Epidemic trend, genetic characteristics, and transmission networks of HIV-1 among treatment-naive men who have sex with men in Hebei province, China.

Introduction: Homosexual transmission has contributed greatly to the current HIV-1 epidemic in Hebei province, China. Dolutegravir (DTG) will be conditionally used as a component of free antiretroviral therapy (ART) according to manual for national free anti-AIDS treatment drugs (2023 edition) issued by China in June 2023. However, current genetic characteristics and pretreatment drug resistance (PDR) to proteinase inhibitors (PIs), reverse transcriptase inhibitors (RTs) and integrase strand transfer inhibitors (INSTIs) of HIV-1 in this population have remained unclear. Methods: Serial consecutive cross-sectional analyses for HIV- 1 infection trend, genetic characteristics, PDR and molecular transmission networks were conducted from 2018 to 2022. All of participants were HIV-1- infected MSM newly diagnosed at the HIV surveillance points (HSPs) in Hebei, China. Evidence of PDR was confirmed using the world health organization (WHO) list for surveillance of drug resistance mutations. Results: In this study, a total of 14 HIV-1 subtypes were circulating in the HSPs of Hebei province, China. CRF01_ AE (51.9%, 350/675), CRF07_BC (30.4%, 205/675), B (6.2%, 42/675) and URFs (5.8%, 39/675) were the four most predominant subtypes among MSM. And, CRF07_BC (r > 0) and URFs (r > 0) indicated an increasing trend, respectively; however, CRF01_AE (r < 0) showed a decline trend. The overall prevalence of HIV-1 PDR showed a substantial increase from 6.3% in 2018 to 7.9% in 2022. The prevalence of NNRTI-PDR was the highest (5.8%, 39/675), followed by INSTIs (2.4%, 16/675), NRTIs (0.6%, 4/675) and PIs (0.3%, 2/675). Furthermore, extensive HIV-1 strains bearing PDR were circulating in the MSM population via molecular transmission networks for major HIV-1 subtypes, especially CRF01_AE and CRF07_BC. Discussion: Our findings reflect that HIV-1 epidemic in the MSM population is complex and severe in Hebei, China. Therefore, it is urgent for us to implement more effective intervention measures to limit the further dissemination of HIV-1, especially the spread of HIV-1 INSTI-PDR strains.

Comprehensive database of HIV mutations selected during antiretroviral in vitro passage experiments.

BACKGROUND: In vitro passage experiments are crucial to the development of antiretroviral (ARV) drugs. METHODS: We created an online database containing data from 102 published studies in which HIV-1 or HIV-2 was cultured with increasing concentrations of the FDA-approved nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), capsid inhibitor (CAI) lenacapavir, and nucleoside RT translocation inhibitor (NRTTI) islatravir. We summarized the mutations selected in the subset of passage experiments with NRTIs lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), tenofovir (TFV), and zidovudine (AZT), NNRTIs doravirine (DOR), efavirenz (EFV), and rilpivirine (RPV), INSTIs bictegravir (BIC), cabotegravir (CAB), and dolutegravir (DTG), and PIs atazanavir (ATV), darunavir (DRV), and lopinavir (LPV). Mutations selected in vitro were compared with those selected in persons receiving the same ARV. RESULTS: Twenty-seven studies described 89 experiments of wildtype isolates passaged with 3TC, FTC, ABC, TFV, or AZT; sixteen studies described 89 experiments passaged with EFV, RPV, or DOR; eleven studies described 76 experiments passaged with the INSTIs BIC, CAB, or DTG; six studies described 33 experiments passaged with ATV, LPV, or DRV. With several exceptions, mutations selected in two or more experiments were among the most common mutations selected in persons receiving the same ARV. CONCLUSIONS: We created a database of published ARV in vitro selection experiments. Mutations emerging from these experiments generally predict those observed in persons receiving the same ARV. However, there are notable differences in mutation frequencies between in vitro and in vivo settings.

Beware of Resistance to 2nd-generation Integrase Inhibitors: A Systematic Meta-analysis of HIV-1 Integrase Inhibitors Resistance and Drug Resistance Mutations.

OBJECTIVE: Assessing the prevalence of resistance and drug resistance mutations (DRMs) in HIV/AIDS patients towards integrase strand transfer inhibitors (INSTIs), particularly the 2nd-generation INSTIs, provides evidence for rational clinical drug use. METHODS: A systematic search was conducted on five databases to identify relevant literature reporting original data on INSTIs resistance. Meta-analyses, cumulative meta-analyses, subgroup analyses, and meta-regression analyses were performed using selected models based on the results of heterogeneity tests. RESULTS: A total of 81 studies were included in this analysis. The prevalence of pre-treatment drug resistance (PDR) to 1st-generation INSTIs and 2nd-generation INSTIs were 0.41% (95% CI: 0.19%-0.70%) and 0.04% (95% CI: 0.00%-0.13%), respectively; and the prevalence of acquired drug resistance (ADR) were 7.60% (95% CI: 3.54%-12.92%) and 4.93% (95% CI: 1.78%-9.36%), respectively, and ADR showed an increasing and then decreasing time trend. The results of subgroup analyses showed differences in ADR to 2nd-generation INSTIs between regions and economic levels, with the highest ADR of 12.83% (95% CI: 3.24%-27.17%) in the European region. DRMs varied among HIV patients and reduced drug sensitivity to varying degrees. CONCLUSION: The prevalence of PDR and DRMs in 2nd-generation INSTIs is currently low, but as the use of DTG-based ART expands, population-level drug resistance monitoring and individual-level genetic testing should be strengthened in order to maximize treatment efficacy. Additionally, attention should be paid to ADR of INSTIs to provide personalized treatments for HIV-infected patients.

Effect of ABCB1 most frequent polymorphisms on the accumulation of bictegravir in recombinant HEK293 cell lines.

Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1.

Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors.

Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.

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

BACKGROUND: The 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. METHODS: In 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). RESULTS: The 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. CONCLUSIONS: BIC/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 REGISTRATION: The 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 ).

Trends in body mass index in the pre-dolutegravir period in South Africa.

Background: Antiretroviral therapy (ART) is associated with weight gain, but this has been shown to be more marked with dolutegravir and other integrase strand transfer inhibitors. Objectives: We studied weight gain in people living with HIV (PLWH) on ART compared to the general population in the period before dolutegravir was introduced in a rural South African cohort. Method: Longitudinal analysis of the Ndlovu Cohort Study including 36-48 months' follow-up data. From 2014 to 2019, data were collected annually in Limpopo, rural South Africa. Linear mixed models using HIV status, demographics, ART use and cardiovascular risk factors were used to estimate trends in body mass index (BMI) over time. Results: In total, 1518 adult, non-pregnant participants were included, of whom 518 were PLWH on ART (79.8%), 135 PLWH not yet on ART (20.2%) and 865 HIV-negative. HIV-negative participants had significantly higher BMIs than PLWH on ART at all study visits. There was a significant increase in BMI in all subgroups after 36 months (PLWH on ART, BMI +1.2 kg/m2, P < 0.001; PLWH not on ART, BMI +1.8 kg/m2, P < 0.001 and HIV-negative, BMI +1.3 kg/m2, P < 0.001). Conclusion: The increase in BMI in PLWH and HIV-negative participants is a serious warning signal as obesity results in morbidity and mortality.

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 µM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Clinical Outcomes of Integrase Strand Transfer Inhibitors Containing Antiretroviral Therapy in HIV-2: A Narrative Review.

The human immunodeficiency virus type 2 (HIV-2) is a particular subtype of HIV, which is endemic in West Africa and is characterized by a more indolent course than HIV-1. As people living with HIV-2 (PWH-2) are at risk for the development of acquired immunodeficiency syndrome and can transmit the virus, antiretroviral therapy is usually indicated. However, the optimal treatment of HIV-2 is unknown and historically the protease inhibitors (PIs) were a regular part of therapy. Nowadays, the use of integrase strand transfer inhibitors (INSTIs) in HIV-2 is increasing but the evidence supporting this approach is limited. In this narrative review, we outline the clinical data on the use of INSTI-containing antiretroviral therapy in HIV-2. We found that in the setting of treatment-naïve PWH-2, the use of INSTIs is successful, but also noted large heterogeneity in reported outcomes and that most cohorts are small with limited follow-up time. There is a lack of studies comparing the efficacy of INSTIs to other first-line options. For treatment-experienced PWH-2, the efficacy of INSTI is highly variable.

Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

Efficacy, safety, and tolerability of dolutegravir-based ART regimen in Durban, South Africa: a cohort study.

BACKGROUND: Dolutegravir is an integrase strand transfer inhibitor that has been recommended for use in first-line antiretroviral regimens by the World Health Organisation and is currently being rolled out globally. There has been safety concerns with dolutegravir which has caused concern about its use in the general population. Dolutegravir first-line regimens have been used in South Africa since early 2020. Therefore, the aim of the present study was to assess the efficacy, safety, and tolerability of first-line dolutegravir-based antiretrovirals amongst adults living with HIV in Durban, South Africa. METHODS: This was a mixed-methods study, which comprised a cross-sectional survey and longitudinal retrospective follow-up of medical records. The study was conducted between October 2020 and January 2022. Data were described using descriptive and summary statistics. Bivariate logistic regression was applied to socio-demographic and clinical variables and crude odds ratios with a 95% confidence interval was calculated. Pearson chi-square tests, paired sample T-tests, and cross-tabulations were performed on selected variables. RESULTS: A total of 461 participants were enrolled in the study. There was a significant change in immunological outcomes (p < 0.001) after dolutegravir initiation. Furthermore, an assessment of laboratory parameters showed that there was a significant decrease in cholesterol (p < 0.001) and increase in creatinine (p < 0.001) levels. Increased weight was shown by 60.7% of the participants but was not associated with age, gender, CD4 counts, and previous antiretroviral usage. The study found that 43.6% of the participants experienced at least one side-effect. A total of 21.6% and 23.2% of the participants experienced neuropsychiatric and central nervous system side-effects, respectively. In the bivariate analyses, only gender was shown to be associated with side-effects, and only 1.7% of the participants discontinued the study due to side-effects. CONCLUSION: Our results suggest that dolutegravir is effective, safe, and well tolerated in the study population.

A Phase-IV Non-interventional Study to Assess Virological Effectiveness, Safety, and Tolerability of DTG-based Antiretroviral Therapy in HIV-1 Infected Indian Persons Living with HIV.

BACKGROUND: Dolutegravir (DTG) is a novel yet preferential first- and -second-line treatment for persons living with HIV (PLH). Owing to its recent introduction, DTG-based regimens have not undergone a comprehensive, systematic evaluation regarding their real-world utilization and safety profile among a sizeable Indian population. OBJECTIVE: This study aimed to assess the 24 week immunovirological outcomes, anthropometric and metabolic changes, tolerability, and adverse events (AEs) of DTG-based antiretroviral (ART) regimens. METHODS: A single-centre phase-IV non-interventional observational study involving 322 ART naïve and treatment-experienced PLH initiating DTG-based-regimens until October 2022 were followed up for outcomes at 24 weeks. RESULTS: At 24 weeks, all PLH (n = 113) in the naïve group, all PLH (n = 67) in the first-line substitution group, 93.9% PLH (n = 46) in the first-line failure group, and 95.7% PLH (n = 89) in the second-line substitution group were virologically suppressed to plasma HIV-RNA <1000 copies/mL. Virological suppression rates to plasma HIV-RNA <200 copies/mL and <50 copies/mL were consistent among PLH who received DTG as first- or second-line ART. The mean-unadjusted weight gain observed was 3.5 kg (SE: 0.330), and it was significantly higher in PLH with poorer health at baseline (either HIV-RNA ≥ 1000 copies/ml or CD4 cell count <350 cells/µL). Overall, 27.3% PLH (n = 88) gained ≥10% of their baseline body weight, corresponding to 3.7% incidence (n = 12) of treatment-emergent clinical obesity. DTG had an overall lipid-neutral effect, with an advantageous effect being observed in PLH switching from non-nucleoside analogue reverse-transcriptase inhibitors (NNRTI) or ritonavir-boosted protease inhibitors (b/PI), especially in dyslipidemic pre-treated PLH (median change in total cholesterol: 28.5 mg/dL and triglycerides: 51 mg/dL), possibly emanating from the withdrawal of the offending ART. The incidence of DTG-specific AEs, including CNS AEs, was low. Two PLH developed proximal myopathy and one developed transaminitis, warranting DTG discontinuation. Asymptomatic serum-CPK elevation and drug-induced transaminitis were seen in 25.2% (n = 27) and 3.2% (n = 10) PLH, respectively. No apparent negative effects on renal function were detected. CONCLUSION: Our results from a large Indian cohort indicate a favourable virological and metabolic response, with good tolerance of DTG-based ART at 24 weeks.

Incidence of low-level viremia and its impact on virologic failure among people living with HIV who started an integrase strand transfer inhibitors: a longitudinal cohort study.

BACKGROUND: Low-level viremia (LLV) has been identified as a potential precursor to virologic failure (VF), yet its clinical implications, particularly within the context of Integrase Strand Transfer Inhibitors (INSTIs)-based regimens, remain insufficiently explored. The study aimed to investigate the relationship between LLV and VF within ART-naïve patients on INSTIs-based regimens in China. METHODS: A longitudinal cohort study was conducted with ART-naïve patients aged ≥ 18 years at Beijing Ditan Hospital, under the Chinese National Free Antiretroviral Treatment Program (NFATP). The LLV was defined as a viral load (VL) ranging from 50 to 199 copies/mL after six months of ART initiation, and VF as a VL ≥ 200 copies/mL. Sensitive analyses were also performed, defining LLV as 50-999 copies/mL and VF as exceeding 1000 copies/mL. Multivariate logistic regression, Kaplan-Meier (KM) curve, and Generalized Estimating Equation (GEE) models were used to evaluate the risk factors associated with LLV and VF events. RESULTS: The study involved 830 ART-naïve patients, comprising 600 in the INSTIs group and 230 in the protease inhibitors (PIs) group. LLV events were observed in 10.4% of patients on PIs-based regimens and and 3.2% on INSTIs-based regimens (P < 0.001). INSTIs-based regimens demonstrated a protective effect against LLV events (aHR = 0.27, 95% CI 0.137-0.532). VF events occurred in 10.9% of patients on PIs-based regimens and 2.0% on INSTIs-based regimens, respectively (P < 0.001). The occurrence of LLV events significantly increased the risk of VF by 123.5% (95% CI 7.5%-364.4%), while the integrase inhibitors were associated with a 76.9% (95% CI 59.1%-86.9%) reduction in VF risk. CONCLUSION: Our findings indicate that INSTIs-based regimens are critical protective factors against LLV and subsequent VF. These results underscore the importance of HIV viral load monitoring to ensuring effective treatment outcomes, highlighting the necessity for prompt and precise monitoring to refine HIV treatment methodologies.

Integrase Strand Transfer Inhibitor Resistance Mutations in Antiretroviral Treatment-naïve Patients in Korea: a Prospective, Observational Study

The present study investigated prevalence of integrase strand transfer inhibitors (INSTI) resistance mutations in HIV-1-infected antiretroviral therapy (ART)-naïve patients in Korea. From 106 plasma samples, amplification and sequencing of integrase genes was performed, and major or minor mutations were calculated by the Stanford HIV drug resistance mutation interpretation algorithm. No major INSTI resistance mutations were found, and 14 minor mutations were detected in 13 (12.3%) patients. The present data support the recommendation that routine testing for INSTI resistance mutations before starting ART is not necessary.