Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens are superior to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based triple combinations, according to a meta-analysis of 14 clinical trials published in the January 31st edition of the British Medical Journal. The indirect comparison of clinical trials found that individuals taking protease inhibitors (PIs) were less likely to progress to a new AIDS-defining illness or death. Further analysis showed that patients taking a PI gained more CD4 T-cells and had better viral suppression than individuals taking NNRTIs.
However, an editorial commentary accompanying the article stresses that the findings of this meta-analysis should be treated with caution, pointing out that the studies involved patients with experience of sub-optimal therapy.
Nevertheless, the editorial suggests that the meta-analysis will be of value in resource-limited settings, especially where patients have been exposed to sub-optimal therapy.
No trials have compared the clinical effectiveness of PI and NNRTI-based HAART, therefore investigators conducted an indirect comparison between PI and NNRTI triple regimens.The investigators included randomised studies reporting clinical end-points in PI and NNRTI naïve patients that were conducted between 1994 and 2000. The studies were designed to compare triple anti-HIV therapy with dual treatment.
A total of 14 studies were included in the investigators analysis, involving a total of 6,785 patients. Seven of the studies involved PIs and seven involved NNRTIs. The studies ran for between 24 and 80 weeks. Patients enrolled to the studies has advanced state of immune damage: the median CD4 cell count at baseline ranged from 19 – 651 cells/mm3.
The primary outcome assessed by the investigators was progression to a new AIDS-defining illness or death. Eleven studies provided data for the investigators to compare changes in CD4 cell count after starting PI or NNRTI-based HAART, and ten studies collected data on HIV viral load.
Of the studies involving protease inhibitors, three involved indinavir, two involved hard-gel saquinavir and two ritonavir. Four of the NNRTI studies used nevirapine, and the remaining three delavirdine. The most commonly used NRTI backbone was AZT and ddI (five studies), followed by AZT and 3TC (four trials).
Unsurprisingly, patients taking triple therapy were found to be less likely than individuals taking dual therapy to experience disease progression (13.1% versus 19.2%). What’s more, the investigators found that individuals taking PI-based triple therapy were less likely to experience disease progression than those taking NNRTI-containing HAART (p
The investigators repeated their analysis, excluding hard gel-saquinavir and delavirdine, as both drugs would now be considered sub-optimal. The protease inhibitor regimens continued to show larger treatment effects than the NNRTI-based regimens.
There were sufficient data to compare CD4 cell gain between PI and NNRTI regimens in eleven studies. The average CD4 cell gain for individuals taking a PI was 49 cells/mm3 compared to 19 cells/mm3 for NNRTI-treated patients. A similar treatment advantage was found for PIs when the investigators looked at viral load data from ten studies. PI-containing regimens resulted in a more substantial reduction in viral load (-0.79 log copies/mL) than NNRTI therapy (-0.20 log/mL), and patients taking a PI were more likely to achieve a viral load below 500 copies/mL (odds ratio 6.0).
The investigators noted several strengths and weaknesses of their indirect comparisons. On the plus side they note that they analysed a “large evidence base, suitable for indirect comparisons of the clinical effectiveness of the antiretroviral regimens. Such comparisons were appropriate because the trials were similar and of high methodological quality. All reports provided data allowed analyses by intention to treat.”
However, the investigators urge that their findings should be treated with caution, noting the observational nature of their indirect comparison and the potential for bias. What’s more, they note none of the studies included in their meta-analysis included the NNRTI efavirenz. However they draw attention to the recent 2NN study showing similar viral efficacy of nevirapine and efavirenz.
The investigators also stress that most of the patients included in their meta-analysis had experience of sub-optimal NRTI therapy, which could have resulted in nucleoside resistance conferring cross-resistance to NNRTIs.
Nevertheless, the investigators believe that their findings have implications for clinical practice. They argue that after extensive NRTI therapy, adding a PI to sub-optimal NRTI therapy was less likely than adding an NNRTI to result in failure because the number of mutations that must accumulate before severe PI resistance is much higher.
Although not mentioned by the investigators, patients failing PI-based HAART have been observe to sustain CD4 cell count increases above baseline, possibly due to effects of PI resistance mutations on viral replication capacity and subsequent virus-induced T-cell loss.
An editorial commentary in the same issue of the British Medical Journal stresses that it is important to understand the context of the results and draw conclusions relevant to treatment options today. First, most of the studies included in the meta-analysis were designed to capture virological and not clinical endpoints. Second, many of the studies included obsolete drugs. Third, many patients had considerable experience of NRTI treatment that could have conferred resistance to NNRTIs. And finally, several studies in treatment naïve individuals have shown that NNRTI-based HAART is at least as effective as PI-containing regimens, if not better.
But there are situations where the meta-analysis could be of relevance, and the commentary suggests that one such situation could be the treatment programmes being initiated under the WHO 3x5 initiative, where many individuals may have received sub-optimal mono or dual NRTI therapy.
Yazdanpanah Y et al. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. BMJ 328: 249 - 253, 2004.
Lundgren JD et al. Commentary: indirect comparisons: a novel approach to assessing the effects of anti-HIV drugs. BMJ 328: 253, 2004.