Lisa Loeb

Amphetamine use is associated with increased HIV incidence among men who have sex with men in San Francisco

We examined the association between amphetamine use and HIV incidence for 2991 men who have sex with men (MSM) who tested anonymously for HIV in San Francisco. HIV incidence among 290 amphetamine users was 6.3% per year (95% CI 1.9–10.6%), compared with 2.1% per year (95% CI 1.3–2.9%) among 2701 non-users (RR 3.0, 95% CI 1.4–6.5). HIV prevention programmes in San Francisco should include efforts to reduce amphetamine use and associated high-risk sexual behaviors.

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

Significance Identifying the source and dynamics of persistent HIV-1 during combinational antiretroviral therapy (cART) is crucial for understanding the barriers to curing HIV infection. Through genetic characterization of HIV-1 DNA in infected cells from peripheral blood and gut-associated lymphoid tissue from patients after long-term suppressive cART, our study reveals that the primary barrier to a cure is a remarkably stable pool of infected memory CD4+ T cells. Through in-depth phylogenetic analyses, we determined that the HIV-1 reservoir in these cells from eight patients is kept stable during long-term cART and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes. The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4–12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4+ T cells [CD45RO+/CD27(+/−)]. The HIV-1 infection frequency of CD4+ T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4–12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4–12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.

Late diagnosis of HIV infection : Trends, prevalence, and characteristics of persons whose HIV diagnosis occurred within 12 months of developing AIDS

Background:Persons diagnosed late in the course of HIV infection may be unknowingly transmitting infection and once diagnosed may have worse outcomes and greater medical expenses. Methods:Persons diagnosed with AIDS in San Francisco between 2001 and 2005 were included. Late testers were persons diagnosed with HIV 12 months or less before their AIDS diagnosis. Prevalence trends, demographic and risk correlates, and predictors of late testing were measured. Results:Among 2139 persons included, 830 (38.8%) were late testers. The prevalence of late testing was stable between 2001 and 2005. Late testing was more likely among persons <30 years old (Odds ratio [OR]: 1.99, 95% confidence interval [CI]: 1.4, 2.8), heterosexuals (OR: 1.88, 95% CI: 1.1, 3.1), persons without a reported risk (OR: 2.88, 95% CI: 1.7, 5.0), persons with private insurance (OR: 1.82, 95% CI: 1.4, 2.4), no insurance (OR: 1.83, 95% CI: 1.4, 2.4), born outside of the United States (OR: 1.64, 95% CI: 1.2, 2.2), and whose initial AIDS diagnosis was an opportunistic infection (OR: 2.24, 95% CI: 1.8, 2.8). Conclusions:A large proportion of persons with AIDS have tested late in the course of HIV infection and this proportion has not declined in recent years. Routine testing in medical settings, and use of rapid oral-fluid testing in traditional and nontraditional settings may increase early HIV diagnosis.

Hematopoietic Precursor Cells Isolated From Patients on Long-term Suppressive HIV Therapy Did Not Contain HIV-1 DNA

BACKGROUND We address the key emerging question of whether Lin(-)/CD34(+) hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) during long-term suppressive therapy. METHODS To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin(-)/CD34(+) HPCs and 3 other cell types (Lin(-)/CD34(-), Lin(-)/CD4(+), and Lin(+)/CD4(+)) from 8 patients who had undetectable viral loads for 3-12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4(+) T cells from contemporaneous peripheral blood samples. RESULTS We analyzed 100,000-870,000 bone marrow Lin(-)/CD34(+) HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin(+)/CD4(+) cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments. CONCLUSIONS The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin(-)/CD34(+) HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin(-)/CD34(+) HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy.

Brief cognitive counseling with HIV testing to reduce sexual risk among men who have sex with men: results from a randomized controlled trial using paraprofessional counselors.

Objectives:To test the efficacy and acceptability of a single-session personalized cognitive counseling (PCC) intervention delivered by paraprofessionals during HIV voluntary counseling and testing. Methods:HIV-negative men who have sex with men (MSM; n = 336) were randomly allocated to PCC or usual counseling (UC) between October 2002 and September 2004. The primary outcome was the number of episodes of unprotected anal intercourse (UAI) with any nonprimary partner of nonconcordant HIV serostatus in the preceding 90 days, measured at baseline, 6 months, and 12 months. Impact was assessed as “intent to treat” by random-intercept Poisson regression analysis. Acceptability was assessed by a standardized client satisfaction survey. Results:Men receiving PCC and UC reported comparable levels of HIV nonconcordant UAI at baseline (mean episodes: 4.2 vs. 4.8, respectively; P = 0.151). UAI decreased by more than 60% to 1.9 episodes at 6 months in the PCC arm (P < 0.001 vs. baseline) but was unchanged at 4.3 episodes for the UC arm (P = 0.069 vs. baseline). At 6 months, men receiving PCC reported significantly less risk than those receiving UC (P = 0.029 for difference to PCC). Risk reduction in the PCC arm was sustained from 6 to 12 months at 1.9 (P = 0.181), whereas risk significantly decreased in the UC arm to 2.2 during this interval (P < 0.001 vs. 6 months; P = 0.756 vs. PCC at 12 months). Significantly more PCC participants were “very satisfied” with the counseling experience (78.2%) versus UC participants (59.2%) (P = 0.002). Conclusions:Both interventions were effective in reducing high-risk sexual behavior among MSM repeat testers. PCC participants demonstrated significant behavioral change more swiftly and reported a more satisfying counseling experience than UC participants.

Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

Background Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009. Methodology/Principal Findings We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27). Conclusions Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.

Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

BACKGROUND The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART). METHODS Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4(+) T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months. RESULTS DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens. CONCLUSIONS Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.

Comparison of three methods to measure HIV incidence among persons seeking voluntary, anonymous counseling and testing

Objectives:The authors compared 3 practical methods to estimate human HIV incidence rates using existing data from persons seeking anonymous testing in San Francisco between 1996-2002. Each method was assessed for strengths and limitations. Methods:Three different approaches were used to determine HIV incidence: one based on self-reported dates of prior tests, one based on linking records of prior tests using an anonymous unique testing code, and one based on the Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS). Results:The 3 methods found comparable rates of seroconversion overall (1.0, 1.2, and 1.3 per 100 person-years) and among men who have sex with men (1.4, 1.6, and 2.0 per 100 person-years). Incidence for all 3 methods saw a peak during 1999 followed by a decline. Greatest variability of incidence was observed among lower-risk populations, in whom few infections were expected. Conclusions:The 3 methods had complementary strengths and limitations, which may prevent proper interpretation of HIV incidence if any one method is analyzed alone. HIV incidence rates among persons seeking HIV testing should be interpreted cautiously using corroborative data on risk behavior and sexually transmitted diseases and other contextual information.

Changes in Seroadaptive Practices from before to after Diagnosis of Recent HIV Infection among Men Who Have Sex with Men

Objective We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices. Methods We collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred. Results A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time. Conclusion Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.

Sexual compulsiveness and change in unprotected anal intercourse: unexpected results from a randomized controlled HIV counseling intervention study.

To the Editor: Sexually compulsive behavior is a nonclinical term used to describe sexual behavior experienced as persistently out of control and as a preoccupying activity interfering with interpersonal relationships and work productivity in daily life. Those who experience their sexual lives as compulsive have also been shown to engage in behaviors that are associated with high risk of HIV transmission. For example, MSM who rate their sexual behavior as compulsive report a greater number of anonymous unprotected sex acts, greater numbers of sexual partners with unknown or discordant serostatus, increased likelihood of recently having a sexually transmitted infection (STI), lower likelihood of disclosure of serostatus to sex partners, greater use of the Internet to seek sex, and lower self-efficacy for condom use. Such men are clearly at high risk for HIV seroconversion. To date, the primary treatment approach for gay men with sexual compulsivity and Internet-enabled sexual addictions has been group therapy or, more recently, the use of serotonin reuptake inhibitors. Outcomes have been mixed. Successful interventions with this population of men at high risk for HIV transmission are sorely needed. We report here on the findings from a secondary analysis of our recent study that sheds some unexpected light on this issue. The study was conducted in an anonymous HIV counseling and testing site, and the methods and results have been previously reported. Briefly, participants were a diverse group of 336 HIV-negative MSM with a history of UAI within the previous 12 months with another man whose serostatus was unknown to the participant or was known to be HIV-positive. The men were recruited from San Francisco’s largest HIV counseling and testing site to participate in a randomized controlled trial of a novel counseling intervention, PCC, compared with standard UC. PCC is a counseling approach that focuses on a single highrisk sexual event (involving insertive or receptive UAI) and asks the participant to provide a detailed narrative of the unfolding of that interaction, identifying an individual’s ‘‘thoughts, attitudes, and beliefs’’ at the point of deciding to engage in high-risk sex and re-evaluating that decision in the counseling session. Risk behaviors were recorded using an audio computer-assisted self-interview immediately preceding the pretest counseling session and again 6 and 12 months after baseline. At the baseline and 12 month visits, participants also completed the Kalichman Sexual Compulsivity Scale, which assesses tendencies toward hypersexuality and sexual preoccupation within the previous 3 months. Men receiving PCC and UC reported comparable levels of HIV-nonconcordant UAI at baseline (mean episodes: 4.2 vs. 4.8 in the preceding 90 days, respectively; P = 0.151). Study results showed that PCC led to a stronger and more rapid reduction of risk in subsequent sexual behavior with ‘‘nonprimary’’ partners (neither a husband, domestic partner, nor boyfriend for longer than 3 months) compared with standard client-centered counseling. Our interest in analyzing these results further was to understand better what effectiveness, if any, the cognitively based single-session PCC intervention had on those participants with higher self-reported sexual compulsivity ratings. To investigate this question, we used the Kalichman Sexual Compulsivity Scale, a 10-item 4-point scale, to calculate a sexual compulsivity score for each respondent at baseline. The scale is internally consistent with a-coefficients that range between 0.85 and 0.91. We used quartiles of the sexual compulsivity score to classify individuals into high-compulsivity and low-compulsivity groups. For example, individuals with a score of 2.2 or greater (highest quartile) were classified in the high-compulsivity group. No significant differences between the PCC intervention and UC control groups were found on our measure of sexual compulsivity at baseline or follow-up. Overall, however, men with higher compulsivity scores were significantly more likely to report greater numbers of sexual partners in the previous 90 days (P < 0.001) and were more likely to report having met sexual partners through Internet sites within the previous 6 months (P = 0.02) at baseline and 12 months. To examine the effect of PCC on reducing risk among participants with varying degrees of sexual compulsivity, we conducted a random intercept Poisson model to determine the effect of sexual compulsivity scores on the change in number of HIV-nonconcordant UAI episodes with a nonprimary partner while accounting for the dependence of repeated measures on individuals over time. Men in the second and third quartiles for sexual compulsivity showed nonsignificant increases in HIV-nonconcordant UAI, 20% and 6%, respectively, from baseline to 12 months, whereas men in the first (lowest) quartile showed a borderline significant decrease of 16% (P = 0.06). The most compulsive group, however, the fourth quartile, showed a 48% reduction in UAI from baseline to 12 months (P = 0.06; Fig. 1). This decrease in UAI, although not at the traditional level of statistical significance (P < 0.05), still raises the possibility that this cognitively based counseling approach may have been particularly helpful to the men rated as the most sexually compulsive in gaining some control over their sexual impulses. Cognitive-based approaches have been shown to be helpful in other compulsive disorders, and this preliminary finding This work was supported in whole or in part by grants RO1MH65138 and 5RO1MH07342503.