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HIV Drug Resistance over the Long Haul - EDITORIAL COMMENTARY
  Clinical Infectious Diseases May 1 2010
P. Richard Harrigan BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
In this issue, The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group present data from a large, long-term study of human immunodeficiency virus (HIV) drug resistance [1]. Their data are derived from a clinic-based collaborative study (the UK Collaborative Group on HIV Drug Resistance), which includes data from >50,000 routinely performed HIV drug resistance tests in the United Kingdom. The collaborative nature of the study group allowed them to examine resistance in almost 8000 individuals for periods of up to 8 years and to gain insight into the determinants of drug resistance in a "real world" setting.
Large longitudinal cohort studies such as this are an important complement to randomized clinical trials, particularly for monitoring drug resistance. As the authors point out, clinical trials of antiretrovirals tend to be relatively short and relatively small. They may also tend to include individuals who are more likely than average to be adherent to treatment. Most importantly, these randomized trials also typically monitor patients only until their initial treatment regimen fails, at which point they may drop out of the study, and no further analyses of resistance are performed.
Cohort studies such as this are one of the few ways to monitor the long-term risk of developing HIV drug resistance. The authors find that the risk of developing a resistant genotype is <20% over 8 years for patients starting "modern" HIV treatment regimens. Given the number of antiretrovirals which are now available, this can only be considered to be good news for patients starting treatment. Other main conclusions of the study are that the risk of detecting mutations conferring resistance to the protease inhibitor class of therapy in those who started highly active antiretroviral therapy (HAART) regimens which included a modern ritonavir-boosted protease inhibitor regimen was about one-third of the risk of detecting nonnucleoside reverse-transcriptase inhibitor resistance. Because there was no difference in the risk of nucleoside reverse-transcriptase inhibitor resistance, the implication of the study is that those who started nonnucleoside reverse-transcriptase inhibitor–based HAART were much more likely to have 2-class HIV drug resistance than those who started therapy with boosted protease inhibitors. This conclusion is consistent with data from clinical trials and with studies by our own group in British Columbia and others.
There are a number of caveats which should be kept in mind when interpreting the data, many of which are addressed in detail in the Discussion section [1]. First, there have been temporal changes in the use of HIV drug resistance testing and in the nucleoside analogue pairs available over the long course of the study (see Table 1 [1]). The authors adjust their analysis for calendar year, but subtle confounding may remain. For example, it was simply impossible to obtain tenofovir-emtracitabine during the first years of the study, but it appears to be one of the most common combinations later in the study. In addition, the observational nature of the study could result in potential contributions of sampling bias—some predictors of resistance may arise from being associated with being tested. The risk of developing resistance may not be simply disentangled from the calendar year of drug availability, the probability of undergoing resistance testing, or variable adherence to medications. It is also important to note that many patients changed their therapies over the course of the study as a normal part of routine clinical management. The main comparisons were made according to the type of regimen that individuals initially started regardless of subsequent drug switches of any part of their regimen.
Finally, many patients no longer initiate HAART with the nucleoside analogue pairs described in this study; thus, the estimates of drug resistance provided for those with the longest follow-up may not accurately mirror those who start antiretroviral therapy in 2010. This statement is not a criticism of the study but merely reflects the fact that it is impossible to have both long term follow-up and today's most clinically relevant therapies in an area that changes as rapidly as HIV treatment. Overall, the study provides an important description of "where we are now." The analysis provided is of the usual high quality of this group.
Financial support. CIHR/GSK Research Cair in Clinical Virology.
Potential conflicts of interest.P.R.H. has received grants from, served as an ad hoc advisor to, or spoken at various events of Pfizer, GlaxoSmithKline, Abbott, Merck, Virco, and Monogram.
* 1.The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long-term probability of detecting drug-resistant HIV in treatment-naive patients initiating combination antiretroviral therapy. Clin Infect Dis 2010;50(9):1275–1285 (in this issue).
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