High efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in Black adults in the United States, including those with pre-existing HIV resistance and suboptimal adherence.

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence.

Electromimetic molecularly imprinted Polymersensor for wastewater emtricitabine.

BACKGROUND: Emtricitabine (FTC) is a commonly prescribed anti-human immunodeficiency virus (HIV) drug that has been classified as an emerging environmental pharmaceutical micropollutant due to its poor metabolism, refractory nature to wastewater treatment, continuous discharge with wastewater effluent and accumulation in the aquatic environment. Although there are no reported limits and toxicity of the drug in the environment yet, it is crucial to develop onsite, rapid, selective and ultrasensitive water sensing systems for FTC to ensure efficient risk management and environmental sustainability. RESULTS: Herein, a molecularly imprinted poly(para-aminobenzoic acid) (MIP) was electrochemically prepared on iron oxide nanoparticles modified glassy carbon electrode (MIP/Fe3O4 NPs/GCE) for selective detection of FTC using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). During the detection, the voltammetric signal of the MIP sensor decreased with increasing concentrations of the non-electroactive FTC, indicating hindrance of the MIP sensor's redox activity by the binding analyte. The sensor generated a calibration curve with a linear dynamic range of 1.24-24.7 µg L-1 and a limit of detection (LOD) and limit of quantification (LOQ) of 0.439 and 1.30 µg L-1, respectively. Moreover, the MIP sensor was 5.2 times more sensitive than the control sensor, a non-imprinted polymer (NIP) sensor, and had a higher apparent binding affinity for FTC than the NIP sensor. The MIP/PABA-Fe3O4/GCE-based sensor achieved recoveries of 98.8 %-101.5 % for applications in real wastewater and drinking water samples. SIGNIFICANCE: The combination of Fe3O4 nanoparticles, electrically conducting polymer, and the MIP technology produced a novel, simple, cost-effective, and high-performance voltammetric MIP sensor for an anti-HIV drug, FTC. The result of this study shows that the sensor holds a significant promise for future onsite monitoring of emtricitabine in wastewater, pharmaceutical, and biological samples without prior sample pretreatment.

Twice-yearly lenacapavir: A milestone for HIV prevention in young African women.

The PURPOSE 1 trial1 demonstrated that after 52 weeks, no cisgender women acquired HIV infection after receiving subcutaneous twice-yearly lenacapavir. HIV incidence with lenacapavir was significantly lower than HIV incidence with daily oral emtricitabine/tenofovir alafenamide (F/TAF) or daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF). It is the first pre-exposure prophylaxis regimen with 100% efficacy in young women.

Combined bictegravir, emtricitabine and tenofovir alafenamide for treating people with HIV: a plain language summary of the BICSTaR study up to 1 year.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about an ongoing study called the BICSTaR study.The BICSTaR study includes people with HIV (human immunodeficiency virus) who are taking a medicine called bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single tablet that contains 3 different drugs for the treatment of HIV. The drugs work together to reduce the levels of HIV so that the virus can no longer be detected by a blood test.People taking part in the study are adults with HIV living in Europe, Canada, Israel, Japan, South Korea, Singapore and Taiwan. People take 1 tablet of B/F/TAF once a day. They are either taking B/F/TAF as their first treatment for HIV, or they have switched to B/F/TAF from another HIV treatment.Researchers looked at how well B/F/TAF worked and how safe it was in people who took B/F/TAF for a year. WHAT ARE THE KEY TAKEAWAYS?: Researchers found that B/F/TAF worked well in almost all people in the study by reducing levels of HIV in the blood. The virus could not be found in the blood of more than 9 out of 10 (94%) people who were taking B/F/TAF as their first HIV medicine and more than 9 out of 10 people (97%) who had taken another HIV medicine before starting B/F/TAF. This is known as having an 'undetectable viral load' and is a major goal for HIV treatment success. Researchers did not find any evidence of HIV developing resistance to B/F/TAF, which might stop B/F/TAF from working properly.Around 1 out of 10 people (13%) had side effects (any unwanted sign or symptom that people have when taking a medicine that researchers think might be caused by the medicine) that might have been caused by B/F/TAF. Most of these side effects were not classified as serious. Less than 1 out of 100 (0.1%) people had serious side effects that might have been caused by B/F/TAF. Only 6 out of 100 people stopped taking B/F/TAF due to side effects caused by B/F/TAF. As a result, more than 9 out of 10 people (95%) took B/F/TAF for at least 1 year. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: B/F/TAF worked well in people with HIV in this study. Most people (around 9 out of 10) did not have any side effects.

A case series of intermittent nucleoside analogue-based (NA) regimen to maintain HBV virological suppression in coinfected HBV/HIV patients with suppressed viremia.

OBJECTIVE: To describe the efficacy of intermittent nucleoside analogue-based (NA) regimen to maintain HBV virological suppression in HBV/HIV-1 patients. METHODS: Conducted between 2014 and 2023, this observational retrospective study included all HBV (positive AgHbs)/HIV-1 coinfected patients with HIV RNA ≤ 50 cp/mL and HBV DNA ≤ 25 UI/mL who were switched to an intermittent (<7/7 days(D)) TDF or TAF-containing antiretroviral (ART) regimen. The primary outcome was the HBV virological success rate (SR) (proportion of patients with HBV pVL < 25 UI/mL) at W48. RESULTS: Among 501 HBV/HIV-1 patients, 19(3.7 %) had switched to an intermittent NA-containing regimen that included TDF/FTC or TDF/3TC or TAF/FTC or TDF alone administered 5D-a-week(n = 7), 4D-a-week(n = 7) or 3D-a-week(n = 5). HBV virological success rates were 100 % [95 %CI 82.3-100] and 100 %[95 %CI 80.5-100] at W48 and W96(n = 17), respectively; with no viral HBV or HIV rebound (61.8 months (32.4-70.3) of follow-up). CONCLUSION: This case series shows the potential for intermittent NA-containing regimens to maintain long-term control of HBV replication among suppressed HBV/HIV-1 patients.

Treatment Management Challenges in Naïve and Experienced HIV-1-Infected Individuals Carrying the M184V Mutation.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.

Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia.

BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.

Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial.

BACKGROUND: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. METHODS: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. RESULTS: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. CONCLUSIONS: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.

A randomised control trial of BIC/F/TAF vs DRV/c/F/TAF in context of HIV test-and-treat, BicTnT.

BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.

Dual therapy based on co-formulated darunavir/ritonavir plus lamivudine for initial therapy of HIV infection: The ANDES randomized controlled trial.

BACKGROUND: Tenofovir-containing antiretroviral therapy regimens may have long-term toxicity-related side effects. This study aimed to compare the virological efficacy of co-formulated darunavir/ritonavir plus lamivudine with darunavir/ritonavir plus tenofovir and emtricitabine or lamivudine. METHODS: The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in treatment-naïve adults living with human immunodeficiency virus (HIV). Patients were randomized on a 1:1 basis to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir/ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir/ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of <50 copies/mL at week 48 in the intention-to-treat population. The US Food and Drug Administration snapshot algorithm and a non-inferiority margin of -12% were used. The secondary objective was to analyse safety in the per-protocol population. This study has been registered at ClinicalTrials.gov (NCT02770508). RESULTS: Between November 2015 and 31 October 2020, 336 participants were assigned at random to the triple therapy arm (n=165) or the dual therapy arm (n=171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the dual therapy group (91%) achieved virological suppression (difference -2.1%, 95% confidence interval -7.0 to 2.9). Drug-related adverse events were more common in the triple therapy group (P=0.04). Two toxicity-related events led to discontinuation in each group. INTERPRETATION: Co-formulated darunavir/ritonavir plus lamivudine showed non-inferiority and a safer toxicity profile compared with the standard-of-care triple therapy regimen including tenofovir in treatment-naïve patients.

Whole-body distribution of tenofovir, emtricitabine and dolutegravir in non-human primates.

BACKGROUND: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. OBJECTIVES: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). METHODS: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. RESULTS: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. CONCLUSIONS: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.

Health care resource utilization and costs for treatment-experienced people with HIV switching or restarting antiretroviral regimens since 2018.

BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.

Adherence and HIV Protection Thresholds for Emtricitabine and Tenofovir Disoproxil Fumarate Preexposure Prophylaxis among Cisgender Women: A Systematic Review.

PURPOSE OF REVIEW: Adherence-concentration-efficacy benchmarks have not been fully characterized for cisgender women using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) oral daily pre-exposure prophylaxis (PrEP) for HIV prevention. RECENT FINDINGS: We conducted a systematic review to investigate current evidence on the adherence-concentration-efficacy relationship of tenofovir-diphosphate (TFV-DP) derived from FTC/TDF PrEP in dried blood spots (DBS) and peripheral mononuclear cells (PBMC) in cisgender women without HIV, including during pregnancy. We searched for completed and ongoing studies published before May 2024 in PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrial.gov.  Overall, 11 studies assessing adherence benchmarks focusing on (n = 5) or involving (n = 6) cisgender women were included. Women-specific median steady-state TFV-DP concentration for daily dosing ranged from 17 to 51 fmol/106 in PBMC and 1389 to 1685 fmol/punch in DBS in non-pregnant women; 50 to 71 fmol/106 in PBMC and 583 to 965 fmol/punch in DBS in pregnant women; and 618 to 1406 fmol/punch in DBS in postpartum women. DBS TFV-DP levels were 14-43% lower in pregnancy versus postpartum or non-pregnant periods, but PBMC TFV-DP levels appear to be comparable. Clinical and modeling studies demonstrate effective HIV protection for women taking at least four doses/week of oral TDF-based PrEP, and emerging evidence suggests that systemic drug levels are more likely to be predictive of efficacy than local tissue levels at the site of exposure. The preponderance of emerging evidence points to comparable efficacy and similar adherence requirement for women as men among those with detectable drug levels, although there was an indication that the highest achievable efficacy may be reached at a lower adherence level in men than women. In this review, we found evidence that women-specific TFV-DP adherence benchmarks in DBS and PBMC are within range of US-based historical thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women as it does in MSM, but more data are still needed to refine intrinsic achievable efficacy estimates for cisgender women.

Metabolic, Mitochondrial, and Inflammatory Effects of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate in Asymptomatic Antiretroviral-Naïve People with HIV.

This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.

Characterizing HIV drug resistance in cases of vertical transmission in the VESTED randomized antiretroviral treatment trial.

Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. Methods: HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.

Nucleoside/nucleotide reverse transcriptase inhibitor-associated weight gain in people living with HIV: data from the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

Weight gain effects of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in people with HIV (PWH) have been sparsely studied.Participants were enrolled in the Copenhagen Comorbidity in HIV Infection (COCOMO) study. PWH receiving a backbone of emtricitabine, or lamivudine combined with abacavir, tenofovir disoproxil, or tenofovir alafenamide were analysed. Weight gain according to ART backbone and to the third drug was analysed using a multiple linear regression model. Non-ART risk factors were also determined using multiple linear regression.A total of 591 participants were included in the analysis. The majority were middle-aged, virally suppressed males with a mean BMI just above the normal range. Both tenofovir disoproxil/emtricitabine or lamivudine and abacavir /emtricitabine or lamivudine, but not tenofovir alafenamide /emtricitabine or lamivudine were associated with weight gain over two years (0.6 kg, p = 0.025; 1.0 kg, p = 0.005). The third drugs associated with weight increase were non-nucleoside reverse transcriptase inhibitors (NNRTI) (p = 0.035), dolutegravir (p = 0.008) and atazanavir (p = 0.040). Non-ART risk factors for gaining weight were low or normal BMI, age <40 years, underweight, inactivity or highly active at baseline.Tenofovir disoproxil and abacavir-based ART regimens were associated with a small weight gain. Third drug NNRTI, dolutegravir and atazanavir were associated with an increase in weight.

Real world community-based HIV Rapid Start Antiretroviral with B/F/TAF versus prior models of antiretroviral therapy start - the RoCHaCHa study, a pilot study.

BACKGROUND: The rapid start of antiretroviral therapy (RSA) model initiates antiretroviral therapy (ART) as soon as possible after a new or preliminary diagnosis of HIV, in advance of HIV-1 RNA and other baseline laboratory testing. This observational study aims to determine if RSA with a single tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) is an effective regimen for achieving viral suppression and accepted by patients at the time of diagnosis. METHODS: Adults newly or preliminarily diagnosed with HIV were enrolled from October 2018 through September 2021. Real world advantage, measured in days between clinical milestones and time to virologic suppression, associated with B/F/TAF RSA was compared to historical controls. RESULTS: All Study RSA participants (n = 45) accepted treatment at their first visit and 43(95.6%) achieved virologic suppression by week 48. Study RSA participants had a significantly shorter time (median 32 days) from diagnosis to ART initiation and virologic suppression, in comparison to historical controls (median 181 days) (n = 42). Qualitative feedback from study RSA participants showed high acceptance positive response to RSA. CONCLUSIONS: RSA is feasible and well accepted by patients in a real-world community-based clinic setting. Promoting RSA in community-based clinics is an important tool in ending the HIV epidemic.

Making new drugs the hard way.

A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).