BMJ  2004;328:253 (31 January), doi:10.1136/bmj.328.7434.253

Commentary

Indirect comparisons: a novel approach to assessing the effect of anti-HIV drugs

¹ Copenhagen HIV Programme, Section 044, Hvidovre University Hospital, 2650 Hvidovre, Denmark, ² Royal Free Centre for HIV Medicine and Department of Primary Care and Population Sciences, Royal Free and Universtiy College Medical Schools, London NW3 2PF

The need to evaluate rapidly and provide access to anti-HIV drugs led, in 1997, to an expedited drug approval process, based on short term trials using viral load and CD4 cell counts as surrogate end points for clinical AIDS. The evidence for efficacy of many drugs is therefore based solely on trials using such end points, but it is useful to evaluate studies using clinical end points where available.

Yazdanpanah and coworkers used an indirect comparison of clinical outcomes from randomised controlled trials to compare the effects of drugs from either the protease inhibitor or the non-nucleoside reverse transcriptase inhibitor (NNRTI) class with two nucleoside reverse transcriptase inhibitors (nucleosides).¹ This approach introduces a novel concept to improve further our understanding of the relative efficacy of the two classes. This review suggests a better efficacy of the protease inhibitors than the NNRTIs.

It is important to understand the context of the results to draw conclusions relevant to today. Most of the randomised controlled trials focused on viral end points and were not designed to capture clinical events after virological failure.² Also, many of the drugs from the NNRTI and protease inhibitor classes are considered obsolete, although the NNRTI drug most represented, nevirapine, is still widely used. Furthermore, most trials were based on people with previous exposure to nucleosides and thus likely to harbour virus with resistance to the nucleosides at enrolment. Since the genetic barrier for NNRTIs is lower than for protease inhibitors (with a single nucleotide mutation sufficient to create resistance), it would be predicted that resistance would develop more rapidly with NNRTI based regimens than with protease inhibitor based regimens in this situation, and hence that the clinical outcome would be poorer. The review seems to confirm this prediction, finding little beneficial effect of NNRTIs at all. Importantly, the results for viral load and clinical outcomes are broadly consistent with a better effect of protease inhibitors. In patients starting anti-HIV therapy for the first time, however, several randomised controlled trials with surrogate end points have directly shown that the efficacy of NNRTIs is comparable and perhaps even superior to protease inhibitors.^3-5

None the less, there are situations in which the findings of Yazdanpanah and coworkers are relevant to today.¹ Frequently, exclusive resistance to nucleosides is seen at failure of current regimens, including triple nucleoside regimens. Furthermore, the WHO has recently launched its 3 by 5 motto of providing anti-HIV therapy to 3 million people by the end of 2005. Hopefully, the therapy will be state of the art, but some may receive inferior regimens of 1-2 nucleosides, increasing the number of patients with resistance to these drugs. It will be critical to start randomised controlled trials with clinical outcomes to establish a rational order of utilisation of the available anti-HIV drugs in this situation. Hopefully, the WHO or other organisations will ensure that this critical knowledge is generated. Yazdanpanah and coworkers provide a strong rationale that this is important.¹

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Contributors: JDL wrote the commentary, which was critically revised by ANP.

Funding: None.

Competing interests: JDL has received grant support and fees from Abbott, Bristol-Myers-Squibb, Roche, Boehringer Ingelheims, Pfizer, Merck, and GlaxoSmithKline. ANP has received consultancy fees, grants or funds for meetings from Abbott, Bristol-Myers-Squibb, Roche, Boehringer Ingelheim, and GlaxoSmithKline.

References

1. Yazdanpanah Y, Sissoko D, Egger M, Mouton Y, Zwahlen M, Chêne G. Clinical efficacy of antiretroviral combination therapy based on protease inhibiters or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. BMJ 2004;328: 249-53.[Abstract/Free Full Text]
2. Kirk O, Pedersen C, Law M, Gulick RM, Moyle G, Montaner J, et al. Analysis of virological efficacy in trials of anti-HIV regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy. Antivir Ther 2002;7: 271-81.[Medline]
3. Van Leeuwen R, Katlama C, Murphy RL, Squires K, Gatell J, Horban A, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003;17: 987-99.[CrossRef][Web of Science][Medline]
4. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341: 1865-73.[Abstract/Free Full Text]
5. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 200311;349: 2293-303.

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Relevant Article

Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials

Yazdan Yazdanpanah, Daouda Sissoko, Matthias Egger, Yves Mouton, Marcel Zwahlen, and Geneviève Chêne
BMJ 2004 328: 249. [Abstract] [Full Text] [PDF]

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