Truvada Research Articles

P-569. Changes in lipid profile in people living with HIV on stable protease inhibitors (PIs)-based regimens as second-line ART regimens switch to dolutegravir (DTG)-based regimens

Abstract Background Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection is associated with metabolic changes, including dyslipidemia and cardiovascular risk. Switching from protease inhibitor (PIs)-based regimens to dolutegravir (DTG)-based regimens offers potential benefits, but its impact on metabolic parameters requires investigation. This study aimed to assess the change in low-density lipoprotein cholesterol (LDL-C) levels, a risk factor for cardiovascular disease, in people living with HIV (PLWH) who switched from stable PIs-based second-line ART regimens to DTG-based regimens.Table 1Baseline characteristics of participants Methods We conducted a prospective cohort study evaluating lipid profile, renal function, and other metabolic parameters in PLWH who switched from PIs-based to DTG-based regimens. The DTG-based regimens comprised two nucleotide reverse transcriptase inhibitors (NRTIs), specifically tenofovir alafenamide (TAF) and emtricitabine (FTC), along with DTG in a single-tablet regimen once daily. The study was conducted at HIV-NAT, and data were collected over 24 weeks.Table 2Comparison of BMI and laboratory tests between PIs-based and 24 weeks after switching to DTG-based regimens Results Among 144 PLWH participants, switching to DTG-based regimens resulted in significant reductions in triglycerides (TG) and improvements in high-density lipoprotein cholesterol (HDL-C), while LDL-C and total cholesterol (TC) remained stable. Post-switching, participants experienced weight gain and increases in body mass index (BMI). Renal function, assessed by estimated glomerular filtration rate (eGFR), showed a decline. Despite these changes, virological suppression was maintained, and depressive symptoms remained stable. Notably, depression scores assessed using the Patient Health Questionnaire-9 (PHQ-9) at 24 weeks post-switching primarily indicated normal (68.3%) and mild depression (19.8%), with only one participant reporting severe depression. Conclusion Switching to DTG-based regimens in PLWH offers benefits in lipid profile and pill burden reduction, with modest increases in weight and LDL-C attributed primarily to the transition from TDF to TAF. Further research is needed to assess long-term effects, particularly on renal function and cost-effectiveness in diverse settings. These findings contribute to optimizing HIV care and treatment strategies globally. Disclosures All Authors: No reported disclosures

Intracellular tenofovir-diphosphate concentrations in HIV pre-exposure prophylaxis users who underwent bariatric surgery.

To measure concentrations of tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) among individuals taking tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) or tenofovir alafenamide plus emtricitabine (TAF/FTC) who were scheduled to undergo or had already undergone bariatric surgery. We enrolled pre-exposure prophylaxis (PrEP) users attending clinics in Toronto or Ottawa who were undergoing or had undergone bariatric surgery. After participants completed a minimum of 7 days of consecutive PrEP dosing, we collected DBS samples immediately before they administered their next daily dose of PrEP. Participants who had already undergone bariatric surgery before enrolment provided a single sample at baseline only. One participant undergoing planned bariatric surgery provided samples preoperatively and on postoperative days 7, 28 and 84. TFV-DP was measured by liquid chromatography tandem mass spectrometry. We compared results against the population range TFV-DP at varying degrees of adherence and stratified by chronology of bariatric surgery, type of bariatric surgery and PrEP regimen. Of seven eligible participants, all were gay, cis-gender men. Median age was 48 years (Q1-Q3: 44-51). Six participants underwent bariatric surgery before enrolment: four Roux-en-Y gastric bypass (RYGB) and two sleeve gastrectomy (SG). Four were taking TDF/FTC and two were taking TAF/FTC. All had therapeutic TFV-DP concentrations, except for one TDF/FTC participant who underwent SG. One participant taking TAF/FTC enrolled before receiving RYGB and displayed a slight decrease in TFV-DP over time, although all concentrations remained in the therapeutic range. Tenofovir diphosphate concentrations were at or near therapeutic values in this small sample of men using oral PrEP who underwent RYGB or SG.

Efficacy of dolutegravir plus lamivudine in treatment-naive people living with HIV without baseline drug-resistance testing available (D2ARLING): 48-week results of a phase 4, randomised, open-label, non-inferiority trial.

Dolutegravir plus lamivudine has emerged as a preferred treatment for HIV; however, initiating this regimen without baseline resistance testing raises concerns about the potential presence of pretreatment lamivudine resistance. We aimed to evaluate the efficacy of dolutegravir plus lamivudine in the absence of information on baseline resistance testing in treatment-naive people with HIV. We did an open-label, non-inferiority, single-centre, phase 4, randomised controlled study (D2ARLING), designed to assess the efficacy and safety of dolutegravir plus lamivudine in treatment-naive people with HIV with no available baseline resistance testing. We included participants aged 18 years or older with HIV-1 diagnosis who were naive to antiretroviral therapy and had no baseline genotypic resistance testing result available. We randomly assigned (1:1) participants to receive dolutegravir 50 mg plus lamivudine 300 mg or a three-drug regimen including dolutegravir 50 mg plus tenofovir disoproxil fumarate 300 mg and either emtricitabine 200 mg or lamivudine 300 mg. Randomisation was stratified by baseline HIV-1 RNA (≤100 000 vs >100 000 copies per mL) and CD4 cell count (<200 vs ≥200 cells per μL). Per protocol, we performed genotypic drug-resistance testing on day 1 and it remained double-masked throughout the study, simulating a scenario of inaccessibility of baseline resistance testing. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48 (intention-to-treat exposed analysis via the Snapshot algorithm) with prespecified non-inferiority margin of 10%. This trial is registered with ClinicalTrials.gov (NCT04549467). Between Nov 17, 2020, and Aug 31, 2022, 214 participants were randomly assigned to and treated with dolutegravir plus lamivudine (n=106) or dolutegravir plus tenofovir disoproxil fumarate and either emtricitabine or lamivudine (n=108). Median age of participants was 31 years (IQR 26-39) and 49 (23%) were female. At baseline, 66 (31%) of participants had an HIV-1 RNA viral load of more than 100 000 copies per mL, and 44 (21%) had a CD4 T-cell count of less than 200 cells per μL. At week 48, 97 (92%) of 106 participants in the dolutegravir plus lamivudine group and 96 (89%) of 108 participants in the dolutegravir plus tenofovir disoproxil fumarate with either emtricitabine or lamivudine group had HIV-1 RNA of less than 50 copies per mL (difference 2·62%; 95% CI -5·3 to 10·6), showing non-inferiority of dolutegravir plus lamivudine to the three-drug regimen. None of the participants in the dolutegravir plus lamivudine group and two in the control group had protocol-defined virological failure, and none developed treatment-emergent resistance mutations to any of the study drugs. Overall adverse event rates were similar between arms. Less than 1% of participants in both groups were discontinued due to adverse events. This study provides evidence supporting the non-inferiority of dolutegravir plus lamivudine compared with a preferred three-drug regimen in treatment-naive individuals without baseline resistance testing. These findings suggest that baseline resistance testing might not be a requirement for initiating treatment with dolutegravir plus lamivudine in settings with low frequency or suspicion of transmitted drug resistance to these drugs. ViiV Healthcare.

Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons.

Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of HIV infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear. In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group. Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions. The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

Therapeutic drug monitoring of tenofovir disoproxil and emtricitabine in oral HIV pre-exposure prophylaxis (PrEP) users who have undergone gastrointestinal surgery.

Oral HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV, but its efficacy depends on adequate absorption of drug, which may decrease following gastrointestinal surgery. Clinicians across eight Genito-urinary Medicine clinics in the United Kingdom submitted data on PrEP users with history of gastrointestinal surgery who were referred to a national complex PrEP multi-disciplinary team between June 2021 and April 2023. Anonymised data were submitted on demographics, surgical history, PrEP regimen, and results of therapeutic drug monitoring (TDM) and HIV screening tests. Descriptive analyses were performed in SPSS version 29. Nine cases described cis-gender men-who-have-sex-with-men (MSM) with median age of 47.4 years (IQR = 43 - 56.5) taking tenofovir disoproxil (TDF)/emtricitabine (FTC) daily (n = 8) or event-based (n = 1) as PrEP. Median time between PrEP initiation and TDM was 53 days (IQR = 8.5-1705). The mean (±SD) trough concentration of tenofovir (TFV) and FTC were 90.2 ± 27.7ng/mL and 76.0 ± 45.9ng/mL, respectively. All patients had a negative HIV test at follow-up. Plasma trough concentrations of TFV observed in our cohort taking TDF/FTC were above the expected concentrations associated with PrEP efficacy as previously described in the literature, suggesting that PrEP can be safely given in this population, with TDM used for reassurance.

Claims-Based Algorithm to Identify Pre-Exposure Prophylaxis Indications for Tenofovir Disoproxil Fumarate and Emtricitabine Prescriptions (2012-2014): Validation Study.

To monitor the use of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and related medicines for pre-exposure prophylaxis (PrEP) as HIV prevention using commercial pharmacy data, it is necessary to determine whether TDF/FTC prescriptions are used for PrEP or for some other clinical indication. This study aimed to validate an algorithm to distinguish the use of TDF/FTC for HIV prevention or infectious disease treatment. An algorithm was developed to identify whether TDF/FTC prescriptions were for PrEP or for other indications from large-scale administrative databases. The algorithm identifies TDF/FTC prescriptions and then excludes patients with International Classification of Diseases (ICD)-9 diagnostic codes, medications, or procedures that suggest indications other than for PrEP (eg, documentation of HIV infection, chronic hepatitis B, or use of TDF/FTC for postexposure prophylaxis). For evaluation, we collected data by clinician assessment of medical records for patients with TDF/FTC prescriptions and compared the assessed indication identified by the clinician review with the assessed indication identified by the algorithm. The algorithm was then applied and evaluated in a large, urban, community-based sexual health clinic. The PrEP algorithm demonstrated high sensitivity and moderate specificity (99.6% and 49.6%) in the electronic medical record database and high sensitivity and specificity (99% and 87%) in data from the urban community health clinic. The PrEP algorithm classified the indication for PrEP in most patients treated with TDF/FTC with sufficient accuracy to be useful for surveillance purposes. The methods described can serve as a basis for developing a robust and evolving case definition for antiretroviral prescriptions for HIV prevention purposes.

Initiation and continued use of oral pre-exposure prophylaxis among pregnant and postpartum women in South Africa (PrEP-PP): a demonstration cohort study

When used effectively, oral pre-exposure prophylaxis (PrEP; tenofovir disoproxil fumarate and emtricitabine) prevents maternal HIV acquisition and reduces the risk of vertical transmission. Our study aimed to better understand PrEP initiation, continued use, and adherence in pregnant and postpartum women. The PrEP in Pregnancy and Postpartum (PrEP-PP) study is a demonstration cohort study that enrolled pregnant women aged 16 years and older without HIV attending their first antenatal care visit in Cape Town, South Africa, between Aug 29, 2019, and Oct 10, 2021. Eligible, consenting women were followed up quarterly up to 12 months postpartum with regular HIV testing and offer of PrEP with ongoing adherence counselling. The primary outcome was distribution of women across the PrEP cascade (ie, initiation and continuation up to 12 months postpartum) with crude and adjusted hazard ratios (HRs). We also report on HIV incidence by pregnancy and postpartum status. Overall, 1195 pregnant women were recruited and followed up (median age 26 years, IQR 23-31; median gestational age 21 weeks, IQR 15-31); 1009 (84·4%) started PrEP at enrolment. Among women who initiated PrEP at enrolment, 668 (67·5%) of 990 continued PrEP at the 1-month follow-up, 485 (49·9%) of 972 continued at 3 months, 392 (39·4%) of 994 at 6 months, and 275 (27·4%) of 1005 at 12 months. Of 186 women who did not accept PrEP at enrolment, 70 (37·6%) of 186 subsequently initiated PrEP. Overall, 200 (18·6%) of 1076 women continued PrEP at 12 months postpartum. Of 186 women who did not initiate PrEP at baseline, 70 (37·6%) subsequently initiated PrEP during the study. Factors associated with PrEP discontinuation up to 12 months postpartum included being married or cohabiting (adjusted HR 1·32, 95% CI 1·16-1·50), condomless sex since last visit (1·43, 1·23-1·65), reporting intimate partner violence (2·03, 1·59-2·59), or depression in the past 12 months (1·53, 1·14-2·05). Overall, 16 women seroconverted over 1673·8 woman-years (HIV incidence rate 0·96 per 100 woman-years, 95% CI 0·49-1·42); 14 discontinued PrEP use and two never initiated PrEP. HIV incidence was 0·28 per 100 woman-years during pregnancy (95% CI 0·22-0·33), and the incidence rate ratio was 1·77 per 100 woman-years (0·53-5·90) 0-6 months postpartum and 2·19 per 100 woman-years (0·61-7·83) 6-12 months postpartum compared with pregnant women. There is an urgent need for the integration of PrEP into antenatal and postnatal care and interventions that address barriers to continued use, including targeted counselling during pregnancy and postpartum to reduce PrEP discontinuation. National Institute of Mental Health and Fogarty International, US National Institutes of Health. For the French translation of the abstract see Supplementary Materials section.

Birth outcomes following bictegravir exposure during pregnancy.

Bictegravir is increasingly prescribed as a co-formulated tablet with tenofovir alafenamide and emtricitabine to pregnant persons with HIV (PWH) despite limited pregnancy and birth outcome data. We sought to provide birth outcome data following exposure to bictegravir during pregnancy. We conducted a descriptive analysis of infants born to pregnant PWH 18-45 years of age enrolled in at least one Pediatric HIV/AIDS Cohort Study (PHACS)-affiliated study who received bictegravir for ≥7 days during pregnancy and completed follow-up through delivery. The outcomes of interest were gestational age at birth, preterm birth (<37 weeks' gestation), gestational-age adjusted birth weight (BWZ) and length (BLZ) z-scores, small for gestational age (SGA, birthweight <10th percentile), congenital anomalies, neonatal deaths in the first 28 days of life, and infant HIV status. A total of 177 infants born to 170 unique PWH were exposed to bictegravir for ≥7 days during gestation; 55% were exposed to bictegravir from the time of conception. Median gestational age at birth was 38.1 weeks. The prevalence of preterm birth was 15.8% and SGA was 9.3%. Mean BWZ and BLZ were -0.48 and 0.03. No neonatal deaths or perinatal HIV transmissions were reported. Among 126 infants exposed to first-trimester bictegravir, 7 (5.6%) had major congenital anomalies with no specific pattern suggestive of a syndrome. These findings provide preliminary data without significant safety concerns for fetal bictegravir exposure in this United States cohort. Comparative data and continued surveillance of outcomes among infants exposed to bictegravir during gestation are warranted.

Evaluation of pharmacokinetics of Tenofovir Alafenamide (TAF) and Tenofovir Disoproxil (TDF) in pregnant and postpartum women in South Africa: PrEP-PP PK study

BackgroundThere are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC). MethodsEligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum. ResultsWe enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25–34); median gestational age was 24-weeks (IQR:21–28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537–849) and postpartum (GM: 583; 95%CI:471–722; GMR-TDF = 1.16; 95%CI:0.74–1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929–1549) versus pregnancy (GM: 832; 95%CI:751–922; GMR-TAF = 1.44; 95% CI: 1.01–2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44–112) in pregnancy and 73 (IQR 50–102) in postpartum (GMR = 1.04; 95%CI:0.44–2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341–985) in pregnancy and 666 (IQR:396–1123) in postpartum (GMR = 1.15; 95%CI:0.30–2.49). ConclusionTFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.

Ultra-Long-Term Delivery of Hydrophilic Drugs Using Injectable In Situ Cross-Linked Depots.

Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as in situ forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create in situ cross-linked depots (ISCD). The ISCD's solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. In vivo studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platform's biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions.

How the Use of prep (Pre-exposure Prophylaxis) Helps to Prevent HIV Infection in Malaysia

Background: HIV remains a significant public health challenge in Malaysia, affecting key populations such as men who have sex with men (MSM), transgender individuals, sex workers, and people who inject drugs (PWID). Despite advancements in prevention and treatment, HIV continues to be a leading cause of morbidity and mortality. Pre-exposure prophylaxis (PrEP) has emerged as a promising biomedical intervention, utilizing antiretroviral tablets (ARVs) to significantly reduce the risk of HIV infection in HIV-negative individuals. Methods and Materials: This study investigates the effectiveness of PrEP in preventing HIV transmission among high-risk groups in Malaysia. The research examines the mechanism of action of the two primary drugs used in PrEP—tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)—and analyzes data from various studies, including the iPrEx, Partners PrEP, PROUD, and IPERGAY studies. Additionally, it addresses the challenges of implementing PrEP in Malaysia, such as stigma, adherence issues, and integration with existing HIV services. Results: PrEP has shown to reduce the risk of HIV infection by more than 90% when used consistently. The iPrEx study demonstrated a 44% reduction in HIV risk, increasing to 92% with consistent use. The Partners PrEP study indicated a 75% reduction, with a potential 90% decrease with strict adherence. The PROUD and IPERGAY studies reinforced these findings, showing 86% reductions in HIV risk. Despite its proven efficacy, the implementation of PrEP in Malaysia faces barriers such as stigma, prejudice, and adherence challenges. Conclusion: PrEP is a highly effective strategy for reducing HIV transmission among high-risk populations in Malaysia. To maximize its potential impact, it is crucial to address barriers to implementation, including stigma, adherence issues, and integration with existing healthcare services. Mathematical modeling suggests that widespread PrEP use could lead to a significant decrease in new HIV infections, potentially reducing cases among MSM by 30% over a decade. Learning from successful PrEP programs in other countries, Malaysia should focus on supportive policies, community engagement, affordability, and adherence support to effectively combat the HIV epidemic.

Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Safety and adherence of bictegravir/emtricitabine/tenofovir alafenamide for HIV post-exposure prophylaxis among adults in Guiyang China: a prospective cohort study

BackgroundThe effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens.MethodsIn this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG).ResultsThe PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events.ConclusionsBIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes.Trial registrationThe study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391).

Plasma, intracellular and lymph node antiretroviral concentrations and HIV DNA change during primary HIV infection: Results from the INACTION P25 study

Despite its effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV DNA reservoir, which establishes early during primary HIV infection (PHI) and is maintained by latency, homeostatic T-cells proliferation, and residual replication. This limited effect can be associated with low drug exposure in lymphoid tissues and/or suboptimal adherence to antiretroviral drugs (ARVs). The aim of this study was to assess ARV concentrations in plasma, peripheral blood mononuclear cells (PBMCs) and lymph nodes (LNs), and their association to HIV RNA and HIV DNA decay during PHI. Participants were randomised to receive standard doses of darunavir/cobicistat (Arm I), dolutegravir (Arm II) or both (Arm III), with a backbone of tenofovir alafenamide and emtricitabine. Total HIV DNA was measured using digital-droplet PCR in PBMCs at baseline, 12 and 48 weeks. Drug concentrations in plasma and PBMCs were determined at 2, 12 and 48 weeks (LNs at 12 weeks) by UHPLC-MS/MS. Seventy-two participants were enrolled, mostly male (n=68), with a median age of 34 years and variable Fiebig stages (V–VI 57.7%, I–II 23.9%, and III–IV 18.3%). Twenty-six patients were assigned to Arm I, 27 to Arm II and 19 to Arm III. After 48 weeks, most patients had undetectable viremia, with minor differences in HIV RNA decay between arms. Patients with Fiebig I–II showed faster HIV RNA and HIV DNA decay. Intracellular tissue penetration was high for nucleoside analogues and low-moderate for darunavir and dolutegravir. Only tenofovir diphosphate concentrations in PBMCs showed correlation with HIV DNA decay. Overall, these results indicate that the timing of treatment initiation and intracellular tenofovir penetration are primary and secondary factors, respectively, affecting HIV reservoir.

User Experience of Persons Using Ingestible Sensor-Enabled Pre-Exposure Prophylaxis to Prevent HIV Infection: Cross-Sectional Survey Study.

A digital health technology's success or failure depends on how it is received by users. We conducted a user experience (UX) evaluation among persons who used the Food and Drug Administration-approved Digital Health Feedback System incorporating ingestible sensors (ISs) to capture medication adherence, after they were prescribed oral pre-exposure prophylaxis (PrEP) to prevent HIV infection. We performed an association analysis with baseline participant characteristics, to see if "personas" associated with positive or negative UX emerged. UX data were collected upon exit from a prospective intervention study of adults who were HIV negative, prescribed oral PrEP, and used the Digital Health Feedback System with IS-enabled tenofovir disoproxil fumarate plus emtricitabine (IS-Truvada). Baseline demographics; urine toxicology; and self-report questionnaires evaluating sleep (Pittsburgh Sleep Quality Index), self-efficacy, habitual self-control, HIV risk perception (Perceived Risk of HIV Scale 8-item), and depressive symptoms (Patient Health Questionnaire-8) were collected. Participants with ≥28 days in the study completed a Likert-scale UX questionnaire of 27 questions grouped into 4 domain categories: overall experience, ease of use, intention of future use, and perceived utility. Means and IQRs were computed for participant total and domain subscores, and linear regressions modeled baseline participant characteristics associated with UX responses. Demographic characteristics of responders versus nonresponders were compared using the Fisher exact and Wilcoxon rank-sum tests. Overall, 71 participants were enrolled (age: mean 37.6, range 18-69 years; n=64, 90% male; n=55, 77% White; n=24, 34% Hispanic; n=68, 96% housed; and n=53, 75% employed). No demographic differences were observed in the 63 participants who used the intervention for ≥28 days. Participants who completed the questionnaire were more likely to be housed (52/53, 98% vs 8/10, 80%; P=.06) and less likely to have a positive urine toxicology (18/51, 35% vs 7/10, 70%; P=.08), particularly methamphetamine (4/51, 8% vs 4/10, 40%; P=.02), than noncompleters. Based on IQR values, ≥75% of participants had a favorable UX based on the total score (median 3.78, IQR 3.17-4.20), overall experience (median 4.00, IQR 3.50-4.50), ease of use (median 3.72, IQR 3.33-4.22), and perceived utility (median 3.72, IQR 3.22-4.25), and ≥50% had favorable intention of future use (median 3.80, IQR 2.80-4.40). Following multipredictor modeling, self-efficacy was significantly associated with the total score (0.822, 95% CI 0.405-1.240; P<.001) and all subscores (all P<.05). Persons with more depressive symptoms reported better perceived utility (P=.01). Poor sleep was associated with a worse overall experience (-0.07, 95% CI -0.133 to -0.006; P=.03). The UX among persons using IS-enabled PrEP (IS-Truvada) to prevent HIV infection was positive. Association analysis of baseline participant characteristics linked higher self-efficacy with positive UX, more depressive symptoms with higher perceived utility, and poor sleep with negative UX.

Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone.

Combination antiretroviral therapy (ART) use in pregnancy has been pivotal in improving maternal health and reducing perinatal HIV transmission. However, children born HIV-exposed uninfected fall behind their unexposed peers in several areas including neurodevelopment. The contribution of in utero ART exposure to these deficits is not clear. Here we present our findings of neurocognitive outcomes in adult mice exposed in utero to ART. Dams were treated with a combination of ritonavir-boosted atazanavir with either abacavir plus lamivudine (ABC/3TC + ATV/r) or tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC + ATV/r), or water as a control, administered daily from day of plug detection to birth. Offspring underwent a battery of behavioral tests that investigated motor performance and cognition starting at 6-weeks of age and ending at 8 months. Changes in brain structure were assessed using magnetic resonance imaging and immunohistochemistry. Expression of genes involved in neural circuitry and synaptic transmission were assessed in the hippocampus, a region strongly associated with memory formation, using qPCR. Pups exposed to TDF/FTC + ATV/r showed increased motor activity and exploratory drive, and deficits in hippocampal-dependent working memory and social interaction, while pups exposed to ABC/3TC + ATV/r showed increased grooming, and deficits in working memory and social interaction. Significant volumetric reductions in the brain were seen only in the ABC/3TC + ATV/r group and were associated with reduced neuronal counts in the hippocampus. Altered neurotransmitter receptor mRNA expression as well as changes in expression of the neurotrophic factor BDNF and its receptors were observed in both ART-exposed groups in a sex-dependent manner. In our model, in utero ART exposure had long-term effects on brain development and cognitive and motor outcomes in adulthood. Our data show that neurological outcomes can be influenced by the type of nucleoside reverse transcriptase inhibitor backbone of the regimen and not just the base drug, and display sex differences.

Assessment of weight gain in adult patients living with HIV receiving first-line dolutegravir-based or efavirenz-based ART regimens in routine care clinics in Tshwane district, South Africa: An observational study.

Although dolutegravir (DTG) is deemed stable, safe, cost-effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG-based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE-to-TLD switchers) in three large primary care facilities in South Africa METHODS: We conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE-to-TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed-effect models among TEE-to-TLD switchers to consider repeated measures. Of 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow-up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m2 (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m2, and CD4 counts <200 cells/μL. Of 298 TEE-to-TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE-to-TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/μL were independent risk factors for lower weight gain after TLD switch. We report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE-to-TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG-based regimen.

Concordance between daily diary reported pre-exposure prophylaxis intake and intraerythrocytic tenofovir diphosphate in the Amsterdam Pre-exposure Prophylaxis demonstration project.

We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations. AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020). Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48 months and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6 weeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250 fmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa. Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( β = 0.77, 95% CI = 0.70-0.84, P < 0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ = 0.44, 95% CI = 0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ = 0.83, 95% CI 0.76-0.90). Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals.

Determination of intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations in dried blood spots for pre-exposure prophylaxis adherence

ObjectivesWe measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS). MethodsA total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 μL of 50% methanol and 400 μL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 μm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 μL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05–12.5 ng/punch. ResultsWe determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration. ConclusionsA multiplex LC–MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP.

Bictegravir/Tenofovir Alafenamide/Emtricitabine: A Real-Life Experience in People Living with HIV (PLWH).

Bictegravir (BIC), a recently introduced integrase inhibitor, is available in a single tablet regimen with tenofovir alafenamide (TAF) and emtricitabine (FTC) (BIC-STR). This study aimed to describe a real-life experience with BIC-STR. We retrospectively analyzed the data of people living with HIV (PLWH) on antiretroviral therapy (ART) with BIC-STR followed by the Clinic of Infectious Diseases of Perugia (Perugia, Italy) from September 2019 to February 2023. 270 PLWH were enrolled with a median follow-up time on BIC-STR of 2.2 years (IQR 1.2-2.7). In the overall population, in treatment-experienced (N = 242), in treatment-naïve (N = 28), and in population with age > 60 years old (N = 86), we observed that CD4 cell count improved in absolute number, percentage and CD4/CD8 ratio, under BIC-STR. Patients with viremia < 50 cp/mL increased in all groups. In the overall population, previous ART with TAF and nadir CD4 cell count favored immunological recovery. In the ART-experienced group, time in therapy with BIC-STR was associated with HIV-RNA undetectability. In the older group, previous opportunistic infection and advanced age were associated with lower CD4 count. BIC-STR was demonstrated, in real-life, to be a valid option for a switch, such as initial ART.