PI Perspective #17

December 1995     View PDF     En español

Opportunistic Infection Update

Results from several new studies on preventing and treating opportunistic infections (OIs) should reduce the uncertainty around managing some OIs, but other results have sparked debate and controversy.

CMV (Cytomegalovirus)
In recent years preventing CMV disease has become a focus of research, and results from two new CMV prevention studies will further fuel the debate on the benefits and costs of prophylaxis. An oral ganciclovir study showed no prevention of CMV disease, while a study of valacyclovir showed benefit to using the drug at the cost of increased side effects and mortality. It now appears that people who are CMV culture positive (have CMV detected in their urine or semen) are at higher risk of developing CMV disease.

A recent study, CPCRA (Clinical Program for Clinical Research on AIDS) study number 023, comparing oral ganciclovir (GCV) to placebo (a dummy pill) for the prevention of CMV indicates that oral ganciclovir does not prevent or delay CMV. This contradicts an earlier study which showed a 50% reduction of CMV for people on oral GCV (for full results of the earlier study, please refer to PI Perspective #16) and which led the FDA to approve oral GCV for CMV disease prevention. The new study, CPCRA 023, enrolled 994 people with fewer than 100 CD4+ cells who received oral GCV (1,000mg three times a day) or placebo. The results have caused great controversy because people on CPCRA 023 were not routinely examined by an eye doctor, unlike the earlier study. They were given full eye exams only when their physicians recognized symptoms and the physicians were not necessarily eye specialists. Although CPCRA 023 was designed to “mimic” the real world scenario, many physicians claim that routine professional eye exams are a standard of care, and that the study did not reflect the way most physicians treat people with HIV. Also, people were not examined for CMV before they enrolled, and they may already have had CMV disease before entering the study (approximately 15% of people with fewer than 50 CD4+ cells will have CMV retinitis upon screening). The results of this study will remain controversial and people with HIV and their physicians should carefully discuss whether to try oral GCV to prevent CMV.

AIDS Clinical Trials Group (ACTG) study 204 enrolled 1227 people with fewer than 100 CD4+ cells who received valacyclovir (two grams four times a day), high dose acyclovir (800mg four times a day) or low dose acyclovir (400mg twice a day). It found people receiving valacyclovir were 30% less likely to develop CMV than those receiving either dose of acyclovir. However, there were more deaths among people receiving valacyclovir than those who received low dose acyclovir. Even people using high dose acyclovir tended to survive longer than those receiving valacyclovir. People using valacyclovir also had more side effects, primarily gastrointestinal, which resulted in people discontinuing therapy. However, a lower dose of valacyclovir may be shown to prevent CMV disease with fewer side effects. Ongoing analysis may also show whether acyclovir is able to prevent other viral infections which valacyclovir can not.

Results from a study of a CMV antisense drug, ISIS 2922, should give hope to people with advanced CMV retinitis. Twenty-two people (28 eyes) with CMV retinitis who had failed all other anti-CMV therapies were given different doses of ISIS 2922 by direct injection into the eye. Doses used were 83, 165, 330 and 495 micrograms once weekly for three weeks, followed by a 330 microgram maintenance dose every other week. People receiving the higher initial doses had better responses, however the one person who was on the 495 microgram dose had severe side effects in the eye. Other side effects were eye inflammation which responded to topical steroids. Some people had their retinitis remain stable for over 50 weeks. New options are always welcome and these results are especially encouraging for people who have failed previous therapies. But the results are not directly comparable to those of larger studies using other approaches, and it is too early to know how ISIS 2922 will fit into the larger picture of CMV treatment.

Fungal Infections
In the first phase of ACTG study 159, 381 people with acute cryptococcal meningitis received intravenous amphotericin B (0.7mg/kg daily) or amphotericin B with flucytosine (25mg/kg daily) for two weeks. In the second phase, they received fluconazole (400mg daily) or itraconazole (200mg twice daily) for eight weeks. Results from phase one indicate adding flucytosine does not significantly reduce symptoms (fever and headaches), mortality or the amount of cryptococcal antigen in the cerebral spinal fluid (CSF). It also appears that flucytosine did not increase the incidence of side effects. Results from the second phase of the study indicate that people on fluconazole are more likely to remain cryptococcal antigen negative. However, there was no difference between the two therapies in reducing symptoms.

A study by the Mycoses Study Group (MSG) enrolled 107 people with stable cryptococcal meningitis and no detectable cryptococcal antigen in their CSF. They received fluconazole (200mg daily) or itraconazole (200mg daily). Significantly more people receiving itraconazole relapsed and became antigen positive than those people receiving fluconazole. Side effects were similar between the two groups.

The two trial designs differed. ACTG 159 looked at the number of relapses (antigen positivity) after 10 weeks of therapy while the MSG study measured time to relapse. Based on the results of these two studies, fluconazole appears better for maintenance treatment of cryptococcal meningitis, supporting past experience with both drugs.

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