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Resistance testing in drug-naive HIV-infected patients: is it time?

Received 1 July 2005; accepted 5 July 2005; electronically published 23 September 2005. Reprints or correspondence: Dr. Frederick M. Hecht, UCSF Positive Health Program, 995 Potrero Ave., Ward 84, San Francisco, CA 94110 (rhecht@php.ucsf.edu). Clinical Infectious Diseases 2005; 41:1324–5 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4109-0018$15.00 Early recommendations for the use of antiretroviral drug resistance testing in 1998 cautiously endorsed its use for persons who have experienced treatment failure, with a possible role for persons identified with recent HIV infection [1]. More recent recommendations now include clear recommendations for resistance testing in persons with treatment failure and in those with HIV infection of !2 years’ duration, and suggest considering resistance testing for drug-naive patients in areas with a prevalence of resistance of 5% [2]. In this issue of the journal, Sax et al. [3] present a cost-effectiveness analysis that supports the use of genotypic drugresistance testing for all drug-naive patients in most settings. Is it time to make this change? Initial recommendations to perform antiretroviral drug resistance testing in recently HIV-infected persons but not in those with chronic HIV infection were based on an assumption that, within 1–2 years, most drug-resistance mutations would be overgrown by wild-type virus [1]. Resistance testing for patients with chronic infection might provide little but false assurance that resistance was not present in those with low levels of drug-resistant virus that could emerge rapidly when treatment was initiated. Although some resistance mutations do revert to wild-type virus within a year [4, 5], recent studies of persons with primary drug resistance (i.e., resistance acquired through transmission of virus from a source with drug resistance) indicate that most resistance mutations persist at detectable levels considerably longer and may be stable for many years [5–7]. Early assumptions that drug-resistance mutations would be lost more quickly were based in part on experience with persons who acquired drugresistance mutations while receiving antiretroviral therapy. In these individuals, drug-susceptible virus usually has a fitness advantage, and cessation of antiretroviral therapy often leads to overgrowth of drugresistant virus that obscures the detection of mutations within months [8]. In persons with primary HIV drug resistance, viral evolution appears to have a different pattern: evidence of primary resistance is lost more slowly and typically involves reversion of mutations one-by-one, rather than larger viral genetic shifts involving decreased frequency of several mutations at the same time. This pattern is consistent with transmission of only a few HIV-1 variants such that no drug-susceptible virus is present to compete with the drugresistant virus, and the emergence of wildtype virus depends on a much slower process of backward mutations to the wild-type genotype. This likely explains why recent reports indicate that the prevalence of drug resistance in drug-naive patients is relatively high regardless of whether they are recently or chronically infected. In a study of 11000 drug-naive individuals in 10 US cities enrolled during the period of 1997– 2001, Weinstock et al. [9] found that 8.3% had at least 1 resistance mutation. This makes sense in light of data on the persistence of transmitted drug-resistance mutations and the frequency of transmission of drug-resistant HIV, which has varied over time and population, but which has consistently been 8% during the past decade in the United States [9–11] and elsewhere in the developed world [12–16]. The cost-effectiveness analysis by Sax et al. [3] provides a third piece of important information that supports the use of antiretroviral drug-resistance testing for all drug-naive patients. This analysis found that the cost-effectiveness ratio for resistance testing of drug-naive patients before commencement of antiretroviral therapy remained less than $50,000 per qualityadjusted life-year, a commonly accepted threshold below which medical interventions are agreed to be cost-effective, as long as the prevalence of drug resistance was 1%. This remained true in sensitivity analyses that varied factors, such as the cost of assays and the benefit of resistance