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Being Alive
REPORT FROM ICAAC '97: Opportunistic Infections in the Protease Era
Bruce Polsky, M.D. and Mark Harrington
November 5, 1997
Being Alive 1997 Nov 5: 1

Evidence continues to accumulate that AIDS-related morbidity and mortality have significantly decreased in places where potent antiretroviral combination therapy is available. For example, a poster by the Hospital Outpatient Study (HOPS), a longitudinal study of 2,957 HIV-infected individuals, demonstrated that AIDS death rates among individuals with fewer than 100 T-cells decreased dramatically over the course of 1996. These data clearly demonstrate that the diffusion of information about the optimal use of combination antiretroviral therapy after the Vancouver meeting has already had a significant impact on AIDS-related illness and death.

Several papers at ICAAC addressed the changing profile of opportunistic infections (OIs) seen in the months since 1996 when protease inhibitors became widely available in many developed countries.

Several presentations were made by French investigators. A group in Rennes followed 452 individuals with baseline CD4 counts below 100 (215 subjects below 50), who added ritonavir or indinavir to their antiretroviral regimen in the first nine months of 1996. Fifty AIDS-defining events occurred in 45 (10%) of these individuals. It is important to note that in the first half of 1996, it was common practice to add protease inhibitors to pre-existing nucleoside analogue regimens rather than, as more recently recommended, switching at least one if not both underlying reverse transcriptase inhibitors when initiating a protease-including regimen.

Cytomegalovirus (CMV) infections, mainly retinitis, were the most common new OI in this group, observed in 18 of 50 reported OIs (36%). There were also CMV recurrences in 5 of 7 individuals on maintenance with oral ganciclovir even with potent antiretroviral therapy, further supporting previous findings of the limited efficacy of oral ganciclovir as secondary prophylaxis. Mean CD4 count at time of CMV diagnosis was 100 (range 7-250) and diagnosis occurred within two months of starting protease therapy. The early appearance of an OI after initiating a potent antiretroviral regimen is not an indicator of that regimen's failure, but rather of pre-existing immune system depletion. More recent studies indicate that immune system restoration is incomplete, even after six months or more of maximally suppressive antiretroviral therapy, although some compartments of cell-mediated immunity appear to recover at least partially.

Two papers from the H�pital Piti�-Salp�tri�re in Paris compared the incidence of disseminated Mycobacterium avium complex (MAC) and CMV infections from January 1995 through June 1996 and after June 1996, with the rapid dissemination of the new antiretroviral treatment strategy after Vancouver. After the introduction of triple therapy, including a potent protease inhibitor, only 7 (1.8%) cases of disseminated MAC and 14 (3.6%) first episodes of CMV retinitis occurred in this cohort of heavily immune suppressed individuals. This suggests that antiretroviral therapy was leading to at least short-term immune protection if not partial reconstitution.

Good News for Untreatable OIs A scattering of anecdotes confirmed previous reports that potent combination antiretroviral therapy could have a positive therapeutic impact on the previously untreatable OIs: progressive multifocal leukoencephalopathy, cryptosporidiosis and microsporidiosis. For example, a German group conducted a retrospective analysis of 29 HIV-infected individuals with histologically or PCR-confirmed PML. The median age was 39 and median CD4 count was 40 (although six individuals had CD4 counts over 200). Fourteen patients (Group A) stopped or never started antiretroviral therapy after PML diagnosis, ten (Group B) were treated with nucleoside analogues only, and five (Group C) took combination therapy including protease inhibitors.

Four of five individuals in Group C were still alive and progressing more slowly or experiencing resolution of some PML symptoms. However, the sample on triple combination therapy remains small. Treatment of PML with Ara-C (cytarabine), foscarnet, or alpha interferon did not affect survival in this cohort.

By contrast, however, an American group reported two cases of rapidly progressive PML which occurred in two men with AIDS, inactivating them within two to four weeks despite their having started HAART four and nine months previously. Viral load had become "undetectable"only in patient A, but he nonetheless developed PML. Both patients were treated with intravenous cidofovir. After two months of cidofovir therapy, both patients regained use of their extremities and were living independently again. Patient A's HIV RNA remained undetectable, while Patient B had a falling viral load and a falling CD4 count. The patients remain stable seven and nine months later. This cautionary tale reminds clinicians that continuing therapeutic research and diagnostic alertness remain necessary for PML and many other conditions associated with late-stage HIV disease.

A French group reported on the disappearance of microsporidiosis symptoms of fifteen individuals previously diagnosed with microsporidiosis and started on HAART in 1996. French researchers also speculated that the introduction of HAART greatly slowed finding study subjects for ANRS 055, a trial of paromomycin (Humatin) for the treatment of intestinal cryptosporidiosis, because the incidence of cryptosporidiosis dropped precipitously.