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Frequent methamphetamine use is associated with primary NNRTI resistance
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AIDS: Volume 21(2) 11 January 2007 p 239-241
[Research Letters]
Colfax, Grant Nasha,b; Vittinghoff, Ericc; Grant, Robertd; Lum, Paulab; Spotts, Geraldb; Hecht, Frederick Mb,e
aAIDS Office, San Francisco Department of Public Health, San Francisco, California, USA
bPositive Health Program, San Francisco General Hospital, USA
cDepartment of Epidemiology and Biostatistics, Division of Biostatistics, USA
dGladstone Institute of Virology and Immunology, USA
eOsher Center for Integrative Medicine, University of California, San Francisco, California, USA.
Abstract
We determined whether methamphetamine use is associated with the increased prevalence of primary HIV drug resistance among a cohort of men who have sex with men recently infected with HIV. In multivariate analysis, we found that frequent methamphetamine use was strongly associated with primary non-nucleoside reverse transcriptase inhibitor resistance, but not with protease inhibitor or nucleoside reverse transcriptase inhibitor resistance. We postulate that this association may be caused by methamphetamine-associated treatment interruptions among source partners.
A case report of primary, drug-resistant HIV was recently reported in a methamphetamine user [1]. Numerous studies have demonstrated independent associations between methamphetamine and sexual risk behavior [2-7]. Because of the high prevalence of both HIV and methamphetamine use among men who have sex with men (MSM), and the high rates of sexual behavior among MSM who use methamphetamine, it is conceivable that methamphetamine may be implicated in the transmission of HIV drug resistance [8-10]. We determined whether methamphetamine use was associated with drug resistance in a cohort of MSM recently infected with HIV.
Participants were from the University of California San Francisco Options Project, previously described in detail [11]. All participants were within 12 months of HIV antibody seroconversion. Participants completed structured interviews at their initial visit to assess HIV risk behavior during the 6-month exposure period in which they were likely to have become infected with HIV. Genotypic resistance was measured by the TRUEGENE HIV-1 genotyping test (Bayer Healthcare, Berkeley, California, USA). Genotypes were interpreted as previously described, based on guideline rules for the assay [12]. We used multivariable logistic regression to assess the independent association of methamphetamine use with resistance to at least one drug class [nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors]. We defined frequent methamphetamine use as weekly or more frequent use. Covariates were specified a priori.
We analysed baseline data collected from participants enrolled between 1996 and 2005. We limited our analysis to 300 MSM participant because they consisted of 95% of the cohort with resistance data, and 95% of methamphetamine users. In these participants, the median age was 35 years. Thirteen participants reported antiretroviral use within 6 months of their exposure period; this may have represented the use of postexposure prophylaxis. Among these participants, antiviral use occurred before resistance testing.
Eighty-three participants (28%) reported methamphetamine use in the previous 30 days. Weekly or more frequent use of methamphetamine was reported by 12% of participants. Seventy-seven participants (26%) had resistance to at least one drug. Among individuals who reported frequent methamphetamine use, 34% were resistant to at least one class of drug, compared with 21% of infrequent users and 25% of non-users.
In a multivariate model, controlling for multiple sex partners, race/ethnicity, other illicit drug use, the previous use of antiretroviral drugs, frequent methamphetamine use was associated with primary drug resistance to any class of HIV drugs [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0-5.3; P = 0.06]. In a less parismonius model, adjusting for the above variables as well as entry year into the study, participant age and education, heavy alcohol use, and any protected vaginal or anal sex, the point estimate for the association remained unchanged. Infrequent methamphetamine use (less than weekly) was not associated with drug resistance in either model.
Next, we examined whether there was an association between frequent methamphetamine use and resistance to any specific drug class. Adjusting for the same variables described above, we found that frequent methamphetamine use was strongly associated with NNRTI resistance in both the parsimonious model (OR 3.9, 95% CI 1.3-11.4; P = 0.01) and the expanded model (OR 3.5, 95% CI 1.2-10.8; P = 0.03). No significant associations were found between infrequent methamphetamine use and NNRTI resistance, or infrequent or frequent methamphetamine use and protease inhibitor or nucleoside reverse transcriptase inhibitor resistance.
Our findings are concerning because probability-based surveys show high rates of methamphetamine use among MSM. In San Francisco, for example, a population-based telephone survey found that 26% of HIV-positive MSM reported methamphetamine use in the previous 12 months [13]. Our results, and such high prevalence rates of methamphetamine use among MSM, suggest that methamphetamine may be an important co-factor in the transmission of NNRTI resistance in this population. The mechanisms by which frequent methamphetamine use is associated with NNRTI resistance remain to be determined. In our analysis methamphetamine was a significant predictor of NNRTI resistance after controlling for the number of sexual partners and high-risk sexual behavior. Several other behavioral factors may provide an explanation for our findings. The source partners who transmitted HIV to participants may have developed drug resistance from suboptimal adherence to antiretroviral therapy, possibly because of their own methamphetamine use. We are aware of only one published study that examined adherence specifically among methamphetamine users [14]; it reported considerable disruptions in medication schedules and dosing as a result of methamphetamine use. Because many methamphetamine users go on episodic 'meth binge' episodes of 24-72 h, repeated cycles of such behavior could result in the emergence of drug resistance because of sporadic treatment interruptions [15,16]. With many methamphetamine users reporting that they have sex with other methamphetamine users during binging episodes, the convergence of treatment interruptions and high-risk behavior could be responsible for the high rates of drug resistance we report here. Our finding that frequent methamphetamine use was strongly associated with NNRTI resistance supports the hypothesis that suboptimal medication adherence by partners may be driving the association, as low levels of adherence are associated with the emergence of NNRTI resistance compared with other drug classes [17]. Furthermore, it is plausible that methamphetamine may exert its influence on adherence in a frequency-dependent manner, and may explain why we found no relationship between infrequent methamphetamine use and NNRTI resistance.
Our analysis has several limitations. As a cross-sectional analysis, causality cannot be determined. We measured methamphetamine in a 30-day period; in contrast, our sexual risk behavior measures covered 6 months. It is possible that the transmission of resistant virus preceeded any methamphetamine use, but it is unlikely that a large proportion of frequent methamphetamine users initiated methamphetamine use after the transmission event. We also did not measure whether methamphetamine was used specifically during high-risk sexual encounters; it is conceivable that methamphetamine is a marker for high-risk sexual behavior, but is not directly responsible for the high-risk behavior. However, event-specific analyses have implicated methamphetamine use as increasing the odds of high-risk sex [18]. Finally, because the OPTIONS cohort is limited to the San Francisco area and our analysis was limited to MSM, our findings may not be representative of other at-risk populations.
These results reinforce recent recommendations to conduct resistance testing before starting antiretroviral therapy in individuals with recent HIV infection, and suggest that such testing is especially important among frequent methamphetamine users [19]. Our analysis also supports the need to develop effective treatment programmes for methamphetamine users, not only to reduce risk behaviors, but also to prevent the transmission of NNRTI resistance.
Sponsorship: The work of G.N.C. was partly supported by the National Institute on Drug Abuse (NIDA) through a mentored patient-oriented research (K23) award. Additional support was provided by NIDA grant no. 3RO1DA017476-03F1.
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