November 21, 2002
The subject of whether different antiretroviral (ARV) regimens produce the same or different levels of benefit in regard to immune reconstitution is of crucial importance in HIV therapy. Obviously, immunological benefit represents a key parameter in regard to choice of an ARV regime. Moreover, this consideration is especially important when choosing a first-line regimen for patients with high viral burden and low CD4 counts.
Accordingly, the current study is important and provides reassuring information by concluding that both a triple nucleoside (NRTI) regimen and a protease inhibitor (PI)-based regimen can provide similar levels of immunological benefit in individuals who respond well to ARVs through reductions in their viral load.
In this study, 55 ARV-naive patients in an open-label study received either a four-drug regimen consisting of three NRTIs (i.e., 3TC [lamivudine, Epivir], d4T [stavudine, zerit], ABC [abacavir, Ziagen]) plus nevirapine (NVP, Viramune) or a PI (lopinavir [LPV, Kaletra]/ritonavir [RTV, Norvir]) plus nevirapine. Multi-parameter flow cytometry was used to evaluate lymphocyte phenotypic markers together with in vitro lymphoproliferation assays and delayed type hypersensitivity (DTH) testing.
The authors excluded 11 patients from analysis because of a loss to follow-up, treatment failure (six in the NRTI arm and five in the PI arm) and drug-related toxicities. Indeed, only 44 individuals who demonstrated at least a 10-fold drop in viral load at weeks 4, 5 and 8 were included in the analysis, and the viral loads and CD4 counts in each group (23,779 and 24,952 copies/ml in the NRTI and PI arms; 375 and 355 CD4 cells/mm3 in the NRTI and PI arms) were similar at baseline.
After 48 weeks of therapy, changes in CD4 counts did not appear to be significantly different between the arms, with only modest changes being noted in each case. Nor did the arms differ in regard to viral load measurements. However, the key point of this paper is that no differences were noted between the arms in regard to the functional immunological assays that were performed or in regard to lymphocyte subset analysis.
The major question is really why significant differences were not seen between the groups, when one arm was seemingly presented as a far more potent antiviral regimen (three NRTIs plus an NNRTI) than its counterpart (one PI plus an NNRTI). One answer is that these findings may not remain as durable in the PI as in the NRTI arm and that treatment failure and drug resistance will occur on follow-up with the less potent regimen.
Of course, the short-term data are encouraging, since they do show that immunological benefit was similar in both groups, as long as a substantial reduction in viral load was demonstrated. Clearly, a longer-term study is required to answer the questions raised in a definitive way. It should also be noted that all the patients had viral loads less than 100,000 at baseline, and this factor was doubtless important in the acceptance by many of the subjects to being treated with a seemingly less potent regimen. One wonders, however, whether patients would agree to be on the PI plus NNRTI drug combination described here if this study were to be initiated today, instead of three years ago (as was actually the case), or how an ethics committee would today view the PI/nevirapine arm?
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