The substantial frequency of drug resistance in persons recently infected with HIV in the United States1,2 and in Europe3 implies exposure among HIV-uninfected individuals to HIV-infected persons with drug-resistant virus. Understanding and reducing the incidence of antiretroviral-resistant primary HIV infection are important for several reasons. From a public health perspective, even small increases in sexual risk behavior can have large effects in fueling successive waves of the transmission of drug-resistant virus.4-7 Also, instituting universal resistance testing in all newly infected individuals, which would become necessary in guiding their future therapeutic management, would be extremely expensive. Finally, from a clinical perspective, the ability to achieve durable viral suppression may be compromised if patients have any drug resistance before initiation of highly active antiretroviral therapy (HAART).
Although there is an increasing emphasis on understanding high-risk behavior among HIV-infected patients in general,8-14 relatively little work has focused on those with drug-resistant virus.15-17 Among the reports focusing on individuals with drug resistance, study populations had a high proportion of injection drug users (IDUs) with relatively few (<10%) men who have sex with men (MSM), still the most common exposure category for HIV transmission in the United States.18 In addition, determinants of unsafe sex in the subset of individuals with drug resistance have not been reported.
The aim of our study was to describe the prevalence of high-risk sexual behavior in HIV-infected individuals with detectable viremia and genotypically proven antiretroviral resistance as well as to compare this prevalence with that of HAART-treated individuals who are experiencing optimal virologic responses to therapy. We studied a clinic-based cohort of HAART-treated individuals in San Francisco, a city with a high prevalence of drug-resistant virus in newly HIV-infected individuals.1 Unlike previous studies, most of our study participants are not IDUs and likely acquired HIV via sexual transmission. Because of recent attention placed on interventions that target HIV-infected patients,12,19 we also sought to determine risk factors for high-risk sexual behavior among persons with drug-resistant virus.
Participants were enrolled in the Study of the Consequences of the Protease Inhibitor Era (SCOPE), a clinic-based cohort of HIV-infected adults at San Francisco General Hospital and San Francisco Veterans Affairs Medical Center. This cohort featured stratified recruitment based on use and response to HAART, which were defined using the most current Department of Health and Human Services recommendations.20 Patients who were (1) untreated for at least 24 weeks, (2) HAART treated with undetectable (<75 copies/mL) plasma HIV RNA levels for at least 24 weeks, and (3) HAART treated for at least 24 weeks but having persistent detectable viremia with the 2 most recent HIV RNA levels >100 copies/mL were sampled at a 1:1:2 ratio. In the present analysis, individuals were evaluated at the baseline SCOPE visit and were included if they were using HAART.
Sexual Behavior and Recreational Drug Use
Each participant reported sexual behaviors and recreational drug use using a self-administered questionnaire. Questions on sexual behavior asked about activity in the previous 4 months with men and women in 3 categories: those who were known or strongly suspected to be HIV infected, those who were known to be HIV uninfected, and those whose HIV status was unknown. Men were asked about receptive penile-anal intercourse with other men, insertive penile-anal intercourse with men and/or women, and insertive penile-vaginal intercourse with women. Women were asked about receptive penile-vaginal and penile-anal intercourse with men. One example of questions used to ask about sexual behavior was: “The following questions are about sexual contact you have had with men. With how many men did you put your penis in the man's rectum without using a condom?” (The same question, employing local colloquial terms for sexual activity, was also used in immediately adjacent text). For injection drug use, participants were asked whether in the prior 4 months they had used a needle after someone else had used it or whether they had given a needle to someone else after they had used it to inject drugs. Individuals were also asked about alcohol consumption and any use of sildenafil or other recreational drugs in the previous 4 months.
Mental Health and Adherence to Antiretroviral Medications
Information on depression was obtained from a 6-point Likert scale in a question asking about symptoms of sadness or depression in the prior week. Adherence was assessed from responses to questions on number of missed doses in the past 4 days for each of the antiretrovirals prescribed.
Virologic and Immunologic Parameters
Plasma HIV RNA levels were determined by branched DNA (bDNA) amplification (Quantiplex bDNA 3.0; Chiron, Emeryville, CA). CD4+ T-cell counts were measured by the clinical laboratories associated with each of the participating medical centers. Genotypic drug resistance was determined by the TRUGENE HIV-1 genotyping test (Bayer Healthcare, Berkeley, CA) using mutations specified by the International AIDS Society-USA Panel.21 Resistance testing was performed on isolates from all participants with a plasma HIV RNA level ≥100 copies/mL. For this analysis, participants whose isolates had at least 1 mutation in the reverse transcriptase gene associated with resistance or at least 1 major mutation in the protease gene were classified as having drug resistance.
Participants were divided into 2 groups based on the presence of genotypically proven antiretroviral resistance: (1) individuals with a plasma HIV RNA level ≥100 copies/mL and genotypically proven drug resistance and (2) those with a plasma HIV RNA level <100 copies/mL for whom genotypic testing could not be performed or those with a plasma HIV RNA level between 100 and 1000 copies/mL who had no evidence of genotypic drug resistance (for most such persons, the detection of plasma HIV RNA was transient, based on longitudinal evaluation). We excluded 8 (3%) individuals from analysis who were not classifiable into either group and who had a plasma HIV RNA level ≥1000 copies/mL and wild-type viremia despite being on HAART. After estimation of the prevalence of unprotected intercourse by drug resistance grouping, unadjusted analyses were first conducted to evaluate the association of unprotected intercourse with various demographic, substance use, clinical, and treatment-related factors. Four multivariable logistic regression models were then developed to investigate independent predictors of unprotected intercourse with (1) HIV-uninfected or status unknown partners among individuals with drug resistance, (2) HIV-uninfected or status unknown partners among individuals without drug resistance or with undetectable plasma HIV RNA, (3) HIV-infected partners among individuals with drug resistance, and (4) HIV-infected partners among individuals without drug resistance or with undetectable plasma HIV RNA. Predictor variables were included in the final models if they were associated with the outcome in unadjusted analysis at P < 0.15 or if there was evidence of their importance from other studies of HIV-infected persons. Analyses were performed using Stata version 8.0 software (Stata Corporation, College Station, TX).
Of the first 287 HAART-treated individuals who enrolled in SCOPE, 168 (58%) had a plasma HIV RNA level ≥100 copies/mL and had evidence of drug resistance to at least 1 antiretroviral agent, 106 (37%) had a plasma HIV RNA level <100 copies/mL and did not undergo resistance testing, and 5 (2%) had a plasma HIV RNA level ≥100 copies/mL and <1000 copies/mL and had no evidence of drug resistance. We excluded 8 (3%) individuals from analysis who had plasma HIV RNA levels ≥1000 copies/mL and wild-type viremia. Of the 279 HAART-treated participants included in the analysis, 219 self-identified as MSM and 60 reported only heterosexual behaviors. The median age of participants was 45 years, and 88% were men. Sixty percent were white, 10% were Latino, 22% were African American, and 3% were Asian. Twenty-two percent were college graduates, 44% were employed in the previous year, and 6% reported that they had been homeless in the past year. Compared with those without evidence of drug resistance or with undetectable plasma HIV RNA, participants with drug resistance had similar baseline characteristics (Table 1) except that the median CD4+ T-cell count was lower and the HIV plasma RNA level was higher in those with drug resistance. Among those with drug resistance, 20% had mutations conferring resistance to 1 antiretroviral class only, 42% had mutations conferring resistance to 2 drug classes only, and 38% had mutations conferring resistance to all 3 classes of antiretrovirals.
Prevalence of Unprotected Penile-Anal or Penile-Vaginal Intercourse
Among 133 MSM with confirmed drug resistance (Table 2), 27% reported any unprotected penile-anal intercourse (as the insertive or receptive partner) in the previous 4 months and 17% reported unprotected penile-anal intercourse with a partner who was known to be HIV uninfected or of unknown serostatus. Among the heterosexual men and women, 11% reported any unprotected vaginal or anal intercourse in the past 4 months and 6% reported this with an HIV-uninfected or unknown serostatus partner. There was no evidence that the prevalence of unsafe sexual behaviors with an HIV-uninfected or unknown status partner among individuals on HAART who had drug resistance was different than in those who had undetectable plasma HIV RNA or no evidence of drug resistance. Finally, regarding behaviors that may place HIV-infected individuals at risk for HIV superinfection or the transmission of other sexually transmitted infections, 18% of MSM and 6% of heterosexual men and women with drug resistance reported having unprotected anal or vaginal intercourse with HIV-infected partners. Again, there was no evidence that this differed significantly compared with those without drug resistance or those who had undetectable plasma HIV RNA.
Magnitude of Unprotected Sexual Activity
Among the 36 MSM with genotypically confirmed drug resistance who reported unprotected penile-anal intercourse with at least 1 other man in the prior 4 months, the median number of partners with whom they had unprotected penile-anal intercourse was 2, with 25% reporting 7 or more partners (see Table 2). Among these men, the median number of HIV-uninfected or status unknown partners with whom they had unprotected penile-anal intercourse was 2 and 25% reported 3 or more partners. Heterosexual men and women with drug resistance engaging in unsafe vaginal or anal intercourse reported a median of 1 unprotected anal or vaginal sex partner in the last 4 months. There was no strong evidence that the number of sex partners in individuals on HAART who had drug resistance was different than in those who had undetectable plasma HIV RNA or no evidence of drug resistance.
The distributions of log10 plasma HIV RNA levels and the number of intercourse partners in the past 4 months among men and women on HAART reporting unsafe vaginal or anal intercourse with partners who were HIV uninfected or of unknown status are shown in Figure 1, stratified by drug resistance status. One previously reported22 plasma HIV RNA threshold for transmission of HIV to uninfected partners is indicated (1500 copies/mL). Among those with evidence of drug resistance, the median HIV plasma RNA level was 10,500 copies/mL (interquartile ratio [IQR]: 4467-32,120 copies/mL); 92% had a level greater than 1500 copies/mL. These 25 subjects reported a median of 1 HIV-uninfected or status unknown anal or vaginal intercourse partner in 4 months, with 25% reporting 3 or more partners. Summing the number of sexual partners per person reporting unsafe sex, as many as 72 previously HIV-uninfected or status unknown partners were exposed to and could have acquired drug-resistant HIV infection in a 4-month period.
Spectrum of Mutations in Individuals With Drug-Resistant HIV Who Report Unprotected Sexual Activity
There was a wide distribution of resistance-conferring mutations in the reverse transcriptase and protease genes of HIV among the 25 participants who harbored drug-resistant viremia and who reported unprotected penile-anal or penile-vaginal intercourse in the prior 4 months with HIV-uninfected or status unknown partners (Table 3). Participants had a median of 9 (IQR: 5-11) distinct mutations overall, a median of 4 (IQR: 3-5) reverse transcriptase mutations, and a median of 4 (IQR: 2-6) protease mutations. Among these 25 individuals, 8% had mutations conferring resistance to 1 antiretroviral class only, 44% had mutations conferring resistance to 2 drug classes only, and 48% had mutations conferring resistance to all 3 classes of antiretrovirals.
Prevalence and Magnitude of Recreational Needle-Sharing Practices
Of the 168 individuals with drug-resistant viremia, 8% reported injection drug use in the prior 4 months. Of the 111 individuals with no drug resistance or undetectable plasma HIV RNA, 4% reported injection drug use in the previous 4 months. No participants reported using a needle after someone else had used it to inject drugs. One individual with drug-resistant virus and 1 individual without drug resistance reported giving a needle to someone else after they had used it for injecting drugs, however. Both individuals reported this behavior infrequently (ie, less than once a month).
Factors Associated With Unprotected Penile-Anal or Penile-Vaginal Sex
In a multivariable logistic regression analysis evaluating factors associated with unprotected penile-anal or penile-vaginal intercourse with an HIV-uninfected or status unknown partner among individuals with confirmed drug resistance (Table 4), there was strong evidence for an independent association with age ≤35 years (odds ratio [OR] = 14.5; P < 0.001), depression (OR = 3.8; P = 0.018), and sildenafil use (OR = 3.4; P = 0.039) and moderate evidence for frequent alcohol use (OR = 6.1; P = 0.06) and protease inhibitor resistance (OR = 2.9; P = 0.11) but no strong evidence for sexual orientation (P > 0.20). The following variables were not significant in unadjusted analysis and were not included in the final model: adherence, education, and injection drug use. In an analysis looking at factors associated with unprotected intercourse with HIV-uninfected or status unknown partners among individuals without drug resistance or those who had undetectable plasma HIV RNA, there was strong evidence for an independent association of unprotected sex with age ≤35 years (OR = 7.5; P = 0.009) and moderate evidence for methamphetamine use (OR = 4.5; P = 0.06) in the past 4 months but no strong evidence for depression, alcohol, sexual orientation, or adherence (P > 0.20).
In analyses looking at factors associated with unprotected intercourse with HIV-infected partners in individuals with drug resistance, there was strong evidence for an independent association of unprotected sex with sildenafil use (OR = 5.1; P = 0.006), methamphetamine use (OR = 4.6; P = 0.048), and frequent alcohol use (OR = 8.1; P = 0.027) but less evidence for age ≤35 years or depression (P > 0.20). When evaluating factors associated with unprotected intercourse with HIV-infected partners among individuals without drug resistance or those who had undetectable plasma HIV RNA, there was strong evidence for an independent association of unprotected sex with sildenafil (OR = 5.1; P = 0.006) and frequent alcohol use (OR = 8.1; P = 0.03) but less evidence for age ≤35 years or depression (P > 0.20).
Our study demonstrates that among HIV-infected men and women harboring genotypically proven antiretroviral-resistant viremia, there is a substantial prevalence of high-risk sexual behavior. We estimated that approximately 1 in 4 men or women with drug resistance in our clinic-based population has engaged in unprotected intercourse in the past 4 months, including 15% with partners who were known to be HIV uninfected or whose HIV serostatus was unknown. We found no evidence that persons with drug resistance have been effectively targeted to reduce their practice of unprotected sex-there were similar frequencies of unprotected sex in HAART-treated individuals who had maintained undetectable or nearly undetectable plasma viral load levels. Finally, we identified several risk factors associated with unprotected sexual activity among persons with drug resistance that may form the basis of targeted interventions.
Our findings complement previous research on sexual behavior of HIV-infected populations with drug-resistant virus.15-17 One study of 333 inner-city HIV-infected patients who primarily acquired HIV via injection drug use and heterosexual transmission16 found that 23% had unprotected anal or vaginal sex in the previous 3 months. Of the participants reporting unsafe sex, 24% had resistant virus, potentially exposing 31 partners to drug-resistant virus. Another study15 reported high-risk sexual behaviors in 638 HIV-infected IDUs in Baltimore. Individuals were considered to be at higher risk of drug-resistant HIV transmission if they were taking HAART, found to have an HIV RNA level ≥1000 copies/mL, and reported unprotected vaginal or anal sex. Fourteen percent of 152 visits contributed by 101 high-risk participants were associated with clinically significant resistance. High-risk individuals with drug-resistant virus reported unprotected anal or vaginal sex at 68% of visits, shared needles at 25% of visits, and engagement in both behaviors at 7% of visits. Our study extends this work by focusing on a subset of HIV-infected persons with sizable public health importance-MSM with known drug resistance and active viral replication.
These are timely questions. Evidence now shows that the proportion of newly infected individuals with resistant virus is substantial. Antiretroviral drug resistance was documented to increase in the United States from 2.5% in 1996 through 1997 to 13.2% in 2000 through 2001 in a study by Grant et al1 and from 2.5% in 1996 through 1997 to 13.2% in 2000 through 2001 in another report by Little et al2 as well as in a European study by Wensing et al.3 The high proportion of newly HIV-infected individuals with drug resistance implies exposure of previously HIV-uninfected persons to HIV-infected patients with drug resistance. For transmission to occur, however, high-risk behavior is necessary but not sufficient. The level of HIV RNA in the blood is also a critical factor. Among serodiscordant couples in Uganda, HIV acquisition by a previously uninfected partner occurred only when serum HIV RNA was >1500 copies/mL in the infected partner.22 In our participants with drug resistance reporting high-risk sex with HIV-uninfected or serostatus unknown partners, more than 90% had plasma HIV RNA levels above this threshold. Thus, assuming that the transmission efficiency of drug-resistant HIV is comparable to that of wild-type HIV in the Rakai cohort, our data suggest that transmission would have been possible in most of the individuals studied here. Even if drug-resistant virus is less transmissible than wild-type virus,23 this would be a significant source of new infections.
Recently, the US Centers for Disease Control and Prevention and the Health Resources and Services Administration have shifted their emphasis from prevention of HIV acquisition in the HIV-uninfected population to prevention of transmission by HIV-infected individuals.12 These recommendations are intended for “all HIV-infected adolescents and adults, regardless of age, sex or race/ethnicity.” Such a broad-spectrum approach may be impractical unless more resources are provided to clinics, including trained staff and longer appointment times.24 To assist in identifying specific subgroups that could be future targets for intervention, we looked for factors associated with unprotected anal or vaginal intercourse with HIV-uninfected or status unknown partners among patients with drug-resistant viremia. We found that age of 35 years or younger, depression, and sildenafil use were strong and independent predictors of unsafe sex. Although, to our knowledge, this work is the first of its kind and should thus be considered preliminary, the fact that we have identified strong determinants is promising for future targeted approaches to identifying those persons most apt to transmit drug-resistant virus.
We found that among persons with drug resistance, individuals aged 35 years and younger had the highest prevalence (60%) of unsafe sex with HIV-uninfected or serostatus unknown partners. This finding is not surprising. Younger persons would have come of age sexually when an HIV diagnosis was softened by the prospects of effective medications and longevity. Other studies have consistently identified this subpopulation as reporting higher rates of unsafe sex.25,26
Although depression has been linked to low adherence to HAART in some studies27,28 and poor adherence is associated with unsafe sex,29,30 there is less information on depression predicting high-risk sexual activity in HIV-infected individuals. Our measures of depression were not comprehensive, but the strength of the relation and the relative ease of developing screening and intervention in the outpatient setting make this a good target for future work.
Any use of sildenafil was also independently associated with high-risk sexual activity by those with drug resistance. Recent studies have documented that sildenafil is associated with high-risk sex in MSM who were recent circuit party attendees,31 patients seeking care at a sexually transmitted disease (STD) clinic,32 and participants in a community-based anonymous survey in San Francisco.33 Our study demonstrates that the relation between sildenafil and high-risk sex is also robust in patients with HIV drug resistance. Although we are unable to assess cause and effect, asking clinic patients about sildenafil use can be an easily obtained marker of the highest risk behaviors and could be used to identify persons who might benefit from behavioral interventions.
It is interesting to note that in the analysis of predictors of unsafe sex with HIV-infected partners, younger age and depression were no longer strong correlates of high-risk behavior. This contrasts with the strong evidence for their role in unsafe sex with HIV-uninfected or unknown status partners by HIV-infected individuals with drug resistance. The reasons for this difference are not clear but may be related to a perception that unprotected sex with a seroconcordant partner is safe.34 Despite reports of documented cases of HIV superinfection,35,36 some clinicians have proposed advocating “sex with positives” for their HIV-infected patients.
This study has several limitations. First, given the low social desirability of reporting high-risk behaviors, we may have underestimated the prevalence of unprotected intercourse. Some of the precautions that we took included using a separate questionnaire for the reporting of sexual behaviors and substance use that was self-administered. Second, we did not have information on certain belief systems, such as “HIV optimism”37 and the level of “safe-sex fatigue”,38 both of which have been studied as predictors of unsafe sex in HIV-uninfected men. Finally, our population is a predominantly low socioeconomic status group residing in a single city. It is unclear how this may generalize to higher income groups in other regions.
Our findings provide an explanation for the substantial prevalence of drug resistance among persons with primary HIV infection. The potential public health impact is sobering. In 4 months, our cohort of 168 HIV-positive men and women with drug resistance could have infected as many as 72 previously uninfected partners. Given that we have identified risk factors for high-risk sex, such as age of 35 years and younger, depression, and sildenafil use, this suggests a role for targeted rather than broad intervention in HIV-infected clinic populations, particularly when resources are limited.
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