Portable Nanopore sequencing solution for next-generation HIV drug resistance testing.

BACKGROUND: Tackling HIV drug resistance is one of major challenges for ending AIDS epidemic, but the elevated expense of cutting-edge genomics hampers the advancement of HIV genotype testing for clinical care. METHODS: We developed a HIV genotype testing pipeline that centers on a cost-efficient portable Nanopore sequencer. Accuracy verification was conducted through comparison with parallel data obtained via fixed-site Pacbio sequencing. Our complete pol-gene sequencing strategy coupled with portable high-throughput sequencing was applied to identify drug resistance mutations across 58 samples sourced from the ART-treated Los Angeles General Medical Center Rand Schrader Clinic (LARSC) cohort (7 samples from 7 individuals) and the ART-naïve Center for HIV/AIDS Vaccine Immunology (CHAVI) cohort (51 samples from 38 individuals). RESULTS: A total of 472 HIV consensus sequences, each tagged with a unique molecular identifier, were produced from over 1.4 million bases acquired through portable Nanopore sequencing, which matched those obtained independently via Pacbio sequencing. With this desirable accuracy, we first documented the linkage of multidrug cross-resistance mutations across Integrase Strand Transfer inhibitors (INSTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from an individual failing a second-generation INSTI regimen. By producing more than 500 full-length HIV pol gene sequences in a single portable sequencing run, we detected Protease Inhibitor (PI), Nucleoside Reverse Transcriptase Inhibitor (NRTI), NNRTI and INSTI resistance mutations. All drug resistance mutations identified through portable sequencing were cross-validated using fixed-site Pacbio sequencing. CONCLUSIONS: Our accurate and affordable HIV drug resistance testing solution is adaptable for both individual patient care and large-scale surveillance initiatives.

Precision detection of recent HIV infections using high-throughput genomic incidence assay.

HIV incidence is a key measure for tracking disease spread and identifying populations and geographic regions where new infections are most concentrated. The HIV sequence population provides a robust signal for the stage of infection. Large-scale and high-precision HIV sequencing is crucial for effective genomic incidence surveillance. We produced 1,034 full-length envelope gene sequences from a seroconversion cohort by conducting HIV microdrop sequencing and measuring the genomic incidence assay's genome similarity index (GSI) dynamics. The measured dynamics of 9 of 12 individuals aligned with the GSI distribution estimated independently using 417 publicly available incident samples. We enhanced the capacity to identify individuals with recent infections, achieving predicted detection accuracies of 92% (89%-94%) for cases within 6 months and 81% (74%-87%) for cases within 9 months. These accuracy levels agreed with the observed detection accuracy intervals of an independent validation data set. Additionally, we produced 131 full-length envelope gene sequences from eight individuals with chronic HIV infection. This analysis confirmed a false recency rate (FRR) of 0%, which was consistent with 162 publicly available chronic samples. The mean duration of recent infection (MDRI) was 238 (209-267) days, indicating an 83% improvement in performance compared to current recent infection testing algorithms. The shifted Poisson mixture model was then used to estimate the time since infection, and the model estimates showed an 88% consistency with the days post infection derived from HIV RNA test dates and/or seroconversion dates. HIV microdrop sequencing provides unique prospects for large-scale incidence surveillance using high-throughput sequencing. IMPORTANCE Accurate identification of recently infected individuals is vital for prioritizing specific populations for interventions, reducing onward transmission risks, and optimizing public health services. However, current HIV-specific antibody-based methods have not been satisfactory in accurately identifying incident cases, hindering the use of HIV recency testing for prevention efforts and partner protection. Genomic incidence assays offer a promising alternative for identifying recent infections. In our study, we used microdroplet technologies to produce a large number of complete HIV envelope gene sequences, enabling the accurate detection of early infection signs. We assessed the dynamics of the incidence assay's metrics and compared them with statistical models. Our approach demonstrated high accuracy in identifying individuals with recent infections, achieving predicted detection rates exceeding 90% within 6 months and over 80% within 9 months of infection. This high-resolution method holds significant potential for enhancing the effectiveness of HIV incidence screening for case-based surveillance in public health initiatives.

Full-spectrum HIV drug resistance mutation detection by high-resolution complete pol gene sequencing.

BACKGROUND: Drug resistance mutation testing is a key element for HIV clinical management, informing effective treatment regimens. However, resistance screening in current clinical practice is limited in reporting linked cross-class resistance mutations and minority variants, both of which may increase the risk of virological failure. METHODS: To address these limitations, we obtained 358 full-length pol gene sequences from 52 specimens of 20 HIV infected individuals by combining microdroplet amplification, unique molecular identifier (UMI) labeling, and long-read high-throughput sequencing. RESULTS: We conducted a rigorous assessment of the accuracy of our pipeline for precision drug resistance mutation detection, verifying that a sequencing depth of 35 high-throughput reads achieved complete, error-free pol gene sequencing. We detected 26 distinct drug resistance mutations to Protease Inhibitors (PIs), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Strand Transfer Inhibitors (INSTIs). We detected linked cross-class drug resistance mutations (PI+NRTI, PI+NNRTI, and NRTI+NNRTI) that confer cross-resistance to multiple drugs in different classes. Fourteen different types of minority mutations were also detected with frequencies ranging from 3.2% to 19%, and the presence of these mutations was verified by Sanger reference sequencing. We detected a putative transmitted drug resistance mutation (TDRM) in one individual that persisted for over seven months from the first sample collected at the acute stage of infection prior to seroconversion. CONCLUSIONS: Our comprehensive drug resistance mutation profiling can advance clinical practice by reporting mutation linkage and minority variants to better guide antiretroviral therapy options.

Randomized Trial of Individualized Texting for Adherence Building (iTAB) Plus Motivational Interviewing for PrEP Adherence in Transgender Individuals: The iM-PrEPT Study.

BACKGROUND: Transgender and nonbinary individuals at risk for HIV may benefit from adherence support for pre-exposure prophylaxis. METHODS: Between June 2017 and September 2020, 255 transgender and nonbinary individuals received daily oral tenofovir disoproxil fumarate/emtricitabine for 48 weeks randomized 1:1 to receive individualized Texting for Adherence Building (iTAB) or iTAB plus motivational interviewing (iTAB + MI) through phone for nonadherence. The primary end point was dried blood spot tenofovir diphosphate concentrations at weeks 12 and 48 (or last on-drug study visit) ≥1246 fmol/punch consistent with ≥7 doses/week (ie, near-perfect adherence). Secondary outcomes included dried blood spot tenofovir diphosphate concentrations ≥719 fmol/punch consistent with ≥4 doses/week (ie, adequate adherence) and self-reported adherence by daily text messages. RESULTS: Adherence for the outcome ≥1246 fmol/punch and ≥719 fmol/punch, respectively, was 49.1% and 57.9% for transgender men, 37.7% and 47.2% for nonbinary individuals, and 31.0% and 44.1% for transgender women. No difference was seen in iTAB + MI compared with iTAB alone by drug levels except where it approached significance in transgender women for the outcome of ≥719 fmol/punch in the iTAB + MI group compared with iTAB only (52% versus 35.7%, P = 0.065). There was a significant difference in self-reported daily dose adherence in the iTAB + MI group compared with iTAB alone (57.9% of days versus 46.4%, P = 0.009). In transgender women, the mean percentage of daily doses taken was 58.5% with iTAB + MI and 37.3% with iTAB alone ( P < 0.001). CONCLUSIONS: In addition to automated approaches to adherence promotion, phone-based MI triggered by repeatedly missing doses may improve pre-exposure prophylaxis adherence among transgender women.

Low incidence and prevalence of hepatitis C in two cohorts of HIV pre-exposure prophylaxis adherence interventions in men who have sex with men in Southern California.

HIV pre-exposure prophylaxis (PrEP) has been associated with incident hepatitis C virus (HCV) infection in men who have sex with men (MSM) due to decreased condom use. We examined rates of HCV among MSM and transgender women at high-risk of HIV on PrEP in Southern California using data from two trials (NCT01761643 and NCT01781806). Five of 599 participants (0.84%, 95% CI, 0.27-1.93) had HCV antibodies detected at entry. Factors associated with HCV seropositivity included being older (p = .002) and lower education level (p < .001). HCV-positive participants had no reported cases of sexually transmitted infection (rectal, urethral or pharyngeal gonorrhoea and/or chlamydia) at entry while HCV-negative participants had a prevalence of 18% (95% CI, 15%-21%). There were no significant differences in substance use and sexual risk behaviour between HCV-positive and HCV-negative participants 1-3 months prior to entry. Among early PrEP adopters, incident HCV did not occur despite ongoing condomless intercourse. Screening intervals for HCV in MSM on PrEP should be led by a risk behaviour assessment.

Sexually transmitted infections among participants in an HIV PrEP adherence trial.

BACKGROUND: HIV PrEP effectiveness is highly dependent on adherence. High STI incidence has been reported among PrEP users. We assessed the relationship between STI incidence (CT, NG, and syphilis) and PrEP adherence. METHODS: We performed a subanalysis of a controlled, open-label, two-arm, randomized clinical demonstration project of a text-message based adherence intervention. Participants had 48 weeks of follow-up and had STI testing every 12 or 24 weeks. PrEP adherence was measured at week 48 using intracellular tenofovir-diphosphate drug concentrations. We calculated incidence rate ratios for STIs among those adherent as compared with those not adherent to PrEP. RESULTS: Of the 381 assessed for CT, NG and syphilis at one or more follow-up visits, there were 16 cases of syphilis or 5.0 per 100 person years (95% CI: 2.6, 7.5); 63 cases of NG or 26.3 per 100 person years (95% CI: 19.8, 32.8); and 81 cases of CT or 36.3 per 100 person years (95% CI: 28.4, 44.2). We found no association between adequate PrEP adherence and STI incidence (aIRR: 0.97 95% CI: 0.67, 1.40). CONCLUSIONS: We found that the incidence of STIs was not significantly different between those adherent to PrEP and those non-adherent. Further research is needed to assess how PrEP use may impact STIs over time.

Method of Calculating Renal Function Estimates Could Inappropriately Exclude Transgender Patients Receiving Gender-Affirming Hormone Therapy from Pre-Exposure Prophylaxis Eligibility.

Purpose: Despite the importance of reliable renal function estimation among the growing transgender population, research describing the variability of existing equations is scarce. Study objectives were to (1) quantify the range of renal function estimates that would be observed if different gender coefficients are used in the estimating equations, (2) compare estimates of renal function (creatinine clearance [CLCR] or estimated glomerular filtration rate [GFR]) between users and nonusers of gender-affirming therapies, and (3) quantify the proportion of subjects who would be deemed ineligible for tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) based on the gender coefficient used. Methods: A retrospective analysis was performed among transgender PrEP users enrolled in a multicenter observational study between June 2017 and October 2021. The primary outcome was estimated kidney function, defined using calculated CLCR or GFR before initiating TDF/FTC for PrEP based on the three most commonly used estimating equations. Results: A total of 258 participants were evaluated. Median differences in renal function ranged from 13 to 25 mL/min based on which gender coefficient and equation was used. Regardless of the method used to compute renal function, there were significant differences between users and nonusers of gender-affirming therapy. There were 17 (6.6%) participants where at least one of the methods would potentially render them ineligible to receive TDF/FTC for PrEP. Conclusions: Renal function estimates vary considerably with different estimating equations in the transgender population and are modified by use of gender-affirming therapy. These variations could result in exclusion from drug therapies such as TDF/FTC for PrEP.

A Randomized, Placebo-Controlled Trial Assessing the Effect of VISBIOME ES Probiotic in People With HIV on Antiretroviral Therapy.

BACKGROUND: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function. METHODS: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample t test with equal variance or the Wilcoxon rank-sum test. For safety, the highest graded adverse events (AEs) were compared between arms using the Fisher exact test. RESULTS: Overall, 93 participants enrolled: 86% male, median age 51 years, median CD4 count 712 cells/mm3. Visbiome ES was safe and well tolerated. There was no difference in mean change in sCD14 from baseline to week 25/26 between placebo (mean change, 92.3 µg/L; 95% CI, -48.5 to 233 µg/L) and Visbiome ES (mean change, 41.0 µg/L; 95% CI, -94.1 to 176.2 µg/L; P=.60). Similarly, no statistically significant differences between arms in inflammatory marker changes were identified. In substudy participants, no statistical differences between arms for change in cellular marker expression or gut permeability were observed (P>.05 for all). The microbiome demonstrated increased probiotic species and a significant decrease in Gammaproteobacteria (P=.044) in the Visbiome ES arm. CONCLUSIONS: Visbiome ES was safe and altered the microbiome but demonstrated no effect on systemic inflammatory markers, pathology, or gut permeability in antiretroviral therapy-treated people with HIV.

Veillonella Bacteremia in Alcoholic Hepatitis.

Veillonella species are commensal bacteria of the human oral, gut, and vaginal microbiota that are rarely identified as clinically relevant pathogens. Here, we describe a novel case of Veillonella atypica bacteremia in a patient with biopsy-proven alcoholic hepatitis. Veillonella species have been correlated with disease severity and hepatic encephalopathy in liver diseases such as autoimmune hepatitis and cirrhosis. Their abundance has also been recently observed to be increased in alcoholic hepatitis, where postinflammatory infections are known to impact mortality. This case report highlights the possible clinical manifestations that result from significant gut dysbiosis in patients with severe alcoholic hepatitis. Early identification and treatment of Veillonella bacteremia in susceptible populations could be crucial to survival given this organism's predilection for causing life-threatening infections, including meningitis, endocarditis, and osteomyelitis.

Gut microbiome in people living with HIV is associated with impaired thiamine and folate syntheses.

People living with HIV have a high incidence of cardiovascular and neurological diseases as comorbid disorders that are commonly linked to inflammation. While microbial translocation can augment inflammation during HIV infection, functional microbiome shifts that may increase pro-inflammatory responses have not been fully characterized. In addition, defining HIV-induced microbiome changes has been complicated by high variability among individuals. Here we conducted functional annotation of previously-published 16S ribosomal RNA gene sequences of 305 HIV positive and 249 negative individuals, with adjustment for geographic region, sex, sexual behavior, and age. Metagenome profiles were inferred from these individuals' 16S data. HIV infection was associated with impaired microbial vitamin B synthesis; around half of the gene families in thiamine and folate biosynthesis pathways were significantly less abundant in the HIV positive group than the negative control. These results are consistent with the high prevalence of thiamine and folate deficiencies in HIV infections. These HIV-induced microbiota shifts have the potential to influence cardiovascular and neurocognitive diseases, given the documented associations between B-vitamin deficiencies, inflammation, and these diseases. We also observed that most essential amino acid biosynthesis pathways were downregulated in the microbiome of HIV-infected individuals. Microbial vitamin B and amino acid synthesis pathways were not significantly recovered by antiretroviral treatment when we compared 262 ART positive and 184 ART negative individuals. Our meta-analysis provides a new outlook for understanding vitamin B and amino acid deficiencies in HIV patients, suggesting that interventions for reversing HIV-induced microbiome shifts may aid in lessening the burdens of HIV comorbidities.

Tesamorelin improves fat quality independent of changes in fat quantity.

OBJECTIVES: Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density. DESIGN: Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated. METHODS: CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader. RESULTS: Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P < 0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P < 0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5-7.3), P = 0.001) or SAT (+3.5 HU, 95% confidence interval (2.3-4.7), P < 0.001] area change. CONCLUSION: In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.

Short Communication: Impact of Fat Changes on the Effect of Protease Inhibitors on Lumbar Spine Bone Mineral Density Changes with Antiretroviral Therapy Initiation.

People living with HIV (PLWH) who are on protease inhibitor (PI)-containing regimens have been shown to have increases in visceral adipose tissue (VAT) and a greater decrease in spine bone mineral density (BMD) than those receiving non-PI regimens when initiating treatment. This increase in VAT has been hypothesized to falsely lower spine BMD measured via dual-energy X-ray absorptiometry, suggesting that the PI-associated BMD loss is an artefact rather than real. To test this, data collected from two completed 96-week clinical trials, AIDS Clinical Trial Group studies A5224s and A5260s, of antiretroviral therapy-naive PLWH initiating treatment with PI and non-PI-containing regimens were analyzed comparing VAT accumulation and spine BMD loss. Results showed no significant decrease in spine BMD in persons in the highest quartile (Q4) of VAT gain versus the rest of the study population (Q1-3) in either the PI and non-PI arms, suggesting that PI-associated BMD loss is not likely to be an artefact of overlying VAT.

Characteristics of a cohort of high-risk men who have sex with men on pre-exposure prophylaxis reporting transgender sexual partners.

Transgender people continue to be at high-risk for HIV acquisition, but little is known about the characteristics of their sexual partners. To address this gap, we examined sociodemographic and sexual characteristics of cisgender men who have sex with men (MSM) on pre-exposure prophylaxis (PrEP) reporting transgender sexual partners.A cohort of 392 MSM in southern California in a randomized clinical trial for PrEP adherence were followed from 2013 to 2016. Multivariable generalized estimating equation and logistic models identified characteristics of MSM reporting transgender sexual partners and PrEP adherence.Only 14 (4%) MSM reported having transgender sexual partners. MSM were more likely to report transgender partners if they were African American, had incident chlamydia, reported injection drug-using sexual partners, or received items for sex. Most associations remained significant in the multivariable model: African American (adjusted odds ratio [AOR] 11.20, P = .01), incident chlamydia (AOR 3.71, P = .04), and receiving items for sex (AOR 5.29, P = .04). There were no significant differences in PrEP adherence between MSM reporting transgender partners and their counterpart.MSM who report transgender sexual partners share characteristics associated with individuals with high HIV prevalence. Identifying this group distinct from larger cohorts of MSM could offer new HIV prevention opportunities for this group of MSM and the transgender community.

Effect of Vitamin D Supplementation on Bone Turnover Markers During HIV Pre-Exposure Prophylaxis Using Tenofovir Disoproxil Fumarate-Emtricitabine in Men Who Have Sex with Men.

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduces bone mineral density in HIV-uninfected men who have sex with men (MSM). We hypothesized that PrEP with TDF-FTC would increase bone turnover markers (BTMs) at week 24 and that vitamin D supplementation from weeks 24 to 48 would blunt this increase. Participants were from a cohort of 398 MSM and transgender women who received daily TDF-FTC for PrEP. At week 24, a prospective intervention group initiated vitamin D3 4,000 IU daily. Concurrent controls were selected from the cohort who took ≤400 IU/day of vitamin D3 matched by age, race, and body mass index. The primary endpoint was the change in procollagen-I N-terminal propeptide (P1NP) from weeks 24 to 48. Paired t-tests were used to compare changes in BTMs between intervention and controls. Among 48 intervention-control pairs, median age was 33 years. At baseline, 68.9% of the intervention group and 77.3% of controls were vitamin D sufficient (≥20 ng/mL, p = .94). P1NP, C-telopeptide, parathyroid hormone (PTH), and 25-OH vitamin D3 did not increase significantly at week 24. P1NP fell by a mean ± SD of -27.6 ± 49.9 pg/mL from weeks 24 to 48 with vitamin D and -2.5 ± 40.2 pg/mL in controls (p = .01). There were no significant between-group differences in the weeks 24-48 change in C-telopeptide, PTH, or 25-OH vitamin D3. Vitamin D3 supplementation with 4,000 IU/day resulted in a significant reduction in the BTM P1NP compared with controls, suggesting that this intervention has potential to improve bone health during PrEP.

Predictors of Long-Term HIV Pre-exposure Prophylaxis Adherence After Study Participation in Men Who Have Sex With Men.

BACKGROUND: Efficacy of HIV pre-exposure prophylaxis (PrEP) among men who have sex with men is well documented in randomized trials. After trial completion, participants are challenged with acquiring PrEP on their own and remaining adherent. METHODS: This was a follow-up study of the TAPIR randomized controlled multicenter PrEP trial. Participants were contacted after their last TAPIR visit (ie, after study-provided PrEP was discontinued) to attend observational posttrial visits 24 and 48 weeks later. Adherence during TAPIR and posttrial visits was estimated by dried blood spot intracellular tenofovir diphosphate levels (adequate adherence defined as tenofovir diphosphate levels >719 fmol/punch). Binary logistic regression analysis assessed predictors of completing posttrial visits and PrEP adherence among participants completing ≥1 visit. RESULTS: Of 395 TAPIR participants who were on PrEP as part of the TAPIR trial for a median of 597 days (range 3-757 days), 122 (31%) completed ≥1 posttrial visit (57% of University of California San Diego participants completed posttrial visits, whereas this was 13% or lower for other study sites). Among participants who completed ≥1 posttrial visit, 57% had adequate adherence posttrial. Significant predictors of adequate adherence posttrial were less problematic substance use, higher risk behavior, and adequate adherence in year 1 of TAPIR. CONCLUSION: More than half of PrEP users followed after trial completion had successfully acquired PrEP and showed adequate adherence. Additional adherence monitoring and intervention measures may be needed for those with low PrEP adherence and problematic substance use during the first year of trial.

A Randomized, Double-blinded, Placebo-controlled Trial of Sitagliptin for Reducing Inflammation and Immune Activation in Treated and Suppressed Human Immunodeficiency Virus Infection.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. METHODS: Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/µL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15-16. RESULTS: Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/µL. At week 15-16, there was no difference in sCD14 change between the 2 arms (P = .69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, -57% to -35%) at week 15 (P < .001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. CONCLUSIONS: Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. CLINICAL TRIALS REGISTRATION: NCT01426438.

Sexual Risk Compensation in a Pre-exposure Prophylaxis Demonstration Study Among Individuals at Risk of HIV.

BACKGROUND: A public health concern regarding HIV pre-exposure prophylaxis (PrEP) is sexual risk compensation (ie, increased unsafe sex among PrEP users that may undermine prevention efforts). METHODS: This demonstration study (NCT#01761643; initiated in 2013) included 398 men who have sex with men who initiated PrEP and were followed over 48 weeks at 4 sites in Southern California. Wilcoxon signed-rank tests compared previous 30-day number of sex partners and condomless insertive anal sex and receptive anal sex (CIAS and CRAS, respectively) acts at weeks 4, 12, 24, 36, and 48 to baseline. At 2 sites, PrEP users were also compared with a lagged, comparison group of 99 men who have sex with men who did not receive PrEP over 24 weeks using linear regression models, adjusting for age, race/ethnicity, education, and respective baseline scores. Logistic regression compared week 24 sexually transmitted infection (STI) rates. RESULTS: Over 48 weeks in the PrEP group, there were significant decreases in the number of unknown HIV status sex partners and increases in CRAS at all study visits; there was no consistent change in number of HIV+ sex partners or CIAS. Among participants at 2 sites, there were no significant differences between PrEP and non-PrEP users in change in number of partners, CIAS, CRAS, or STI rates at week 24. CONCLUSIONS: Among early adopters of PrEP, there is some evidence for sexual risk compensation. Results support current guidelines of regular STI screening and behavioral risk reduction and adherence counseling with the provision of PrEP.

Substance Use and Adherence to HIV Preexposure Prophylaxis for Men Who Have Sex with Men1.

The effectiveness of oral HIV preexposure prophylaxis (PrEP) strongly depends on maintaining adherence. We investigated the association between substance use and PrEP adherence, as well as incident sexually transmitted infections (STIs) in a high-risk cohort of 394 participants (391 men who have sex with men and 3 transgender women) who were enrolled in a PrEP demonstration project. We assessed baseline and ongoing substance use over a 48-week period for stimulants and nonstimulant substances and for each substance separately. We measured PrEP adherence by using dried blood spots to obtain levels of tenofovir diphosphate. No differences in these levels were found between substance users and nonsubstance users. Baseline stimulant use was strongly associated (odds ratio 3.4; p<0.001) with incident STIs during the study. Thus, PrEP adherence was not decreased by substance use. Because substance users had increased rates of STIs, indicating higher-risk behavior, they might be excellent candidates for PrEP.

Trajectories and Predictors of Longitudinal Preexposure Prophylaxis Adherence Among Men Who Have Sex With Men.

Background: Adherence is necessary for efficacy of preexposure prophylaxis (PrEP), and text-messaging methods are promising tools for both adherence assessment and support. Although PrEP adherence is variable, little research has examined patterns of variability or factors associated with longitudinal use. Methods: In the context of a randomized controlled trial of text-messaging versus standard of care for PrEP adherence, 181 men who have sex with men received once-daily tenofovir disoproxil fumarate/emtricitabine and daily adherence texts for 48 weeks. Growth mixture modeling (GMM) was used to identify subgroups of individuals with similar trajectories of text-reported adherence. Between-group differences in pharmacologic measures of adherence (ie, tenofovir diphosphate and emtricitabine triphosphate levels), as well as predictors and study-end attitudes associated with group membership, were examined. Results: GMM identified 4 trajectories of text-reported adherence. Classes with higher text-reported adherence had higher drug concentrations. Younger age and minority race were associated with lower adherence, and individuals in classes with lower adherence had greater baseline levels of depression, substance use concerns, and sexual risk. Differences in study satisfaction were also associated with adherence. Conclusions: This study supports the use of text-reported PrEP adherence. Identifying factors associated with less-than-optimal adherence may aid clinicians in anticipating at-risk patients requiring augmented intervention. Clinical trials registration: NCT01761643.