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Summary Background In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov , number NCT02842086 . Findings Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07–0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17–0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78–82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p Interpretation Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding Gilead Sciences.

Background Unhealthy alcohol use among persons living with HIV (PLWH) is linked to significant morbidity and use of alcohol services may differ by HIV status. Our objective was to compare unhealthy alcohol use screening and treatment by HIV status in primary care. Methods Cohort study of adult (≥18 years) PLWH and HIV-uninfected participants frequency-matched 20:1 to PLWH by age, sex, and race/ethnicity who were enrolled in a large integrated healthcare system in the United States, with information ascertained from an electronic health record. Outcomes included unhealthy alcohol screening, prevalence, provider-delivered brief interventions and addiction specialty care visits. Other predictors included age, sex, race/ethnicity, neighborhood deprivation index, depression, smoking, substance use disorders, Charlson comorbidity index, prior outpatient visits, insurance type, and medical facility. Cox proportional hazards models were used to compute hazard ratios (HR) for the outcomes of time to unhealthy alcohol use screening and time to first addiction specialty visit. Poisson regression with robust standard errors were used to compute prevalence ratios (HR) for other outcomes. Results 11,235 PLWH and 227,320 HIV-uninfected participants were included. By 4.5 years after baseline, most participants were screened for unhealthy alcohol use (85% of PLWH and 93% of HIV-uninfected), but with a lower rate among PLWH (adjusted hazard ratio [HR] 0.84, 95% CI 0.82-0.85). PLWH were less likely, compared with HIV-uninfected participants, to report unhealthy drinking among those screened (adjusted PR 0.74, 95% CI 0.69-0.79), and among those who screened positive, less likely to receive brief interventions (adjusted PR 0.82, 95% CI 0.75-0.90), but more likely (adjusted HR 1.7, 95% CI 1.2-2.4) to have an addiction specialty visit within one year. Conclusions Unhealthy alcohol use was lower in PLWH, but the treatment approach by HIV status differed. PLWH reporting unhealthy alcohol use received less brief interventions and more addiction specialty care than HIV-uninfected participants.

Summary Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov , NCT02607930 and NCT02607956 . Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference −1·9%, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (−0·1 vs −0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. Interpretation These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Funding Gilead Sciences.

We implemented self-collected gonorrhea/chlamydia testing in 17 medical centers in California serving men who have sex with men living with HIV. From 2012 to 2018, gonorrhea/chlamydia testing increased from 45.2% to 63.4%. Among those tested, rectal testing increased from 42.0% to 77.3%; pharyngeal testing increased from 31.0% to 79.9% (all, Ptrend < 0.0001).

Background Cabotegravir and rilpivirine long-acting (CAB+RPV LA) administered by monthly injection demonstrated non-inferiority compared to standard daily oral antiretroviral therapy (ART) at 48 weeks. This novel treatment offers a less frequent dosing alternative to daily oral pills but requires more frequent clinic visits. Patient perspectives on implementation of CAB + RPV LA in US healthcare settings were evaluated in an innovative Hybrid III implementation-effectiveness study (CUSTOMIZE). Methods This single-arm study enrolled virologically suppressed patients to receive monthly CAB+RPV LA across eight diverse US clinics. Patients were surveyed at Baseline (BL) prior to the first injection and at Month 4 (M4) prior to the fourth injection to evaluate clinic implementation of CAB+RPV LA, including Acceptability of Intervention (AIM) and Intervention Appropriateness (IAM) Measures. Subgroups were compared with Fisher’s exact test. Results A total of 109 and 105 patients completed BL and M4 surveys, respectively, and were 87% male; 59% Caucasian and 35% African American; 27% Hispanic/Latino; mean age 39 years (range 20-65). At BL, 33% reported hiding their oral ART from others, 22% reported problems remembering to take daily ART (female 43% > male 19%, p< 0.05), while 47% reported no problems with daily ART (male 51% > female 21%, p< 0.05). Patient “interest in a more convenient treatment option” (83%) was a top reason for choosing CAB+RPV LA treatment. Acceptability and appropriateness of CAB+RPV LA were high at BL and M4 (Figures). At M4, 84% of patients reported that monthly clinic visits were very/extremely acceptable and 66% reported no logistical challenges to clinic administered CAB+RPV LA. Injection pain/soreness was the most common worry at BL (58%); at M4, 28% reported injection pain/soreness as a concern. For Months 2-4, 95% of injections were within a +/-7-day dosing window (5% were early, -7 to -14 days). No patients missed an injection or required oral bridging. Figure 1. Acceptability of CAB+RPV LA: AIM Figure 2: Appropriateness of CAB+RPV LA: IAM Conclusion Most patients found CAB+RPV LA to be acceptable and appropriate, and a majority reported monthly appointments were highly acceptable. Initial implementation data suggest CAB+RPV LA is a convenient, appealing alternative treatment option for patients, with few reported logistical challenges. Disclosures Cindy Garris, MSPH, GlaxoSmithKline (Other Financial or Material Support, Stockholder)ViiV Healthcare (Employee) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paul Wannamaker, BA, ViiV Healthcare (Employee) Nobuhle Mpofu, MS, GlaxoSmithKline (Employee, Shareholder) Colleen A. McHorney, PhD, Evidera (Employee) Sonal Mansukhani, PhD, MBA, BS Pharm, Evidera (Employee) Maggie Czarnogorski, MD, MPH, ViiV Healthcare (Employee)

HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF).We examined differences in the proportion of participants with HIV-1 RNA 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen.STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch).At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA 50 copies/mL (difference 6.1%; 95% CI -1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96.E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.

Background Substance use disorders (SUDs) and psychiatric disorders are common among people with HIV (PWH) and lead to poor outcomes. Yet these conditions often go unrecognized and untreated in primary care. Methods The Promoting Access to Care Engagement (PACE) trial currently in process examines the impact of self-administered electronic screening for SUD risk, depression and anxiety in three large Kaiser Permanente Northern California primary care clinics serving over 5000 PWH. Screening uses validated measures (Tobacco, Alcohol, Prescription medication, and other Substance use [TAPS]; and the Adult Outcomes Questionnaire [AOQ], which includes the Patient Health Questionnaire [PHQ-9] and Generalized Anxiety Disorder [GAD-2]) delivered via three modalities (secure messaging, tablets in waiting rooms, and desktop computers in exam rooms). Results are integrated automatically into the electronic health record. Based on screening results and physician referrals, behavioral health specialists embedded in primary care initiate motivational interviewing- and cognitive behavioral therapy-based brief treatment and link patients to addiction and psychiatry clinics as needed. Analyses examine implementation (screening and treatment rates) and effectiveness (SUD, depression and anxiety symptoms; HIV viral control) outcomes using a stepped-wedge design, with a 12-month intervention phase implemented sequentially in the clinics, and a 24-month usual care period prior to implementation in each clinic functioning as sequential observational phases for comparison. We also evaluate screening and treatment costs and implementation barriers and facilitators. Discussion The study examines innovative, technology-facilitated strategies for improving assessment and treatment in primary care. Results may help to inform substance use, mental health, and HIV services. Trial registration NCT03217058

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

OBJECTIVES To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor-based single-tablet regimen (STR) for initial treatment of HIV-1 infection. METHODS Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥ 70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks. RESULTS At week 24, viral suppression (HIV-1 RNA

Introduction Screening for syphilis, gonorrhoea (GC) and chlamydia (CT) is recommended at least annually for HIV-positive men who have sex with men (MSM) in the United States (US). Recent analyses from the US Medical Monitoring Project demonstrate that STD screening of HIV-positive MSM remains far below that recommended by guidelines; specific data on extragenital GC/CT screening is not reported. We implemented a quality improvement intervention to improve STD screening (syphilis, GC/CT) in a large managed care organisation (16 centres) including didactic training and implementation of self-collected swabs for GC/CT. Methods We analysed data from the Kaiser Permanente Northern California HIV Registry to calculate the proportion of MSM tested for syphilis and GC/CT (any site, rectal/pharyngeal site) at least once in the prior year. Laboratory validation of self-collected swabs was completed by 1/2014, rolled out at five centres by 12/2014, and 11 centres by 11/2016. Screening data were finalised for analysis in 1/2017. Three time periods were examined: baseline (6/2012), 1 year (11/2015), and 2 years (11/2016) post initial implementation of self-collection. Cochran-Armitage was used to test for trends. Results During the study period, the denominator of eligible HIV-positive MSM increased from n=4499 to 5866. Annual screening for GC/CT (any site) significantly increased from 45.2% to 58.3% (p trend trend trend =0.0002). Conclusion Implementation of self-collected GC/CT swabs is an effective intervention to increase STD screening among MSM in a large US managed care organisation. This intervention should be disseminated to other settings to improve currently suboptimal STD screening rates among MSM.

OBJECTIVE To evaluate the efficacy and safety of antiretroviral simplification from a ritonavir-boosted protease inhibitor-based regimen [protease inhibitor+RTV+two nucleos(t)ide reverse transcriptase inhibitors (NRTIs); ≥6 months of exposure prior to study entry with no prior treatment failure] to the single-tablet regimen (STR) rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) in virologically suppressed, HIV-1-infected participants. DESIGN Phase 3b, randomized, open-label, international, 48-week switch study. METHODS Participants were randomized 2 : 1 to switch to RPV/FTC/TDF immediately or stay on their baseline protease inhibitor+RTV+2NRTIs regimen with a delayed switch to RPV/FTC/TDF at week 24. The primary endpoint was noninferiority (12% margin) of RPV/FTC/TDF compared with protease inhibitor+RTV+ two NRTIs in maintaining plasma HIV-1 RNA less than 50 copies/ml at week 24 by Snapshot analysis. RESULTS A total of 476 participants were randomized and received at least one dose of study drug. Demographics and baseline characteristics were similar between arms. The primary objective of noninferiority at week 24 was met: HIV-1 RNA less than 50 copies/ml by Snapshot analysis, 93.7% of RPV/FTC/TDF versus 89.9% of protease inhibitor+RTV+ two NRTIs (difference 3.8%, 95% confidence interval -1.6 to 9.1%). Through week 48, 89.3% of participants in the immediate switch group maintained virologic suppression. High rates of suppression were maintained with RPV/FTC/TDF regardless of participant's pre-antiretroviral HIV-1 RNA level. Overall development of resistance mutations after switching to RPV/FTC/TDF was low. Decreases in total cholesterol, low-density lipoprotein (LDL), and triglycerides were significantly greater among RPV/FTC/TDF recipients than those in the protease inhibitor+RTV+ two NRTIs group. CONCLUSION Switching to the STR RPV/FTC/TDF from an RTV-boosted protease inhibitor regimen in virologically suppressed, HIV-1-infected participants maintained virologic suppression with a low risk of virologic failure, while improving total cholesterol, LDL, and triglycerides.

Background Black adults are disproportionately affected by HIV. Methods We conducted a 96-week subgroup analysis by race (Black vs. non-Black) for efficacy (pre-specified) and safety (post-hoc) from a randomized, double blind, active-controlled study in virologically suppressed HIV-infected individuals who switched to emtricitabine/tenofovir alafenamide (FTC/TAF) from FTC/tenofovir disoproxil fumarate (FTC/TDF) vs. continuing FTC/TDF while remaining on the same third agent. Results Of 663 treated patients, 136 (20.5%) self-identified as Black (FTC /TAF n = 69, FTC /TDF n = 67). Baseline viral load, CD4 counts, renal laboratory parameters, and bone mineral density (BMD) were similar between the two arms within Blacks and non-Blacks. For Blacks, virologic success by FDA snapshot algorithm at week 96: FTC /TAF 87.0% vs. FTC /TDF 88.1%; for non-Blacks 89.0% vs. 89.7%. Few participants discontinued study drug due to adverse events in either subgroups (FTC/TAF vs. FTC/TDF: Black 0 vs.. 1.5%; non-Black, 3.0% vs. 1.1%). In assessment of renal and bone safety using estimated glomerular filtration rate (eGFR), renal biomarkers, and BMD, there were differences between two arms that generally favored FTC/TAF over FTC/TDF (Table). In the overall population, no cases of Fanconi syndrome or proximal renal tubulopathy occurred with FTC/TAF; one FTC/TDF participant discontinued study drug due to proximal tubulopathy. Conclusion In virologically suppressed Black adults, FTC/TAF demonstrated improvements in renal and bone safety over FTC/TDF with similar sustained efficacy at week 96. These results support switching to FTC/TAF from FTC/TDF for the treatment of HIV-1 infection in Black adults. Disclosures J. A. Flamm, Gilead: Investigator, Research support; T. Vanig, Gilead: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; J. Gathe, Gilead: Investigator, Research support; C. Kinder, Gilead: Investigator, Research support; M. Para, Gilead: Investigator, Research grant and Research support; B. Rashbaum, Gilead: Investigator and Shareholder, Research support and Speaker honorarium; S. Segal-Maurer, Gilead Sciences: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; Janssen Therapeutics: Speaker’s Bureau, Speaker honorarium; D. Shamblaw, Gilead: Investigator, Research support; M. Wohlfeiler, Gilead: Investigator, Research support; B. Young, Gilead Sciences: Independent Contractor, Investigator, Research Contractor and Scientific Advisor, Consulting fee, Research support and Speaker honorarium; Merck & Co: Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; ViiV Healthcare: Scientific Advisor, Research grant; C. Zurawski, Gilead: Investigator, Research grant; M. S. Rhee, Gilead: Employee and Shareholder, Salary

Interruption of suppressive highly active antiretroviral therapy (HAART) in HIV-infected patients leads to increased HIV replication and viral rebound in peripheral blood. Effects of therapy interruption on gut-associated lymphoid tissue (GALT) have not been well investigated. We evaluated longitudinal changes in viral replication and emergence of viral variants in the context of T cell homeostasis and gene expression in GALT of three HIV-positive patients who initiated HAART during primary HIV infection but opted to interrupt therapy thereafter. Longitudinal viral sequence analysis revealed that a stable proviral reservoir was established in GALT during primary HIV infection that persisted through early HAART and post-therapy interruption. Proviral variants in GALT and peripheral blood mononuclear cells (PBMCs) displayed low levels of genomic diversity at all times. A rapid increase in viral loads with a modest decline of CD4 + T cells in peripheral blood was observed, while gut mucosal CD4 + T cell loss was severe following HAART interruption. This was accompanied by increased mucosal gene expression regulating interferon (IFN)-mediated antiviral responses and immune activation, a profile similar to those found in HAART-naive HIV-infected patients. Sequence analysis of rebound virus suggested that GALT was not the major contributor to the postinterruption plasma viremia nor were GALT HIV reservoirs rapidly replaced by HIV rebound variants. Our data suggest an early establishment and persistence of viral reservoirs in GALT with minimal diversity. Early detection of and therapy for HIV infection may be beneficial in controlling viral evolution and limiting establishment of diverse viral reservoirs in the mucosal compartment.

Human immunodeficiency virus (HIV) infection leads to severe CD4+ T-cell depletion in gut-associated lymphoid tissue (GALT) that persists despite the initiation of highly active antiretroviral therapy (HAART). It is not known whether restoration of gut mucosal CD4+ T cells and their functions is feasible during therapy and how that relates to immune correlates and viral reservoirs. Intestinal biopsies and peripheral blood samples from HIV-infected patients who were either HAART naive or on long-term HAART were evaluated. Our data demonstrated that gut CD4+ T-cell restoration ranged from modest (50%) to high (50%), compared with uninfected controls. Despite persistent CD4+ T-cell proviral burden and residual immune activation in GALT during HAART, effective CD4+ T-cell restoration (50%) was achieved, which was associated with enhanced Th17 CD4+ T-cell accumulation and polyfunctional anti-HIV cellular responses. Our findings suggest that a threshold of50% CD4+ T-cell restoration may be sufficient for polyfunctional HIV-specific T cells with implications in the evaluation of vaccines and therapeutics.

HIV-1 genotypic resistance test results were obtained on clinical samples from 116 patients with plasma HIV-1 RNA levels of less than 75 copies/mL. Genotype validity was confirmed in 49 of 50 patients with a previous or follow-up genotype. The belief that genotypic resistance testing is unreliable in samples with low-level viremia should be reassessed.

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+T-cell restoration, gene expression, and HIV-specific CD8+T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+T cells were predominantly of a memory phenotype and expressed CD11α, αEβ7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+T-cell restoration. Our findings suggest that the discordance in CD4+T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+T cells and the gut microenvironment.

Limited information is available on the molecular mechanisms by which long-term HIV-1-infected nonprogressors suppress HIV-1 infection and maintain immune functions. The intestinal mucosal immune system is an early target for HIV-1 infection and severe CD4 + T cell depletion. We evaluated mucosal T lymphocyte subsets, virus-specific cellular responses, gene expression profiles, and viral loads in intestinal mucosal biopsies of long-term nonprogressor (LTNP) patients as compared to chronically HIV-1-infected patients with high viral loads (HVLs) and CD4 + T cell loss, as well as HIV-seronegative healthy individuals. This study aims to identify the mucosal correlates of HIV disease progression and to determine the molecular changes associated with immune and intestinal dysfunction. LTNP patients had undetectable viral loads, normal CD4 + T cell levels, and virus-specific cellular responses in peripheral blood and mucosal compartments. Microarray analysis revealed a significant increase in gene expression regulating immune activation, cell trafficking, and inflammatory response in intestinal mucosa of HVL patients as compared to LTNP patients. Genes associated with cell cycle regulation, lipid metabolism, and epithelial cell barrier and digestive functions were down-regulated in both HVL and LTNP patients. This may adversely influence nutrient adsorption and digestive functions, with the potential to impact the efficacy of antiretroviral therapy. We demonstrate that the maintenance of mucosal T cells, virus-specific responses, and distinct gene expression profiles correlate with clinical outcome in LTNP patients. However, the intestinal mucosal immune system remains an important target of HIV-1 infection in LTNP, and these effects may ultimately contribute toward disease progression.

Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body and is an important target for human immunodeficiency virus type 1 (HIV-1). We analyzed longitudinal jejunal biopsy samples from HIV-1-infected patients, during both primary and chronic stages of HIV-1 infection, prior to and following the initiation of highly active antiretroviral therapy (HAART) to determine the onset of CD4+T-cell depletion and the effect of HAART on the restoration of CD4+T cells in GALT. Severe depletion of intestinal CD4+T cells occurred during primary HIV-1 infection. Our results showed that the restoration of intestinal CD4+T cells following HAART in chronically HIV-1-infected patients was substantially delayed and incomplete. In contrast, initiation of HAART during early stages of infection resulted in near-complete restoration of intestinal CD4+T cells, despite the delay in comparison to peripheral blood CD4+T-cell recovery. DNA microarray analysis of gene expression profiles and flow-cytometric analysis of lymphocyte homing and cell proliferation markers demonstrated that cell trafficking to GALT and not local proliferation contributed to CD4+T-cell restoration. Evaluation of jejunal biopsy samples from long-term HIV-1-infected nonprogressors showed maintenance of normal CD4+T-cell levels in both GALT and peripheral blood. Our results demonstrate that near-complete restoration of mucosal immune system can be achieved by initiating HAART early in HIV-1 infection. Monitoring of the restoration and/or maintenance of CD4+T cells in GALT provides a more accurate assessment of the efficacy of antiviral host immune responses as well as HAART.

Background Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn’s disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites.

Antiretroviral regimen simplification improves quality of life and medication adherence while reducing the risk of HIV virologic failure (VF) and long-term drug-related toxicities. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) is a well-tolerated and efficacious once-daily single-tablet regimen (STR) treatment option. Here we report the Week 48 safety and efficacy results of SPIRIT, the first study to evaluate switching from boosted protease inhibitor (PI+RTV)-based HAART to a simplified regimen of FTC/RPV/TDF STR. SPIRIT is a phase 3b, randomized, open-label, multi-center, international, 48-week study to evaluate the safety and efficacy of switching from PI+RTV regimens to FTC/RPV/TDF in virologically-suppressed HIV-1 infected participants. Participants were randomized 2:1 to switch to FTC/RPV/TDF at baseline or maintain their current PI+RTV regimen with a delayed switch to FTC/RPV/TDF at Week 24. The primary endpoint was non-inferiority (12% margin) of FTC/RPV/TDF relative to PI+RTV regimens in maintaining plasma HIV-1 RNA

ARTEMIS demonstrated significantly greater efficacy of once-daily darunavir/ritonavir (DRV/r) 800/100 mg versus lopinavir/ritonavir 800/200 mg (total daily dose) in treatment-naïve, HIV-1-infected patients at week 96. The influence of baseline characteristics on efficacy and safety was analyzed in DRV/r patients.Patients received once-daily DRV/r plus fixed-dose tenofovir/emtricitabine. Week 96 efficacy and safety data were analyzed by gender (males, n=239; females, n=104), age (≤30, n=115; 31-45, n=175;45, n=53), race (Asian, n=44; Black, n=80; Caucasian/White, n=137; Hispanic, n=77), and hepatitis B and/or C virus coinfection (n=43).Week 96 virologic response rates (HIV-1 RNA50 copies/mL) were as follows: gender: 79% for both males and females; age: 72% (≤30), 81% (31-45), and 89% (45); race: 96% (Asian), 71% (Black), 77% (Caucasian/White), and 79% (Hispanic); coinfection status: 72% (coinfected) and 80% (non-coinfected). The incidence of treatment-related adverse drug reactions (ADRs) and laboratory abnormalities were comparable across gender, age, and race subgroups. Coinfected patients had a higher incidence of liver-related ADRs than non-coinfected patients.DRV/r 800/100 mg qd is an effective, well-tolerated treatment option for treatment-naïve patients of different gender, age, race, or coinfection status.

Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4 + T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4 + T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4 + T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

Hypothesis Matched patients who test positive or negative for human immunodeficiency virus (HIV) who are undergoing comparable operations have similar complication rates and outcomes. Design A retrospective study of surgical outcomes in HIV-infected and matched HIV-noninfected patients. Baseline information including HIV-related laboratory results, complications, and mortality was collected from printed and electronic records through 12 postoperative months. Setting Kaiser Permanente Medical Care Program–Northern California, an integrated health organization with more than 3 million members, including more than 5000 HIV-infected members. Patients From July 1,1997, through June 30, 2002, HIV-infected members undergoing surgical procedures were matched 1:1 with HIV-noninfected patients undergoing surgical procedures by type, location, and year of surgery as well as by sex and age. Surgical procedures studied included appendectomy, arthrotomy or arthroscopy, bowel resection, cholecystectomy, cardiothoracic procedures, hernia repair, hysterectomy, hip or knee replacement, laparoscopy or laparotomy, and mammoplasty. Main Outcome Measures Complications and mortality through 12 postoperative months, comparisons between HIV-infected and HIV-noninfected patients using matched-pair analyses, and HIV-infected cohort data were analyzed using the Fisher exact test and logistic regression. Results Of 332 HIV-infected–HIV-noninfected pairs (mean age, 46.7 years; male sex, 91%), more than 95.0% were followed up through 12 postoperative months or until their deaths. Pairs had similar comorbidities, length of hospital stay, and number of postoperative surgical visits ( P >.05, all variables). Among HIV-infected patients, the median years with HIV infection was 8.4 years; median CD4 T-cell count was 379/μL; 61.5% of these patients had an HIV RNA level less than 500 copies per milliliter; and 68% were receiving highly active antiretroviral therapy. Various complications were no more frequent among HIV-infected than in HIV-noninfected patients (11.1% vs 10.2%; P = .79), except for pneumonia ( P = .04). There were more deaths within the 12 postoperative months in HIV-infected patients (10/332 vs 2/332; P = .02); 2 patients died 30 days or less after being operated on. Among HIV-infected patients, viral load of 30 000 copies per milliliter or more was associated with increased complications (adjusted odds ratio, 2.95; P = .007), but a CD4 cell count less than 200/μL was not associated with poorer outcomes. Conclusions The HIV-infected patients had more incidences of postoperative pneumonia and higher 12-month mortality, although other operative outcomes were comparable for HIV-infected and HIV-noninfected patients. Viral suppression to fewer than 30 000 copies per milliliter reduced surgical complications.

Objective: This randomized pilot study evaluates whether seropositive patients who are randomly assigned to receive a supportive-expressive group therapy plus education intervention show greater improvements in increased immune function and decreased viral load compared to those randomly assigned to an education-only intervention. Method: Fifty-nine individuals who had been HIV-seropositive for at least 6 months prior to inclusion in the study and had been receiving standard pharmacologic treatment were entered in a prospective randomized trial of the effects of weekly supportive-expressive group therapy on changes in immune status. Participants were matched for AIDS status and sex and randomized to receive weekly sessions of group psychotherapy plus educational materials on HIV/AIDS, or to receive the educational materials alone. Participants were assessed before treatment and then 12 weeks later. Results: Individuals who were randomized to group therapy showed a statistically significant increase in CD4 count and decrease in HIV viral load. Among individuals randomized to the education only condition, no significant change occurred in CD4 count or viral load. Conclusions: These results provide preliminary data suggesting that HIV-seropositive individuals who receive supportive-expressive group psychotherapy may experience concomitant improvements in CD4 cell count and viral load. Further research with a larger sample should examine the possible underlying mechanisms of such benefits.

This study examined social support and maladaptive coping as predictors of HIV-related health symptoms. Sixty-five men and women living with HIV/AIDS completed baseline measures assessing coping strategies, social support, and HIV-related health symptoms. The sample was primarily low-income and diverse with respect to gender, ethnicity, and sexual orientation. Three, 6, and 12 months after completing baseline assessments, physical health symptoms associated with HIV disease were assessed. After controlling for demographic characteristics, CD4 T-cell count, and baseline HIV-related health symptoms, individuals reporting lower increase in HIV-related health symptoms used less venting (expressing emotional distress) as a strategy for coping with HIV. However, when satisfaction with social support was added to the model, the use of this coping strategy was no longer significant, and individuals reporting more satisfying social support were more likely to report lower increase in their HIV-related health symptoms, suggesting that social support is a robust predictor of health outcomes over time independent of coping style and baseline medical status. These findings provide further evidence that social support can buffer deleterious health outcomes among individuals with a chronic illness. Future research needs to examine mediating pathways that can explain this relationship.

Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.

Introduction : Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults [ 1 ]. We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects. Materials and Methods : Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA

Address: 1Department of Internal Medicine, Medical Hospital of the University of Cologne, Cologne, Germany, 2Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, UAB, Barcelona, Spain, 3Service des Maladies Infectieuses, APHP, Hopital Tenon, Paris, France, 4HIVNAT, Thai Red Cross AIDS Research Centre and Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 5Community Research Initiative of New England, Boston, USA, 6Kaiser Permanente Medical Group, Sacramento, USA, 7Tibotec BVBA, Mechelen, Belgium and 8Janssen-Cilag B.V., Tilburg, Netherlands * Corresponding author