Oliver Bacon

Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services

IMPORTANCE Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM). OBJECTIVE To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States. DESIGN, SETTING, AND PARTICIPANTS Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015. INTERVENTIONS A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring. MAIN OUTCOMES AND MEASURES Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition. RESULTS Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion. CONCLUSIONS AND RELEVANCE The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

Detection of Acute HIV Infections in High-Risk Patients in California

Background: Given the strong relation between sexually transmitted diseases (STDs) and the spread of HIV infection, recent outbreaks of syphilis in the United States could lead to increased rates of new HIV infection. STD clinics serving persons at risk for syphilis would be logical sites to monitor rates of acute HIV infection. The detection of acute HIV infection, however, is not routine and requires the use of HIV RNA testing in combination with HIV antibody testing. Methods: To determine the rate of acute HIV infection, we performed HIV RNA testing on pooled HIV antibody-negative specimens from persons seeking care at San Francisco City Clinic (SFCC) and from men seeking care at 3 STD clinics in Los Angeles. We compared prevalence of acute HIV infection among those groups. Results: From October 2003 to July 2004, we tested 3075 specimens from persons at the SFCC, of which 105 (3%) were HIV antibody-positive and 11 were HIV RNA-positive/HIV antibody-negative, resulting in a prevalence of acute HIV infection of 36 per 10,000 (95% confidence interval [CI]: 26 to 50 per 10,000) and increasing by 10.5% the diagnostic yield of HIV RNA testing compared with standard testing. From February 2004 to April 2004, 1712 specimens were tested from men at 3 Los Angeles STD clinics, of which 14 (0.82%) were HIV-positive by enzyme immunoassay testing and 1 was HIV RNA-positive/HIV antibody-negative, resulting in a prevalence of 6 per 10,000 (95% CI: 3 to 13 per 10,000) and increasing the diagnostic yield for HIV infection by 7.1%. Conclusions: In our study, the addition of HIV RNA screening to routine HIV antibody testing in STD clinics identified a substantial increased proportion of HIV-infected persons at high risk for further HIV transmission, who would have been missed by routine HIV counseling and testing protocols. Further evaluation of the addition of HIV RNA screening to routine HIV antibody testing is warranted.

High interest in preexposure prophylaxis among men who have sex with men at risk for HIV infection: baseline data from the US PrEP demonstration project.

Background:Preexposure prophylaxis (PrEP) is the first biomedical intervention with proven efficacy to reduce HIV acquisition in men who have sex with men (MSM) and transgender women. Little is known about levels of interest and characteristics of individuals who elect to take PrEP in real-world clinical settings. Methods:The US PrEP Demonstration Project is a prospective open-label cohort study assessing PrEP delivery in municipal sexually transmitted disease clinics in San Francisco and Miami and a community health center in Washington, DC. HIV-uninfected MSM and transgender women seeking sexual health services at participating clinics were assessed for eligibility and offered up to 48 weeks of emtricitabine/tenofovir for PrEP. Predictors of enrollment were assessed using a multivariable Poisson regression model, and characteristics of enrolled participants are described. Results:Of 1069 clients assessed for participation, 921 were potentially eligible and 557 (60.5%) enrolled. In multivariable analyses, participants from Miami (adjusted Relative Risk [aRR]: 1.53; 95% confidence interval [CI]: 1.33 to 1.75) or DC (aRR: 1.33; 95% CI: 1.2 to 1.47), those who were self-referred (aRR: 1.48; 95% CI: 1.32 to 1.66), those with previous PrEP awareness (aRR: 1.56; 95% CI: 1.05 to 2.33), and those reporting >1 episode of anal sex with an HIV-infected partner in the last 12 months (aRR: 1.20; 95% CI: 1.09 to 1.33) were more likely to enroll. Almost all (98%) enrolled participants were MSM, and at baseline, 63.5% reported condomless receptive anal sex in the previous 3 months. Conclusions:Interest in PrEP is high among a diverse population of MSM at risk for HIV infection when offered in sexually transmitted disease and community health clinics.

Commercial sex work and risk of HIV infection among young drug-injecting men who have sex with men in San Francisco.

Objective: The objective of this study was to investigate the relationship between sex work and HIV infection among young injection drug-using men who have sex with men (MSM-IDU). Study Design: This study was a cross-sectional analysis of behavioral and serologic data collected from 227 street-recruited MSM-IDU in San Francisco, California, between January 2000 and November 2001. Results: Sixty-eight percent of participants reported being paid by another man for sex. HIV prevalence was 12% (95% confidence interval, 8–16%); 42% of seropositive participants were unaware of their infection. HIV was independently associated with higher number of paying male partners and history of gonorrhea and inversely associated with number of female partners, education, and syringe-sharing. Consistent condom use overall was 41%, but varied significantly by type of partner. Conclusions: Among MSM-IDU in San Francisco, sex work with men is strongly associated with HIV infection and the prevalence of condom use is low. HIV prevention among MSM-IDU must be tailored to address the excess risk associated with sex work.

HIV intervention for providers study: a randomized controlled trial of a clinician-delivered HIV risk-reduction intervention for HIV-positive people.

Clinician-delivered prevention interventions offer an opportunity to integrate risk-reduction counseling as a routine part of medical care. The HIV Intervention for Providers study, a randomized controlled trial, developed and tested a medical provider HIV prevention training intervention in 4 northern California HIV care clinics. Providers were assigned to either the intervention or control condition (usual care). The intervention arm received a 4-hour training on assessing sexual risk behavior with HIV-positive patients and delivering risk-reduction-oriented prevention messages to patients who reported risk behaviors with HIV-uninfected or unknown-status partners. To compare the efficacy of the intervention versus control on transmission risk behavior, 386 patients of the randomized providers were enrolled. Over six-months of follow-up, patients whose providers were assigned the intervention reported a relative increase in provider-patient discussions of safer sex (OR = 1.49; 95% CI = 1.06 to 2.09), assessment of sexual activity (OR = 1.60; 95% CI = 1.05 to 2.45), and a significant decrease in the number of sexual partners (OR = 0.49, 95% CI = 0.26 to 0.92). These findings show that a brief intervention to train HIV providers to identify risk and provide a prevention message results in increased prevention conversations and significantly reduced the mean number of sexual partners reported by HIV-positive patients.

HIV-1 persistence following extre277277mely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

Background It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

Healthcare Access and PrEP Continuation in San Francisco and Miami Following the U.S. PrEP Demo Project.

Background: Pre-exposure prophylaxis (PrEP) for prevention of HIV infection has demonstrated efficacy in randomized controlled trials and in demonstration projects. For PrEP implementation to result in significant reductions in HIV incidence for men who have sex with men in the United States, sufficient access to PrEP care and continued engagement outside of demonstration projects is required. Methods: We report the results of a follow-up survey of 173 former participants from the Miami and San Francisco sites of the US PrEP Demo Project, administered 4–6 months after study completion. Results: Survey respondents continued to frequently access medical care and had a high incidence of sexually transmitted infections after completion of the Demo Project, indicating ongoing sexual risk behavior. Interest in continuing PrEP was high with 70.8% indicating that they were “very interested” in continuing PrEP. Among respondents, 39.9% reported continuation of PrEP after completion of the Demo Project, largely through their primary care providers and frequently at low or no cost. Variability in access and engagement was seen, with participants from the San Francisco site, those with medical insurance, and those with a primary care provider at the end of the Demo Project more likely to successfully obtain PrEP medication. Two respondents reported HIV seroconversion in the period between study completion and the follow-up survey. Conclusions: Additional effort to increase equitable access to PrEP outside of demonstration projects is needed to realize the potential impact of this evidence-based prevention intervention.

Brief Report: Informing Strategies to Build PrEP Capacity Among San Francisco Bay Area Clinicians.

Abstract: A large pool of clinicians are needed to meet the growing demand for HIV preexposure prophylaxis. We surveyed a mixed group of HIV specialists and nonspecialists in the San Francisco Bay Area to determine their attitudes toward and training needs regarding prescribing preexposure prophylaxis to persons at increased risk of HIV infection. Willingness to prescribe was associated with experience in caring for HIV-infected patients (adjusted odds ratio 4.76, 95% confidence interval: 1.43 to 15.76, P = 0.01). Desire for further training was associated with concerns about drug resistance (P = 0.04) and side effects (P = 0.04) and was more common among noninfectious disease specialists. Clinicians favored online and in-person training methods.

Authors' Reply: Race and the Public Health Impact Potential of Pre-Exposure Prophylaxis in the United States.

We appreciate the authors’ careful reading of our paper reporting on uptake and characteristics of enrolled participants in the US PrEP demonstration project, and we share the authors’ concerns regarding the potential for disparities in PrEP uptake across race, ethnicity, age, income, geographic region and other factors. The authors raise a number of questions including how we defined race/ethnicity, whether “clinic referred” participants were representative of the populations served at the study sites, and what risk criteria should be used to determine PrEP eligibility across racial and ethnic groups. Race and ethnicity were assessed using a two-part question based on federal guidelines: “Which ethnic and racial groups(s) do you identify with?: 1) Ethnicity (mark only one): Hispanic/Latino or Non-Hispanic/Latino and 2) Race (mark all that apply): White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and other, specify.”1 Participants were not asked to describe which race best describes them. For the purpose of the analysis, we combined race/ethnicity into a single variable. Participants who reported being of Hispanic/Latino ethnicity were classified as “Latino”, regardless of what race they chose. Non-Hispanic/Latino participants who selected only one race were categorized as that race, whereas those who selected multiple races were categorized as “other.” Categorizing race and ethnicity is complex,2 and several studies have indicated that the distinction between ethnicity and race is not meaningful to respondents.3-5 In our study, 31% of Latino participants selected “other” for their race and wrote-in “Latino”. Using a single variable for “ethnicity” with categories that include Latino, non-Latino White, non-Latino Black, non-Latino Asian, and non-Latino other is recommended by the American Anthropological Association6 and is common throughout the literature.2,7,8 Of the 354 Latino clients who were assessed for participation in the study, 23 (6.5% of Latino clients and 2.2% of all clients assessed) selected Black as their only race, and an additional six selected Black in addition to one or more racial groups. Among the 62 multi-racial individuals assessed for participation, 14 selected Black as one of their races. If Black race is re-defined as selecting Black as at least one of the races an individual identified with, the number of blacks assessed increases from 90 to 133 (9.2% to 12.4%). While Blacks (defined as anyone who selects Black, alone or in addition to other race and ethnicities) have lower PrEP uptake in bivariate analysis, they are not less likely to choose to enroll in the study after controlling for referral status, site, age, education level, prior PrEP awareness and risk behaviors (aOR 0.89; 95% CI 0.76-1.04).9 Some studies have suggested that Black men who have sex with men (BMSM) are more concerned about PrEP side effects than White MSM, however among our sample, Blacks were less likely to report this as a reason for declining participation (26.2% of Whites, 20.5% of Latinos, and 13.0% of Blacks reported a concern about side effects as their reason for declining). Blacks were more likely to report that they “needed more time to think about it” as a reason for declining, compared with Whites (8.3% of Whites, 16.7% of Latinos and 17.4% of Blacks). We agree that understanding the racial/ethnic make-up of the populations served at the participating clinics would be useful in assessing whether “clinic referred” participants were representative of the clinic populations. While all three clinics are able to report the racial and ethnic make-up of all patients seen at the clinic, only San Francisco City Clinic (SFCC) and Whitman Walker Health (WWH) have available data on the racial and ethnic make-up of HIV-negative MSM and transgender women (TGW). At the Miami STD clinic, sexual orientation or sexual behaviors are not recorded electronically, and the majority of clinic clients are not MSM, thus overall clinic demographics are not reflective of the population eligible for referral to the Demo Project. To approximate the racial/ethnic make-up of HIV-negative MSM seen at the Miami downtown clinic, we used data from a previous record review of 56 HIV-negative MSM who tested positive for pharyngeal gonorrhea or chlamydia in 2012. The table below compares the race/ethnicity of study participants who were “clinic-referred” with HIV negative MSM and TGW seen at the SFCC and WWH sites in a one-year period, and with the subset of HIV negative MSM from the Miami clinic described above. The race/ethnicity of clinic-referred participants did not differ significantly from those of the respective clinic populations at WWH or the Miami clinic. However in San Francisco, clinic-referred participants were more likely to be Latino or “other”, and less likely to be White or Black, compared with the population of HIV-negative MSM and TGW who were behaviorally eligible for referral to the study team (see Table). The reasons for this are unclear, and may represent differential rates of referral to the study team by clinicians, differential acceptance of the clinician’s referral, or differences in how race/ethnicity were assessed by registration staff at the clinic as compared with the study team. Table Race/Ethnicity of HIV-negative MSM seen at the US PrEP Demo Project participating clinics compared with those who were “clinic referred” and assessed for participation in the study We agree and highlighted in the original manuscript that BMSM were less likely to self-refer to the study than White MSM. This likely reflects lower levels of PrEP awareness, and less demand for PrEP, among BMSM in the participating cities. In addition, Black individuals were more likely to be diagnosed with HIV-infection during the screening process. Of 90 Black individuals assessed for participation, 5 (5.6%) were HIV-positive, compared with 4/411 (1.0%) of Whites, 9/354 (2.5%) of Latinos, 0/57 Asians and 1/69 (1.5%) of those of “other” race (p=0.053). We did not actively recruit MSM of color to the study as we were interested in assessing the feasibility of PrEP delivery in our varied clinical settings and interest in PrEP among our clinic populations. However, based on our study findings, we agree with the urgent need to increase PrEP knowledge and interest among BMSM and transgender individuals, two groups that were underrepresented in our study, and to ensure cultural competency of clinics and providers in delivering PrEP to these communities. Diffusion of innovations through communities takes time, and opinion leaders are critical to the process.10 In our study, 65% of self-referred participants had learned about PrEP from a friend or sex partner. Disseminating information about PrEP to MSM of color and transgender individuals through social marketing and peer-to-peer communication will be critical to increasing uptake. The authors raise a concern that the provision of free medication and remuneration for study participation may have contributed to PrEP uptake. Compensation was not excessive (

Commitment issues: PrEP adherence in injecting drug users

25.00/scheduled study visit) and was meant to offset opportunity costs related to being in the study. We agree that affordability is critical to PrEP dissemination and this is evidenced by significant differences in PrEP access across our three clinics and jurisdictions. WWH has fully integrated PrEP into its primary care clinic, and now has >200 individuals on PrEP, 11.5% of whom are Black. At SFCC PrEP is now being offered as part of routine sexual health services, and uninsured clients are assisted with applying for a patient assistance program. Over 100 SFCC patients have been initiated on PrEP since the end of the demonstration project, 8% of whom are Black, compared with 3% who enrolled in the Demo Project. Access to PrEP in Miami, while increasing, is still limited. The Miami STD clinic has not integrated PrEP into routine services, and Miami participants were much less likely to report being on PrEP 6-months after study completion, despite being equally likely to express an interest in post-study PrEP use, compared with those in San Francisco (Susanne Doblecki-Lewis, personal communication, April 20, 2015). Cost is a major barrier to PrEP in Miami given the lack of Medicaid expansion and fewer safety net resources. Additional efforts are needed to improve affordability in order to ensure that PrEP is accessible by all individuals at risk. Finally, the authors question whether the behavioral risk criteria used to determine PrEP eligibility are generalizable, and whether they would adequately identify young BMSM at risk for HIV. We used relatively broad behavioral risk criteria, including condomless anal sex with >1 male or TGW sex partner; > 1 episode of anal sex with at least one HIV-infected partner (regardless of condom use); or having syphilis or rectal gonorrhea or rectal chlamydia in the prior 12 months.9 These criteria can be easily implemented in clinical and non-clinical settings, and are consistent with guidelines issued by the Centers for Disease Control and Prevention.11 We chose to launch the US PrEP demonstration project in three diverse clinical settings, in three different metropolitan areas. HIV and STD incidence is high among patients served at all three study sites and 3 of 557 participants were found to have acute HIV infection at the enrollment visit. Other projects focused on younger MSM and BMSM are underway and will provide critical information about barriers to PrEP uptake among these disproportionately impacted populations.12-14 There is a complement of studies planned and moving forward, and we agree with prioritizing those with the highest incidence of HIV for PrEP.