Rescue of Severely Immunocompromised HIV‐Positive Persons. Part 2
The main finding is that although ritonavir‐boosted lopinavir results in a slightly slower decline in plasma HIV RNA level and a slightly greater increase in CD4 cell count, compared with efavirenz, the 2 regimens result in a very similar risk of AIDS and death. On the other hand, the infrequently tested combination of zidovudine and didanosine showed inferior HIV RNA and CD4 cell count responses, compared with the combination of stavudine and lamivudine. The study had to be interrupted prematurely and, hence, was not fully powered, but there also was a trend toward a higher risk of AIDS and death with zidovudine and didanosine.
Consistent with the findings of previous studies, this trial observed a more robust recovery of CD4 cell counts for patients receiving a ritonavir‐boosted PI versus patients receiving NNRTI as the third drug. Of note, this difference was not explained by differences in viral response and as such cannot necessarily be interpreted to imply a better clinical outcome. Consistent with this, the risk of clinical end points was similar in the current trial. Several studies have now been published that compare NNRTI‐ versus PI‐based primary ART in advanced HIV infection; none of them have been powered to assess clinical outcome. We suggest that the research groups that have performed these comparisons might combine their data sets and performed a meta‐analysis to further clarify that the better CD4 cell count improvement associated with the ritonavir‐boosted PI is indeed not associated with better clinical outcome.
New World Health Organization (WHO) recommendations for the treatment of HIV infection suggest using zidovudine or tenofovir with lamivudine in first‐line regimens. The inferior outcomes for zidovudine plus didanosine in this trial may well, of course, be partly related to the use of didanosine, so it is difficult to draw inferences for the decision by the WHO guidelines panel to emphasize zidovudine above stavudine. WHO recommendations on the use of stavudine have been revised recently because of a growing realization that although stavudine is inexpensive to produce and has a comparable virological efficacy relative to other drugs in its class, it is toxic to subcutaneous adipocytes and peripheral nerve fibers; hence, extended use leads to disfiguring lipoatrophy and peripheral neuropathy. Unfortunately, the report from the Phidisa project does not contain any particularly detailed information relating to the drug‐induced adverse effect profile. However, the reported findings are consistent with this revision of the WHO recommendations, given that 13% of the patients had to discontinue stavudine because of treatment‐limiting adverse effects over the 2‐year study period, and lipoatrophy and peripheral neuropathy predominated as the cause thereof. However, stavudine‐containing combinations remain very widely used, and the authors of this report make the important point that although recent data and guidelines recommend limiting stavudine use because of toxicity, stavudine was well tolerated in the trial by many participants for up to 36 months. The authors suggest that a reasonable approach would be to still consider the use of stavudine when no other options exist and closely monitor its use.
It is interesting to compare the death rates observed in the current trial with those observed in the DART trial of strategies for monitoring people receiving ART in 2 countries in sub‐Saharan Africa (Uganda and Zimbabwe). Eligibility criteria were similar in the 2 trials, although DART patients had a slightly lower median CD4 cell count (86 vs 106 cells/μL) and the proportion of people with clinical symptoms (tuberculosis or WHO stage 4 event) was slightly higher in DART. DART compared laboratory monitoring for toxicity and CD4 cell counts with clinical monitoring alone. In the current trial, laboratory monitoring for toxicity was used and, unlike in DART, viral load measures were used to determine treatment switches to second‐line therapy. DART used a regimen of zidovudine, lamivudine, and tenofovir. The overall death rate in DART was 2.6 per 100 person‐years, compared with 5.5 per 100 person‐years in the South African trial. Losses to follow‐up was particularly low in DART, so this is unlikely to explain the difference. Cross‐trial comparisons have to be interpreted with extreme caution (and there are differences in the regimens used and other differences between the trials), but the use of virological monitoring in the South African trial, which is standard in developed countries but was not used in DART, does not appear to have been markedly beneficial in reducing the death rate among people receiving ART. This could be partially related to the relatively high viral load threshold (>20,000 copies/mL) used for changing regimens in the trial.
The Phidisa investigators deserve applause for their conduct of a large‐scale controlled trial in what appears to have been a challenging research environment. There are shortcomings (eg, lower‐than‐projected enrollment and less emphasis on pharmacovigilence than on efficacy assessment), but the data are highly informative. Let us hope that this will be the first in a series of research projects that further improve the body of evidence regarding how to best manage HIV infection in a resource‐constrained environment.