Resistance was much more prevalent among patients who were very early adopters of HAART or who were taking nucleoside analogs at the start of the HAART era (1996) compared with patients who had not taken antiretroviral therapy up to that time. For example, 2 years later, resistance to any drug was estimated to be present in 87, 82, and 43% of these subpopulations, respectively, and resistance to all three drug classes was present in 27, 11, and 2%.
An estimated 88% of viremic survivors taking antiretroviral therapy when blood was collected had detectable resistance to one or more drugs compared with 30% of those not currently taking therapy (P = 0.001). A significantly higher prevalence of resistance was also associated with advanced disease stage [odds ratio (OR), 2.95; 95% CI, 1.04–8.35], lower current viral load (OR, 1.57; 95% CI, 1.18–2.09), and lowest self-reported CD4+ T-cell count (OR, 11.07; 95% CI, 4.24–28.89), but not current CD4+ T-cell count (OR, 1.24; 95% CI, 0.59–2.60). A significantly higher resistance prevalence was also associated with male sex (OR, 1.63; 95% CI, 1.16–2.28), being a man who has sex with men (OR, > 1.25 with 95% CI, > 1 for all other risk groups), insurance coverage (OR, 1.87; 95% CI, 1.28–2.73), and more education (OR for college or more, 1.72, 95% CI, 1.20–2.48). However, among all these predictors in univariate analysis, only lowest reported CD4 count (OR, 7.51; 95% CI, 1.93–29.17) and current viral load (OR, 2.91; 95% CI, 1.93–4.39) were demonstrated to be persistent independent predictors of resistance in a multiple logistic regression. (Table 4).
As the cutoff criteria used to define resistance were not derived from treatment response criteria for all drugs, the study results may slightly over or under-estimate the true drug resistance prevalence, although the cutoffs utilized reflect the best current estimate of clinically significant criteria for impaired treatment responses due to drug resistance. When a much more conservative IC50 ratio of 10 is used to define resistance for all classes of drugs, despite the fact that with several drugs significantly impaired treatment responses have been documented with lower cutoff values, the prevalence of resistance to one or more drugs among the viremic population decreased slightly to 72.6%, whereas the prevalence of resistance to non-nucleoside reverse transcriptase inhibitors decreased to 21.8% and protease inhibitors to 27.4%. These small reductions in estimated prevalence of resistance did not substantially impact the results from analyses of drug resistance risk factors.
These first estimates of the prevalence of HIV drug resistance in adults across the United States have several clinical and public health implications, mostly deriving from the fact that suppression of circulating HIV is an important goal for improving patient outcomes and reducing transmission. We found that most adult Americans who received medical care for HIV infection at urban clinics at the start of the HAART era, including essentially all urban residents and over half of the small number of rural residents receiving HIV care, survived until late 1998. However, even when considering all patients including those with early disease and those not on therapy, most survivors had viremia with > 500 copies HIV RNA/ml plasma, and most of these viremic patients had drug-resistant virus. Clinicians and policymakers need to be aware that this large population of patients with viral loads above 500 copies/ml while on therapy are likely to have more limited treatment options and a diminished probability of complete suppression of viral replication as a treatment outcome.
The drug resistance rates reported do not reflect the level of resistance among those with very low viral loads in whom resistance was not measured, and should not be generalized to that population. Even if all patients with < 500 copies HIV RNA/ml plasma were assumed to harbor no drug-resistant virus, then an estimated 48% of all 208 900 surviving adults would have drug resistance. Nevertheless we know that suppression of viremia with potent combination therapy in patients with drug-resistant virus can be attained, but the resistant virus can be archived indefinitely in the latently infected cell reservoir [13–15]. Thus the true rate in the total population regardless of plasma HIV RNA falls between the two values. The patient population characterized in this study represents a large reservoir for potential transmission of drug-resistant virus, consistent with the reports of increasing rates of transmission of drug-resistant HIV in North America with resulting impaired treatment responses and heightened urgency to prevention efforts targeted at this group . An additional public health concern is that patients infected with resistant virus may not come to medical attention or receive specific prevention messages for a considerable period of time. Only about one-half of the between 850 000 and 950 000 Americans infected with HIV get regular care, and that an estimated one-quarter are unaware of their infection [7,16].
As the data were generated from specimens taken 3 years into the era of potent combination antiretroviral therapy with protease and reverse transcriptase inhibitors, factors have been in place that could potentially impact the prevalence of drug resistance either higher or lower. The more prolonged and wider utilization of the non-nucleoside reverse transcriptase inhibitors and protease inhibitors may have increased resistance to these drug classes as well as multiple class resistance. On the other hand the diminishing practice of sequential therapy and the availability of more effective and better tolerated combination regimens, especially for patients without prolonged nucleoside treatment experience, have been shown to increase the likelihood of suppression of viremia with resulting prevention of acquired resistance [17,18]. Active surveillance efforts will be required to monitor the trends of drug resistance among HIV-infected populations in order to assess the evolution of resistance patterns and to define optimum HIV treatment and prevention strategies. Nevertheless, these data indicate the magnitude of drug resistance that can be selected in a decade for nucleoside reverse transcriptase inhibitors in only 1 to 2 years for non-nucleoside reverse transcriptase and protease inhibitors.
Clinical approaches to address this growing drug resistance problem include the routine use of drug resistance testing to manage patients, development of new drugs active against drug-resistant virus, and the more careful and effective use of these drugs by both health care providers and patients. Because of the high rates of replication and mutation of HIV, the extensive use of antiretroviral therapy provides one of the most dramatic examples of the impact of human intervention on evolution in an ecological system . HIV drug resistance frighteningly recapitulates the history of antimicrobial drug resistance in bacteria, with a pernicious twist: HIV is not curable and drug-resistant variants are archived within each patient for life. In addition, the ability of HIV to avoid inhibition by antiretroviral therapy through accumulating mutations indicates that newer and more effective therapies will continue to be needed to control the pandemic.
We gratefully acknowledge many generous sources of support: Agency for Healthcare Research and Quality, Department of Veterans Affairs (San Diego VA Research Center for AIDS and HIV Infection), Health Services and Resource Administration, National Institutes of Health (Center for AIDS Research and R01 AI 29164), ViroLogic, Quest Diagnostics, Gen-Probe, Glaxo Wellcome, Bristol Myers Squibb, Merck.
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Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
HIV; antiretroviral drugs; drug resistance; AIDS