The Body Covers: The 7th Conference on Retroviruses and Opportunistic Infections
Primary and Secondary Prevention of Opportunistic Diseases in the Era of HAART
January 31, 2000
poster 241) presented the rates of opportunistic infections in a cohort of patients with advanced HIV disease who were enrolled in CPCRA 048, a randomized placebo-controlled study of azithromycin for DMAC prophylaxis.
Patients enrolled in CPCRA 048 had a CD4+ nadir of <50 cells/µl with rebound above 100 cells/µl following HAART. For the 520 patients enrolled in this cohort, the mean CD4+ nadir was 24 cells/µl with a mean CD4+ of 261 cells/µl at study entry. After an average of 12 months, rates of opportunistic infections were extremely low, with no cases of CMV disease or DMAC, and rates of invasive fungal infections, PCP, and bacterial pneumonia of 0.6, 1.0, and 2.0 per 100 patient years, respectively.
Of significance, the rates of disease following CD4+ rebound were compared with those in trials of first-line prophylaxis in the pre-HAART era. Disease rates were higher in patients who were on prophylaxis and no HAART, than in patients in this cohort who had experienced CD4+ rises on HAART. Thus, CD4+ reconstitution appears to provide protection against opportunistic disease superior to that of first-line prophylactic regimens. This study supports the growing evidence that even patients with advanced HIV disease can experience meaningful immune reconstitution as a result of effective therapy.
In an analysis from a similar trial (ACTG 362), rates of opportunistic infections were also low: DMAC occurred at 0.252 per 100 patient years, and other infections at 4.028 per 100 patient years. This trial showed a marginally significant protective benefit of azithromycin on the development of new AIDS defining-conditions (p = 0.045), although half of the diseases that occurred in the placebo group were due to CMV disease and Kaposi's sarcoma, against which azithromycin has no apparent activity. The significance of this finding is not clear and may be an artifact of low event rates (see: poster 242). The fact that opportunistic diseases still occur -- although infrequently -- in patients with CD4+ rebound, underlines the need to better understand risk factors for opportunistic diseases for patients on HAART so that prophylaxis can be provided when appropriate.
Discontinuation of Prophylaxis or Suppressive Therapy Following CD4+ Rebound: Posters 243, 244, 247, 250Results were presented from ACTG 888 -- an observational study of patients who discontinued PCP prophylaxis following CD4+ rebound to >200 cells/µl after either a CD4+ nadir of <100 cells/µl and no prior PCP (Group I, 144 patients) or prior PCP >6 months prior to study entry (Group II, 125 patients). With a mean follow-up of over 60 weeks in group I and 38 weeks in group II, no cases of PCP have occurred. Three cases of serious bacterial infections and one death due to pancreatitis have been seen. Follow-up is continuing (see: poster 243).
These data are consistent with others that have been previously reported supporting the safety of discontinuing PCP prophylaxis in this group of patients. An additional poster in this session from the Swiss HIV Cohort (see: poster 244) reported similar findings, and additionally showed that the results were consistent among those with CD4+ nadir <100 cells/µl, detectable plasma viral load, or seropositivity for toxoplasma gondii IgG.
As previously mentioned, CPCRA 048 is a placebo-controlled study of azithromycin 1,200 mg/week for DMAC and bacterial pneumonia prophylaxis in patients with nadir CD4+ <50 cells/µl but rebound to above 100 cells/µl. These data, presented by Wafaa El-Sadr, support the discontinuation of DMAC prophylaxis in this patient population. No events of DMAC occurred in 520 patients followed for 12 months with an extremely low loss to follow-up rate of 0.6%. There was no difference between azithromycin and placebo for bacterial pneumonia, progression of HIV disease, or survival. Of note, 36% of the patients in this trial were African-American, 12% were women, and 14% were Hispanic (see: poster 247). Based on this study, one can have a high level of confidence in discontinuing DMAC prophylaxis in patients who are doing well following the initiation of potent antiretroviral therapy.
A small observational study of discontinuing maintenance fluconazole for cryptococcal disease provided a preliminary but optimistic suggestion that this illness might not require lifetime suppressive therapy. In the setting of immunologic reconstitution (CD4+ cell rebound to >150 cells/µl) following at least 16 weeks of antiretroviral therapy and 12 months of treatment with fluconazole, six patients discontinued antifungal therapy. After 8-9 months of follow-up, no recurrences were seen, although one patient maintained a persistently positive cryptococcal antigen. While anecdotal, these findings are encouraging and consistent with other anecdotal reports about discontinuation of CMV and DMAC treatment in patients who have responded well to HAART. It is unlikely that a randomized study of sufficient power will ever be done to explore this issue, although larger observational cohorts will undoubtedly be looked at. In the meanwhile, these data demonstrate that, at least for some patients, immune reconstitution may be sufficient to suppress or cure diseases that once required lifetime therapy.
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