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00002030-201311280-0000600002030_2013_27_2873_soeters_antiretroviral_18article< 130_0_23_5 >AIDS© 2013 Lippincott Williams & Wilkins, Inc.Volume 27(18)28 November 2013p 2873–2881Opportunities for sexual transmission of antiretroviral drug resistance among HIV-infected patients in care[CLINICAL SCIENCE]Soeters, Heidi M.a; Napravnik, Soniaa,b,c; Zakharova, Oksana M.b,c; Eron, Joseph J.b,c; Hurt, Christopher B.baDepartment of EpidemiologybInstitute for Global Health and Infectious DiseasescCenter for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Correspondence to Christopher B. Hurt, Institute for Global Health and Infectious Diseases, 130 Mason Farm Road, CB #7030, Chapel Hill, NC 27599-7030, USA. Tel: +1 919 966 2789; fax: +1 919 966 6714; e-mail: Received 24 May, 2013Revised 14 June, 2013Accepted 8 July, 2013Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ( ).AbstractObjective: To assess opportunities for transmitted drug resistance (TDR), we examined sexual risk behaviours, HIV viraemia and antiretroviral resistance among patients in care.Design: A retrospective, cross-sectional analysis of clinical cohort data.Methods: For 244 UNC Center for AIDS Research HIV Clinical Cohort participants, demographic and behavioural data were obtained during in-person interviews between 2000 and 2011. Genotypic resistance tests were interpreted using WHO surveillance drug resistance mutations (SDRMs). Log-linear binomial regression was used to evaluate associations with TDR risk, defined as unprotected sex in the prior 6 months, HIV RNA at least 400 copies/ml and at least one SDRM.Results: Participants included 91 (37%) women and 153 men, of whom 92 (60%) were MSM. Median age was 43 years; 70% were Black (n = 171). Most (97%) were antiretroviral-experienced; 44% had exposure to more than four regimens. Among 204 individuals on antiretrovirals, 42% reported suboptimal adherence and 29% were viraemic. Over half of participants had at least one SDRM (n = 131); 26 (11%) had triple-class resistance. Overall, 70% were sexually active, and 55% used condoms inconsistently. Thirty (12%) reported unprotected sex during periods of drug-resistant viraemia. Higher TDR risk was associated with prior homelessness [adjusted prevalence ratio (aPR) 2.20, 95% confidence interval (CI) 1.16–4.18], active substance use (aPR 3.12, 95% CI 1.47–6.62) and nonsignificantly with MSM (aPR 1.75, 95% CI 0.93–3.28).Conclusion: A small but significant proportion of clinic patients with drug-resistant HIV engage in sexual behaviours that place others at risk for TDR. Targeted efforts in secondary prevention could have an impact on TDR incidence, over time.IntroductionPrimary acquisition of drug-resistant HIV at the time of initial infection, referred to as transmitted drug resistance (TDR), is an underappreciated public health challenge. Of the estimated 48 600 HIV infections in the US in 2006 [1], approximately 7100 involved acquisition of HIV already resistant to at least one antiretroviral [2]. Two different mechanisms for TDR have been proposed. In the first scenario, patients in care but suboptimally adherent to antiretrovirals acquire resistance mutations [3–6] and transmit them to others. In the second scenario, viremic persons initially infected with resistant HIV pass it on to recipients [7] during sexual or needle-sharing risk behaviour [8–10]. Both mechanisms likely contribute to the stable approximately 10–20% prevalence of TDR seen in North America [11–15] and Europe [16–19]. Although opinions differ on which is the more significant of the two [7,20,21], opportunities clearly exist for persons already engaged in HIV care to transmit resistant viruses to others.Over 70% of HIV-infected persons report some form of sexual activity following their HIV diagnosis [22], but estimates of the proportion engaging in unprotected sex vary considerably. As many as 60% of seropositive men and women use condoms inconsistently with primary or casual sex partners [22–26]. Investigations into behavioural change following HIV diagnosis among MSM demonstrate a period of decreased risk behaviour [27], with half relapsing to unprotected sex within three years [28,29]. A small but significant proportion of individuals (<5%) report no change in risk behaviours following diagnosis [29].Patients who engage in ongoing risk behaviour tend to be less adherent to prescribed antiretroviral regimens [30–34]. This combination of poor antiretroviral adherence and sexual (or injection drug) risk activity provides a pathway for the transmission of resistance. Evidence suggests that although this subgroup of nonadherent patients is small, they may contribute disproportionately to the forward transmission of resistant viruses [32,34]. We sought to better characterize the extent to which nonadherent patients contribute to the risk of TDR, using cross-sectional clinical and behavioural data from the University of North Carolina at Chapel Hill (UNC) Center for AIDS Research HIV Clinical Cohort (UCHCC). The present study had two aims: to examine patterns of nonadherence, high-risk sexual behaviour, detectable HIV viraemia and antiretroviral drug resistance, and to identify factors associated with potential transmission of drug-resistant HIV among patients engaged in HIV care.Materials and methodsPatients and designAll HIV-infected patients aged at least 18 years and receiving HIV care at the UNC Infectious Diseases Clinic are approached for their willingness to participate in the ongoing, observational UCHCC study. Written informed consent is obtained from all individuals; less than 5% of patients decline participation. Clinical and demographic data are collected through standardized medical record abstractions at enrolment and every 6 months thereafter. Details about data collection, laboratory measurements and clinical care were previously described [35]. To improve capture of social and behavioural data not consistently available in medical records, UCHCC participants were offered the opportunity to complete a comprehensive, standardized, face-to-face interview, the Clinical, Sociodemographic and Behavioral Survey (CSDS), which incorporates multiple validated instruments, including 4-day adherence recall [36] and alcohol and substance use assessments [37,38]. The present study is a retrospective, cross-sectional analysis at the time of interview. If a participant completed multiple interviews over time, only the most recent was included. Only patients with complete outcome data were included in our analysis.MeasuresOur primary outcome was a combination of having unprotected sex, detectable HIV viraemia and evidence of antiretroviral resistance around the time of the interview. We defined unprotected sex as having at least one sex partner in the past 6 months and not consistently using condoms. Detectable viraemia was defined as HIV RNA at least 400 copies/ml; the level closest to the interview date was used, within a window beginning 6 months prior and ending 1 month thereafter. As HIV RNA assays used during the collection of these data had lower limits of detection of either 400 or 50, patients with undetectable HIV RNA were assigned average values of 200 and 25, respectively, for use in calculating viral load distributions.Resistance was defined by the 2009 WHO list of surveillance drug resistance mutations (SDRMs) [39], a curated list specifically created for epidemiological analyses of TDR prevalence [40]. Genotypic resistance tests (GRTs) conducted prior to or on the interview day were included.Two interview questions concerned antiretroviral adherence: ‘How many doses have you missed in the last 4 days: 0, 1, or 2 or more?’ and ‘Thinking about the past 4 weeks, on average how would you rate your ability to take all of your HIV medications as your doctor prescribed: excellent, very good, good, fair, poor or very poor?’ We considered at least one missed dose in the prior 4 days as not adherent. ‘Very good’ and ‘good’ were grouped together, as were ‘fair’, ‘poor’ and ‘very poor’.Statistical analysesDemographic, behavioural and clinical variables were described, and associations with unprotected sex and presence of a known SDRM were assessed. Wilcoxon rank-sum tests were used to compare continuous variables and Pearson's χ2 test was used for categorical variables, with exact P values calculated where appropriate. Statistical significance was defined as a P value of less than 0.05.On the basis of the number of sexual partners, condom utilization, HIV RNA detectability and presence of any SDRM, we constructed a flow chart to help define those individuals at a greater risk of transmitting drug resistance to others. Log-linear binomial regression models were used to calculate prevalence ratios and 95% confidence intervals (CI) associated with predictors of membership in this high-risk group. Bivariate associations with P values less than 0.1 were considered for inclusion in the multivariable analysis. All analyses were performed with SAS (version 9.3, SAS Institute, Cary, North Carolina, USA).A number of sensitivity analyses were performed. Because patients may underestimate the number of partners or overestimate condom utilization, a bounded analysis was conducted to assess the range in the proportion of the study population at risk for transmitting drug-resistant HIV. Regression models were repeated to examine whether predictors remained the same with the expanded definition of the high-risk group.Ethics approvalThe UNC Institutional Review Board previously approved the UCHCC and CSDS, which also covered associated secondary data analyses.ResultsDemographicsOf 482 unique face-to-face interviews completed between 2000 and 2011, 244 met inclusion criteria (Supplemental Figure, ). Median age was 43 years (range, 19–74 years; Table 1), and 37% were women. Nonwhite participants represented 79% of the sample; blacks accounted for 70%. A majority had at least a high school education, and 13% were college graduates. One-fifth of respondents described being homeless at some point since their HIV diagnosis. Thirty-eight percent were MSM (60% of male respondents). Thirty-two percent of included patients were interviewed in 2000–2003; 19% in 2004–2006; and 50% in 2007–2011. Demographics of interviewees were very similar to the overall UCHCC [35]. Patients excluded from analysis due to incomplete data did not differ demographically, but had fewer diagnoses of clinical AIDS, higher CD4+ cell counts and less antiretroviral experience than those included in analysis (Supplemental Tables 1 and 2, ).Table 1 Demographic and behavioural characteristics of 244 HIV-infected adult participants in the UNC CFAR HIV Clinical Cohort, by sexual activity and antiretroviral resistance.Clinical characteristicsMedian time from HIV diagnosis to interview was 8 years (range, 0.1–21.9 years; Table 2), with 28% meeting a clinical definition of AIDS during their care. Median CD4+ cell count among interviewees was 426 cells/μl (range, 9–1496 cells/μl), and 59% had HIV RNA viral loads below 400 copies/ml. Eighty-four percent of the group were on antiretrovirals, with a median of 6.7 years since their first regimen was prescribed (range, 0.1–20.4 years). Forty-four percent of participants were heavily treatment experienced, with exposure to more than four antiretroviral regimens. Only eight were antiretroviral-naive (3%).Table 2 Clinical and treatment-related characteristics of 244 HIV-infected adult participants in the UNC CFAR HIV Clinical Cohort, by sexual activity and antiretroviral resistance.Depression and substance useJust over half had a history of depression (Table 1). Thirty-eight percent of participants noted active substance use at the time of the interview. Marijuana (23%) and crack cocaine (19%) were most common; injection drug use was rare (n = 2, 0.8%). Only 9% of respondents used alcohol heavily, defined as consumption at least four times per week.AdherenceAmong the 204 participants on antiretrovirals when interviewed, 58% self-reported ‘excellent’ adherence (Table 2). Eight percent missed at least two doses in the prior 4 days. Viral loads were strongly associated with adherence; 80% of those self-reporting ‘excellent’ adherence had undetectable HIV RNA, compared with 48 and 24% among those with ‘good’ and ‘poor’ adherence, respectively (P < 0.01).Sexual behaviour and condom utilizationSeventy percent of individuals reported some sexual activity in the prior 6 months (n = 172); among these, 23% had two to four partners (n = 39), and 6% reported more than four partners (n = 10). Nearly two-thirds of sexually active participants reported vaginal sex (56 women, 49 men), with 65 (61%) indicating they used a condom ‘all of the time’ for vaginal intercourse. Three women and 56 men had anal sex; only 49% consistently used condoms.Factors associated with unprotected sexual activityParticipants reporting unprotected sex were younger than those who either consistently used condoms or were abstinent (41 versus 45 years, P < 0.01; Table 1). No sexual differences existed in frequency of unprotected sex, but MSM were more likely to report unprotected sexual activity than heterosexual men (P = 0.04). Unprotected sex was more common among active substance users (P = 0.04), and we observed nonsignificant trends towards more unprotected sex among whites and Native Americans (P = 0.40).Persons with a clinical history of AIDS were less likely to report unprotected intercourse (P < 0.01; Table 2). Median viral loads were higher among interviewees reporting unprotected sex [295 copies/ml, interquartile range (IQR), 25–13 000 copies/ml] than among those who consistently used condoms or were abstinent (62 copies/ml, IQR, 25–3687 copies/ml; P = 0.04). Suboptimal adherence was nonsignificantly associated with unprotected sexual activity. Among individuals who reported unprotected sex, 20% missed at least one antiretroviral dose in the prior 4 days, compared with 13% among those not engaging in unprotected sex (P = 0.12). Those with self-assessed ‘good’ or ‘poor’ adherence were more likely to have unprotected intercourse than those with ‘excellent’ adherence (P = 0.33).Prevalence of drug-resistant mutationsOne hundred and thirty-one study participants (54%) had at least one SDRM (Fig. 1), including 12 antiretroviral-naive individuals with any SDRM at entry to care. The most frequently observed reverse transcriptase mutation was M184V, seen in 94 individuals (39%). K103N and K70R were also frequently detected (23 and 13% prevalence, respectively). The most common protease mutations were L90M (9%) and I54V (7%). Overall, 45% harboured SDRMs for nucleoside reverse transcriptase inhibitor (NRTIs) (n = 110), 31% had nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance (n = 76) and 23% had protease inhibitor (PI) resistance (n = 56). Triple-class resistance was noted in 26 cases (11%).Fig. 1. Results of genotypic resistance testing among 244 participants in the UNC CFAR HIV Clinical Cohort.NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.Factors associated with drug-resistant mutationsAge, sex and race were not associated with having SDRMs (Table 1). However, those with a history of homelessness, depression or active cocaine use were more likely to have resistance (all P ≤ 0.04). Participants with a longer time since HIV diagnosis, a longer time on antiretrovirals or a greater number of regimens were more likely to have an SDRM (all P < 0.01). Compared with poorly adherent participants, those with excellent adherence harboured SDRMs less often (86 vs. 51%; P = 0.03). The proportion with newly identified resistance decreased over time (P = 0.1).Potential transmission of drug resistanceAs shown in Fig. 2, 70% reported sexual activity in the prior 6 months, and a majority used condoms inconsistently (n = 94). Among the 44 individuals with inconsistent condom use and HIV RNA more than 400 copies/ml, 30 had documented resistance (12% of the subset). Viraemia in this high-risk group was significant; 90% had HIV RNA more than 1500 copies/ml. Nine individuals had single-class resistance, 14 had dual-class and seven had triple-class SDRMs.Fig. 2. Flow diagram of risk factors for transmitting drug-resistant HIV among 244 participants in the UNC CFAR HIV Clinical Cohort.aDetectable HIV RNA was defined as ≥400 copies/ml. b Antiretroviral resistance was defined as the presence of ≥1 surveillance drug resistance mutation [39].In bivariate analyses (Table 3), we found that individuals who completed some college education had a two-fold greater prevalence in the high-risk group (prevalence ratio 2.03, 95% CI, 1.02–4.02) and noted a nonsignificant trend towards a greater prevalence of MSM (prevalence ratio 1.89, 95% CI, 0.97–3.69). However, in bivariate and multivariate analyses, substance use and homelessness emerged as having the two strongest associations with membership in the high-risk group. Participants who used any illicit substance in the prior year or who reported heavy alcohol use had a three-fold greater prevalence in the high-risk group than nonusers [adjusted prevalence ratio (aPR) 3.12, 95% CI, 1.47–6.62]. Interviewees who reported any homelessness since HIV diagnosis had an adjusted high-risk group prevalence 2.2 times that of individuals with continuous housing (95% CI, 1.16–4.18).Table 3 Associations between demographic and clinical characteristics and risk for transmitting drug resistant HIV, in the UNC CFAR HIV Clinical Cohort (N = 244).Sensitivity analysisParticipant underestimation of sexual activity and/or overestimation of condom use would alter the proportion categorized into our defined high-risk group. Considering all patients with detectable drug-resistant viraemia as members of our high-risk group increased the size of this group to 56, or 23% of those with complete data. Our findings were consistent using this expanded high-risk group definition, with substance abuse (aPR 1.82, 95% CI, 1.15– 2.88) and homelessness since HIV diagnosis (aPR 1.99, 95% CI, 1.28– 3.10) remaining associated with risk of transmitting antiretroviral resistance to others.DiscussionGiven revised US treatment guidelines advocating antiretroviral initiation for all HIV-infected persons regardless of CD4+ cell count [41] and a shift towards ‘test, link and treat’ models of HIV care [42], we are poised to see greater numbers of patients on therapy in the coming years. With this increase in the number of people taking antiretrovirals, we will likely observe an increase in the number of nonadherent patients engaged in sexual risk behaviour, even if the proportions of such patients observed in our study (12%) and other cohorts (5–20%) [31–34] remain unchanged. As this group may contribute disproportionately to transmission of resistant HIV [32], an expansion of TDR could be seen over time. Thus, improving our understanding of potential sources of TDR is perhaps more important than ever before.In our cross-sectional study of HIV-infected patients in care, we observed all the requisite factors needed for sexual transmission of resistant HIV to occur. Forty percent reported suboptimal adherence to their antiretrovirals. Nearly 60% of sexually active participants had unprotected sex at least once in the previous 6 months and tended to be younger and active substance users. The presence of an SDRM was associated with active cocaine use, a history of homelessness since HIV diagnosis, depression and poor antiretroviral adherence. Finally, we found that the risk of having an opportunity to transmit resistant HIV was doubled by a history of homelessness and tripled by active substance use. The relationship of homelessness to the presence of antiretroviral mutations and potential TDR has not been previously reported, but housing instability is a recognized contributor to poorer adherence [43].These findings add to the limited existing literature on the potential for sexual transmission of resistant HIV among patients in care. Because poor adherence often leads to the development of antiretroviral resistance [3], studies of opportunities for TDR have primarily examined the link between nonadherence and sexual risk behaviour. Several clinic-based cohort studies in the United States have shown that the odds of high-risk sexual behaviour are increased 1.5–2.5 times among patients with suboptimal antiretroviral adherence, despite significant differences among the studies in terms of demographics, geography and participant behaviours [30,31,34,44]; the prevalence of patients in this group ranged from 8.5 [34] to 18% [31]. Three additional studies took a more direct approach, focusing on patients with genotypically proven antiretroviral resistance who reported high-risk behaviour. Kozal et al.[32] studied 333 patients in care (but not necessarily taking antiretrovirals) and found that 23% reported unprotected anal or vaginal sex in the prior 3 months; among these, 18 had resistance, for an overall prevalence of 4.5%. Notably, this small subset reported 207 sexual events in the recall period, 80% of which were unprotected, providing evidence that a few individuals might account for a disproportionately large number of potential transmission events. Chin-Hong et al.[33] evaluated 279 patients in San Francisco, noting that 17% of MSM and 6% of heterosexual men and women with resistant viruses had unprotected sex with serodiscordant or status-unknown partners in the prior 4 months. Finally, at 14% of encounters with members of a Baltimore IDU cohort, participants with significant antiretroviral resistance described unprotected sex and/or needle-sharing during periods of incomplete virological suppression on antiretrovirals [45].Clearly, not every patient who develops resistance has unprotected sex. However, the strength of this association – observed across multiple, diverse clinical cohorts – suggests that nonadherence and the accumulation of resistance could serve as a marker of coincident sexual risk behaviour. As many HIV providers check HIV RNA more often than they update a patient's sexual history [46], any detectable viraemia should prompt a discussion with the patient about not only adherence but also transmission risk behaviour. Targeted interventions to reduce sexual partner number and improve condom utilization among patients with new or documented resistance could be important first steps towards reducing the spread of TDR. Finally, the role of substance abuse as a factor in both nonadherence and transmission risk cannot be underestimated; appropriate treatment for addiction is essential for preventing resistance and reducing high-risk sexual behaviours.Our study is not without limitations. Only 250 of 482 participants completing face-to-face interviews had ever undergone resistance testing (52%). We felt the likelihood was low that undocumented mutations were present among the 232 who never had a GRT, as our institutional practice has long been to check for resistance in the setting of treatment failure. Social desirability bias during the face-to-face interview may have led participants to underestimate the number of sexual partners or overestimate adherence, but we explored this with our bounded sensitivity analysis and found similar factors associated with our primary outcome. Finally, our composite primary outcome reflects the factors necessary for transmission of resistant HIV to occur; it is impossible to know what viruses were circulating in the blood or genital tract at exactly the time of potential transmission events.In summary, we found a small but significant proportion of clinic patients with viraemia and documented resistant HIV continue to engage in sexual behaviours that place others at a risk for TDR. Clinic-based, targeted secondary prevention and adherence interventions could substantially reduce opportunities for forward transmission of resistant HIV in the future.AcknowledgementsThis study was originally presented by H.M.S. at the XIX International AIDS Conference, 22–27 July 2012, Washington, DC, USA (Poster MOPE169). The authors thank Elizabeth Yanik, Sam Stinnette, Brant Stalzer and Luca Vernazza for their assistance.H.M.S. extracted data, conducted all statistical analyses, produced the tables and cowrote and revised the manuscript; S.N. provided statistical advice and helped revise the manuscript; O.M.Z. supervised data collection for the clinical cohort, assisted with data extraction and helped revise the manuscript; J.J.E. assisted in the design of the study and helped revise the manuscript; and C.B.H. designed and supervised the study, performed literature searches, produced the figures and cowrote and revised the manuscript.This work was supported by the Social and Behavioral Science Research Core of the University of North Carolina Center for AIDS Research, the Agency for Healthcare Research and Quality (5R01HS018731 to S.N.) and the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences at National Institutes of Health (2T32AI070114 to H.M.S., 2P30AI50410 to J.J.E, 8KL2TR000084 to C.B.H.).Conflicts of interestThe authors have no conflicts of interest to report.References1. 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resistance among HIV-infected patients in careSoeters, Heidi M.; Napravnik, Sonia; Zakharova, Oksana M.; Eron, Joseph J.; Hurt, Christopher B.Clinical Science1827