprednisolone 80 mg/day (Gagnon, 1990). The incidence of respiratory failure requiring ventilatory assistance was dramatically reduced. A smaller trial (WB2237) failed to show any benefit from corticosteroids. The additional immunosuppressive effect of corticosteroids must also be borne in mind as mycobacterial, fungal and viral infections may complicate the picture. The combination of Trimethoprim and Dapsone is a useful alternative especially in patients who react adversely to Co-trimoxazole.

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462 FLORENCE SUMMARIES:E. K. BAGDADES

In patients failing to respond or those with severe adverse reactions a combination of Clindamycin 600-900 mg iv/day and Pyrimethamine 15-30 mg/day is effective (ThB42, WB2229). If the pneumonitis remains unresponsive to conventional regimens the so called ‘salvage’ treatments can be tried. The folate antagonist Trimetrexate plus Leucovorin have been used with some success but Efluornithine has not been convincing. An experimental Hydroxynapthoquinone, 566680 may prove useful. It was well tolerated and safe with 80% efficacy in initial trials (WB2239). Primary and secondary prophylaxis against PCP is also extremely important. Low dose Co-trimoxazole 960 mg given 3 times per week seems to be the most cost effective agent but the high incidence of side effects remains a problem (Ruskin, 1991). Inhaled Pentamidine is also effective but there are concerns about atypical presentations of PCP, pneumothoraces, and extrapulmonary Pneumocystis occurring after prolonged administration. Oral Dapsone is a third alternative for prophylaxis. Candidiasis Oral candidiasis is very common and usually responds to topical treatment with Nystatin or Amphotericin B. Systemic agents like Fluconazole, Ketocanazole, and Itraconazole are also highly effective. Oesophageal candidiasis requires systemic therapy. In a prospective double blind comparative trial with Ketoconazole, Fluconazole achieved far greater rates of clinical and endoscopic response (WB2264). Fluconazole also has a superior safety profile and is therefore the drug of choice. Doses of 100 mg/day are adequate (WB2345). Systemic candidiasis is rare and almost always a nosocomial infection occurring in patients with Central Venous Catheters and those on parenteral nutrition. Removal of the catheter is essential and systemic therapy may also be required (MB2312). In patients

with frequent recurrent candidiasis Fluconazole 50 mg/day is effective prophylaxis and smaller doses may also be adequate. Cross prophylaxis against other systemic mycoses like Cryptococcal meningitis may also be provided (WB2301). There are, however, increasing reports of resistant fungal strains after prolonged administration and, therefore, no clear recommendations can be made on this matter (WB2317, WB2357).

Cytomegalovirus Cytomegalovirus (CMV) is responsible for a wide range of pathological states in HIV disease. The most important are CMV retinitis and CMV colitis but pulmonary, biliary, neurological, adrenal, cardiac and other problems can occur. Both Ganciclovir 5 mg/kg/bd and Foscarnet 200 mg/kg/day are effective in acute retinitis and are usually given for 3 weeks. Response is of the order of 80-97% (WB2257, MB2373). Relapse rates after treatment are close to 100% and, therefore, lifelong maintenance therapy should follow the acute course. The maintenance dose for Ganciclovir is 5 mg/kg/day, 5 times weekly. Foscarnet is given at 100 mg/kg/day 5 times weekly but results of a recent trial suggest that 120 mg/kg/day achieves lower relapse rates (WB2285). Some 80% of cases which are resistant to ganciclovir respond to foscarnet (MB2423, WB2293). Combination therapy can also be effective in such cases (WB2286). Adverse effects are common with both drugs. Ganciclovir is myelotoxic especially in combination with other myelosuppressive drugs e.g. Zidovudine or Cotrimoxazole. Foscarnet can be highly nephrotoxic and must be administered slowly diluted in large volumes of saline. It can also cause abnormalities of calcium and phosphate metabolism. In addition long term use of these agents requires the use of central venous lines. The rate of infective complications is quite high even when totally implantable

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CURRENT TREATMENT OF OPPORTUNISTIC INFECTIONS

catheters are used and administration is clinically supervised (WB2406). An interesting alternative to intravenous treatment is intravitreal injection of ganciclovir. This has to be repeated every 5 to 6 days but a slow release preparation, which can be implanted under local anaesthesia, is also available and can provide adequate cover for 120 days (WB2255). As there is far less risk of systemic toxicity this method allows the concomitant use of Zidovudine. There is, however, concern that up to 40% of patients with retinitis have disseminated CMV infection and that topical treatment may not provide adequate cover (MB2416). In gastrointestinal CMV disease both Ganciclovir and Foscarnet are effective in symptom control and improve survival. There is not as yet consensus of opinion as to the need for maintenance therapy in such cases. Pneumonitis due to CMV remains a controversial diagnosis but there is speculation that patients with CD4 counts greater than 0.200 x 109/1 are more likely to develop severe disease (ThB40). This may be due to the fact that part of the pathological process involves an immunological reaction to the presence of CMV in the lung. It seems reasonable to also treat patients when typical CMV cytopathic effects are seen on Trans-Bronchial Biopsy. On the new drug front there has been some success and good tolerability in retinitis and colitis using a Human Monoclonal Antibody to CMV (WB2291). Good tolerability is also reported from Phase I1 studies on FIAU, an oral antiviral nucleoside (WB2290). Oral ganciclovir is also under study and has a reasonable safety profile (WB2309). Atypical mycobacteria Mycobacterium tuberculosis (MTB) IS ' commonly a pathogen in HIV patients. Response to conventional treatment regimens is generally very good.

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Atypical mycobacteria although poorly pathogenic in comparison to MTB become an important problem in the light of the severe immunosuppression seen in HIV patients. Epidemiologically they seem to be more of a problem in the developed world. The reasons for the apparent lower incidence in third world regions is unclear but may be a reflection of higher mortality from other causes at earlier stages of HIV infection. In a study from Melbourne, Australia, mycobacteria were isolated from 49% of patients with AIDS. Ninety-two per cent of these strains were atypical (Lucas, 1991). The treatment of atypical mycobacterial infection has been rather disappointing. Total elimination is an unlikely goal and the aim is to reduce mycobacterial load in the hope that this will result in symptomatic re1ief. Only a few patients respond to conventional combinations of Rifampicin, Pyrazinamide, Ethambutol and Isoniazid. Rifabutin at doses of 300 mg/day to 600 mg/day in combination with the other agents achieves better results than Rifampicin. In vim sensitivities and Minimal Inhibitory Concentration (MIC) studies show many more strains to be susceptible to Rifabutin and at lower concentrations (Hoffner, 1991). Clinically 40-70% of patients treated with Rifabutin reported overall symptomatic improvement evident as weight gain, improvement in fever, and negative cultures (WB2300; Esposito, 1991; Lippe, 1991). As rifabutin has a good profile against MTB as well (Gonzales-Montaner, 1991) and since most isolates in severely immunosuppressed patients are atypical it seems reasonable that this drug could become first line treatment. Some regimes use Clofazimine 100 mg/day instead of Pyrazinamide. The addition of Amikacin also seems to improve success rates (WB2367, MB2365). The newer macrolides e.g. Clarithromycin have shown promise (WA1051, WB2358) but Ciprofloxacin has been disap-

464 FLORENCE SUMMARIES: E. K.

BAGDADES

pointing. Liposome-encapsulated Gentamicin 1.7 mg/kg/day was ineffective in a phase I study (WB2341). The question of primary prophylaxis in susceptible populations remains unanswered both in terms of suitable agents and starting points.

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Cryptosporidiosis

Microsporidiosis Although not included in the CDC classification as AIDS defining opportunist pathogens, these parasites are increasingly recognized as a major cause of persistent diarrhoea in HIV infected populations. In some series they were the most frequently isolated intestinal parasites. They seem to remain localized in the small bowel and duodenal or jejunal biopsy material should provide the diagnosis (MB2216, WB2276). Metronidazole 500 mg/tds improves symptoms in the majority of patients. The mean duration of treatment is two weeks. Although most patients will relapse, response to Metronidazole is again good (WB2267). Albendazole 400 mg bd for 4 to 6 weeks shows excellent results in initial studies. Stool frequency improved from a mean of 12/day to 2/day, and motions were formed in the majority of patients (WB2265).

Cryptosporidia cause moderate to severe diarrhoea in up to 35% of AIDS patients. This may be extremely frequent and significant fluid loss can occur. In addition Cryptosporidia are one of the major causes of sclerosing cholangitis in these patients. Symptomatic treatment with rehydration measures and antimotility agents is of paramount importance. Specific treatment is aimed at microbial load reduction as complete eradication is only achieved in a small number of cases. Spiramycin 4 g/day has been extensively used but has actually been Cryptococcal meningitis disappointing. Newer macrolides like Azithromycin 600 mg/day or Paromomycin 500 This affects 5 4 % of European and mg/qds hold more promise and have few American patients and tends to occur late in side effects. They are also effective in the the course of HIV infection. treatment of relapses (MB2270). Treatment is usually with Amphotericin Small series on the use of Fluconazole B 0.3-1.0 mg/kg/day plus Flucytocine suggest some improvement both in acute 75-100 mg/day and must be continued until cases and relapses (MB2199). CSF clearance has been achieved. Toxicity Hyperimmune Bovine Colostrum pro- with Amphotericin is common and potenduced by hyperimmunization of cows with tially serious. Fever, rigors, nausea, vomitcryptosporidial antigens can be given to ing, hypokalaemia and renal impairment are patients by direct intestinal infusion. It has all frequently seen. AmBisone is liposome shown highly inhibitory activity in vitro and coated Amphotericin and in recent trials it has been promising in early trials has shown efficacy and a far safer profile (WB2269). than ordinary Amphotericin (WB2177, Sandostatin (a Somatostatin analogue) WB2305). Fluconazole has also been used in treathas been used to control diarrhoea. Doses vary according to tolerance from 150 to ment but recent comparative trials with Am4,500 micrograms daily. Seventy-five per photericin, albeit small in numbers of pacent of patients showed partial or complete tients, showed a higher rate of treatment response (WB2362). failures and some early deaths in the FlucoOctreotide has also been reported to nazole arm. This may be due to delayed reduce diarrhoea and fluid loss (WB2319). clearance of cryptococci from the CSF

CURRENT TREATMENT OF OPPORTUNISTIC INFECTIONS

which may be improved by the addition of Flucytosine 150 mg/kg/day (WB2337). Itraconazole 400 mg/day has also shown promise in early trials. Secondary prophylaxis is essential after recovery from the acute episode. Fluconazole is the drug of choice and appears superior to Amphotericin. It may also provide cross-prophylaxis against other systemic mycoses (WB2279).

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(MB2027). 566C80 is highly active against toxoplasma both in vim and in oivo. More importantly it is the only agent shown to reduce the number of cysts in the brains of experimental infected mice. In a recent trial 8 patients were treated with this agent. Six showed complete response and the other two partial response. No severe adverse reactions were recorded (WB31).

Prophylaxis

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Toxoplasmosis This protozoal infection is the leading cause of mass lesions in AIDS patients. In the majority of cases this is a reactivation of latent protozoal forms from previous infection. About a third of HIV patients who have serological evidence of previous exposure will develop reactivation with dissemination and clinical disease. Cerebral involvement is the commonest but pulmonary, ophthalmic and other sites can be affected. Treatment options: Sulfadiazine 4-8 g/day plus Pyrimethamine 50-100 mg/day plus Folinic acid. Side effects include marrow toxicity, fever, crystalluria and skin rashes in about 50% of cases (MB2188, MB2091, MB2407). Clindamycin up to 4.8 g/day plus Pyrimethamine 50-100 mg/day. Side effects include myopathy, diarrhoea which may be due to pseudomembranous colitis, and rashes in 60% of cases (MB2188). An interim analysis of 225 cases in a comparative study of these two regimens showed significantly more failures in the Clindamycin treated group (WB30). Dapsone is also useful in cerebral toxoplasmosis. The macrolides Clarithromycin (WB2284), Roxithromycin and primarily Azithromycin have had good early reports. More encouraging is an apparent therapeutic synergy of the macrolides with Interferon. Doxycicline was successfully used in a small number of patients and was well tolerated

Secondary prophylaxis is imperative to prevent recurrence and may provide some cross-prophylaxis against Pneumocystis. The case for primary prophylaxis has not yet been evaluated. Patients with serological evidence of previous infection and CD4 counts below 0.100 x 109/1 are obviously at risk. A trial of Pyrimethamine 25 mg/week alone or with Co-trimoxazole or Dapsone was ineffective in prevention (WB2342). Another trial of Dapsone 100 mg twice weekly was more encouraging (WB2248). References BOZZE-ITE, S.A. et al. (1990) A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the Acquired Immunodeficiency Syndrome, New England Journal of Medicine, 323, pp. 1451-1457. ESPOSITO, R. et al. (1991) European Cooperative study of Rifabutin for the treatment of localised and disseminated Mycobacterial disease in AIDS patients. Abstract in Proceedings of Satellite Symposium on Mycobacterial Infections, Smenth International Conference on AIDS, Florence. GAGNON, S . et al. (1990) Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the Acquired Immunodeficiency Syndrome, New England Journal of Medicine, 323, pp. 1444-1450. J. et al. (1991) Efficacy and GONZALES-MONTANER, safety of Rifabutin in newly diagnosed pulmonary tuberculosis. Abstract in Proceedings of Satellite Symposium on Mycobacterial Infections, Sewenth International Conference on AIDS, Florence. HOFPNER,S.E. (1991) Rifabutin: antimycobacterial activity and synergism with other drugs. Abstract in Proceedings of Satellite Symposium on Mycobacterial Infections, Smenth InternariOnal Confmence on AIDS, Florence. LIPPE,M. et al. (1991) Rifabutin therapy for Mycobac-

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terium Avium Complex (MAC) disease in AIDS patients. Abstract in Proceedings of Satellite Symposium on Mycobacterial Infections, 'seventh International Conjierence on AIDS, Florence. LUW, C.R. et al. (1991) Mycobacterium Avium Complex (MAC) in AIDS. Abstract in Proceedings of Satellite Symposium on Mycobacterial Infections,

Seventh International Conference on AIDS, Florence. RUSKIN, J. et al. (1991) Low-dose Co-trimoxazole for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus disease, Lancet, 337, pp. 468-471.

Current treatment of opportunistic infections in HIV disease.

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