Search Results (904)

Background: People living with HIV (PLWH) are at increased risk of cardiovascular disease (CVD). Aortic stiffness measured with carotid-femoral pulse wave velocity (PWV) is a validated predictor of CVD and has been shown to be elevated in PLWH at HIV diagnosis. Objectives: To prospectively evaluate the effect of 9 months of contemporary antiretroviral therapy (ART) on aortic stiffness in newly diagnosed PLWH. Methods: A group of ART-naïve PLWH with modest cardiovascular risk and without known CVD were recruited at the time of HIV diagnosis. Aortic stiffness was measured using carotid-femoral PWV (ViCorder, Skidmore Medical, UK) before ART initiation and after 9 months on treatment. Results: Seventy-three participants were analysed (mean age 32 ± 7 years; 45% female). PWV decreased significantly after 9 months of ART (5.93 ± 1.0 vs. 5.69 ± 1.0 m/s; p = 0.01) with increased aortic distensibility (0.36 [IQR 0.30 to 0.46] vs. 0.40 [IQR 0.34 to 0.50] mmHg⁻¹; p = 0.02). The reduction in PWV remained significant after adjustment for covariates (mean change −0.26 m/s; 95% CI −0.07 to −0.45; p = 0.01). Conclusions: Aortic stiffness improved in a group of newly diagnosed PLWH after ART initiation at 9 months, in keeping with a modifiable component of HIV-associated vascular dysfunction. The findings are consistent with reversible functional vascular abnormality, potentially mediated by changes in vasomotor tone, although it is unknown if this effect will be sustained long-term. The trajectory of aortic stiffness in PLWH and the mechanisms that underpin vasomotor tone require further study. Full article

Tuberculosis (TB) is a leading global cause of infectious disease. Growing evidence suggests that TB significantly increases the risk of comorbidity in HIV+ patients, particularly acute ischemic stroke (AIS). Prognosis is often poor, highlighting the need for early prevention and intervention. However, exact mechanisms linking HIV-Mtb coinfection and stroke remain poorly understood. A review of articles from 2016 to 2026 was conducted to study the risk of ischemic stroke and treatment strategies in HIV-Mtb coinfection. Both HIV and Mtb can increase stroke risk, but pathogenesis of the coinfection and relationship between the coinfection and stroke remain as proposals. Antiretroviral therapy (ART) has shown variable success rates; it may increase the risk of stroke or be associated with worse outcomes. Multi-drug-resistant TB (MDR-TB) can be treated with a combination of bedaquiline, linezolid, and pretomanid (BPaL). Steroids and vitamin D supplementation with ART are associated with improved outcomes. For coinfection screening, the monocyte-to-lymphocyte ratio (MLR) and a clinical scoring system for triage may prove useful for early detection, leading to prompt intervention. A clearer understanding of the association between HIV-Mtb coinfection and stroke is essential for developing effective prevention strategies and eliminating transmission. Advancement of current treatments will help improve long-term outcomes in HIV-Mtb coinfection. Full article

The spectrum of diseases in individuals with human immunodeficiency virus (HIV) receiving successful antiretroviral therapy has evolved over time. In the past, they developed opportunistic infections and malignancies, whereas today, cardiovascular disease is among the most common causes of illness and premature death. Traditional risk factors for atherosclerosis (hypertension, hyperlipidemia, smoking, diabetes, family history of heart disease) are more prevalent in people with HIV than in the general population. However, it is well established that HIV itself causes increased immune activation, chronic inflammation, vascular dysfunction, and a cluster of metabolic abnormalities that contribute to a faster-than-usual rate of biological aging and a higher risk of developing atherosclerosis, a risk not fully captured by current risk models. In the REPRIEVE study, treatment with pitavastatin was shown to reduce the rate of first cardiovascular events among individuals with HIV receiving antiretroviral therapy. Importantly, the beneficial effects of statins on atherosclerosis likely extend beyond lowering cholesterol to include effects on vascular function and on immune and metabolic systems altered by HIV. Even among individuals on statins, a considerable risk of cardiovascular disease remains. Here, We provide a narrative review of current evidence and an expert perspective on emerging approaches to residual cardiovascular risk after REPRIEVE. We review the current understanding of atherosclerosis pathogenesis in individuals with HIV, focusing on recent findings from the REPRIEVE trial. We outline current approaches to improving cardiovascular risk assessment across clinical, biological, and computational levels. We also examine a growing number of therapeutic options that address residual inflammation and atherogenic metabolic disturbance in individuals with HIV on long-term, effective antiretroviral therapy. Significantly, after REPRIEVE, we must move from prescribing statins to all individuals with HIV toward more individualized cardiovascular disease prevention strategies, integrating clinical information, a variety of biomarkers, imaging studies, and even molecular information to generate optimal individualized cardiovascular disease prevention regimens that reflect the complexity of this outcome in naturally diverse individuals. Full article

Background: Classical reverse transcriptase (RT) drug resistance mutations (DRMs) are primary determinants of antiretroviral treatment failure, but polymorphisms within the RT connection and RNase H domains may also influence RT inhibitor susceptibility. These regions remain poorly characterised in HIV-1 subtype C (HIV-1C), the predominant subtype in sub-Saharan Africa. This study investigated RT connection and RNase H polymorphisms in treatment-experienced people with HIV (PWH) experiencing virologic failure (VF) in Botswana. Methods: Seventeen plasma samples from the Botswana National HIV Drug Resistance Programme with documented VF (viral load >200 copies/mL) and prior Sanger resistance results were selected. One sample was excluded because of insufficient Oxford Nanopore Technologies (ONT) sequencing coverage, leaving 16 samples for analysis. Samples were amplified using the DeepChek^® HIV-1 Full PR/RT/INT assay and analysed using the HIVgenomeR™ v2.0 ONT pol DRM pipeline. ONT-derived RT resistance profiles were compared with historical Sanger results, and RT connection and RNase H polymorphisms were characterised. Results: ONT identified additional RT DRMs in five sequences previously classified as lacking classical RT DRMs. Of the remaining six sequences without classical DRMs, four harboured minority RT variants. RT connection polymorphisms were common, including G335D (13/16) and T377M (9/16). Recurrent mutation combinations included T377M–T470A, A371V–E399D, T377M–E399D, and T377M–A360T. Conclusions: The extended HIV-1 pol genotyping assay enabled characterisation of the RT connection and RNase H domains while improving detection of classical RT DRMs and minority variants. These findings support further investigation of extended RT sequencing for HIV-1C molecular surveillance. Full article

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

Background/Objectives: Comparator selection can change disproportionality findings when multidrug therapies are represented by report-level listings rather than verified treatment histories. We evaluated a proxy-comparator framework for cardiometabolic reporting with long-acting cabotegravir/rilpivirine (CAB/RPV), including sensitivity to comparator definition and reporting context. Methods: We conducted a disproportionality analysis of publicly available individual case safety reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), restricted to study-defined markets and the period from the first quarter of 2022 through the second quarter of 2025. Reports were classified as CAB/RPV, regimen-only (a complete oral regimen listing alone), or regimen-plus (that listing plus other antiretrovirals). Three contrasts assessed 3-point and expanded major adverse cardiovascular events (MACE), diabetes, dyslipidemia, and hypertension using inverse probability weighting and adjusted reporting odds ratios (aRORs). Post-review analyses examined demographic completeness, reporter source, geography, and tenofovir disoproxil fumarate (TDF) inclusion. No binary signal threshold, case-by-case review, or causality adjudication was used. Results: The cohorts comprised 10,082 CAB/RPV, 4434 regimen-plus, and 14,559 regimen-only reports. In the internal oral contrast, regimen-plus showed statistically supported upward disproportionality for 3-point MACE (aROR 1.88, 95% confidence interval 1.44–2.15), expanded MACE (1.88, 1.47–2.40), and dyslipidemia (3.03, 2.39–3.84). CAB/RPV estimates were below 1 versus both proxies, although CAB/RPV versus regimen-plus lacked acceptable balance. Sensitivity analyses changed estimates and diagnostics; TDF inclusion left the CAB/RPV versus regimen-plus dyslipidemia estimate essentially unchanged but altered proxy-comparator findings. Conclusions: Proxy-comparator construction influenced cardiometabolic reporting patterns; reporting-context analyses qualified their interpretation. These hypothesis-generating findings do not establish incidence, clinical risk, causal effects, comparative safety, or a protective effect. Full article

Background: Alcohol and tobacco use remain important public health concerns among people living with HIV (PLWH), even after achieving viral load suppression. This study examined the socio-demographic factors associated with alcohol and tobacco use among virally suppressed PLWH in the Eastern Cape Province, South Africa. Methods: A cross-sectional study was conducted among 244 adults receiving antiretroviral therapy with suppressed viral loads at public healthcare facilities in the Eastern Cape Province. Data were collected using the Alcohol Use Disorders Identification Test (AUDIT) and the WHO STEPwise questionnaire. Alcohol use was classified according to the AUDIT, and participants were further categorised into low-risk (AUDIT score < 8) and risky drinking (AUDIT score ≥ 8) for regression analyses. Associations between socio-demographic characteristics and alcohol use were initially examined using cross-tabulations and exact tests where appropriate. Univariable and multivariable binary logistic regression analyses were subsequently performed to identify factors independently associated with risky alcohol use and smoking. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were reported, with statistical significance set at p < 0.05. Results: Of the 244 participants, 57.0% were female, and 61.5% were employed. Based on the total AUDIT score, 60.2% of participants were classified as risky drinkers, while 44.3% were current smokers. In the multivariable analysis, employment was independently associated with risky alcohol use (AOR = 2.03, 95% CI: 1.11–3.73) and current smoking (AOR = 3.75, 95% CI: 1.98–7.08). Compared with single participants, married (AOR = 2.61, 95% CI: 1.25–5.45), separated (AOR = 5.19, 95% CI: 1.98–13.60), and divorced participants (AOR = 3.32, 95% CI: 1.05–10.49) had higher odds of risky alcohol use. Conclusion: Alcohol use and tobacco smoking remain common among virally suppressed PLWH in the Eastern Cape Province. Although viral load suppression is an important treatment outcome, it does not fully reflect broader health behaviours that may compromise long-term health. Integrating routine screening for alcohol and tobacco use, together with targeted behavioural interventions and harm reduction strategies, into comprehensive HIV care may improve long-term health outcomes. Full article

The molecular epidemiology and antiretroviral (ARV) drug resistance of human immunodeficiency virus type 1 (HIV-1) remain incompletely outlined in the Middle East and North Africa (MENA). The aim of this retrospective molecular epidemiology study was to analyze MENA HIV-1 sequences for phylogenetic clustering and to delineate surveillance drug-resistance mutations (SDRMs) for nucleoside reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) across various periods, locations, and subtypes/circulating recombinant forms (CRFs). Viral sequences were retrieved from the Los Alamos HIV Sequence Database as of 15 April 2026. Analyses were done using multiple sub-gene regions (two env regions (n = 224 and n = 60) and PR (n = 2413) and RT (n = 2103) of the pol gene). Phylogeny construction was conducted using maximum-likelihood estimation, while ARV drug resistance analysis was conducted using the Stanford HIVdb algorithm. The HIV-1 MENA sequences showed a remarkable genetic diversity, with co-circulation of multiple subtypes/CRFs, including subtype B in the Maghreb, Levant, and Egypt sub-regions, subtypes A1, G, CRF01_AE, and CRF02_AG in the Gulf Cooperation Council (GCC) and Yemen sub-region, and subtypes C and D in the Horn of Africa and Sudan sub-region. The percentage of MENA HIV-1 sequences in clusters was 10.3% for env1, 8.3% for env2, 22.0% for PR and 37.2% for RT. Phylogenetic reconstruction hinted at a structured epidemic dominated by small transmission units, with most clusters comprising dyads (n = 260) or networks (n = 142) and a limited number of large clusters (n = 8) that were largely confined within national boundaries, with only occasional cross-border linkages (n = 8). Overall SDRM prevalence was 3.2% in the PR region and 14.9% in the RT region, with a higher percentage of NNRTI-associated mutations (10.0%) than NRTI-associated mutations (9.1%) and dual-class resistance observed in 4.1% of sequences. Phylogenetic clustering was not associated with the probability of harboring SDRMs; however, negative binomial models showed that non-clustered sequences had a greater burden of NRTI-associated mutations, whereas no such association was observed for NNRTI- or PI-associated mutations. The findings showed predominantly localized and fragmented MENA HIV-1 transmission dynamics. Heterogeneous ARV drug resistance dynamics indicated that resistance emergence might be shaped by broader epidemiologic and treatment-related factors rather than ongoing clustered transmission. There is a need for coordinated molecular surveillance and optimized ART strategies across the MENA countries. Full article

Background/Objectives: Tenofovir disoproxil fumarate (TDF)-containing regimens remain the cornerstone of first-line antiretroviral therapy (ART) in many low- and middle-income countries. However, concerns regarding treatment failure and antiretroviral resistance highlight the need to evaluate the effectiveness of treatments under routine clinical conditions. This study evaluated the virologic outcomes of treatment-naïve individuals living with HIV who received predominantly TDF-based first-line ART in Davao City, Philippines. Methods: A retrospective observational study was conducted among treatment-naïve HIV patients who initiated ART between 2016 and 2020. Demographic and clinical characteristics, ART regimens, HIV surveillance stage classifications, and viral load results were extracted from routinely collected medical records. Virologic suppression was defined as an HIV RNA viral load of <1000 copies/mL and virologic failure as ≥1000 copies/mL. The availability of viral load monitoring and the interval between ART initiation and the latest viral load measurement were also evaluated. Results: A total of 494 treatment-naïve patients with HIV were included. Most patients were male (97.8%) and received TDF-containing regimens (99.0%), predominantly TDF + 3TC + EFV (95.1%). Viral load results eligible for outcompe analysis were available for 174 (35.2%) patients. Among these patients, 165 achieved virologic suppression, corresponding to a suppression rate of 94.8% (95% CI: 90.5–97.3), whereas virologic failure was observed in nine patients (5.2%; 95p% CI: 2.7–9.5). Viral load availability declined substantially among patients initiating ART in recent years, reflecting shorter follow-up durations and fewer opportunities for routine viral load monitoring. High levels of virologic suppression were observed across the demographic and clinical subgroups. Conclusions: Predominantly TDF-based first-line ART demonstrated high virologic effectiveness among treatment-naïve HIV patients with evaluable viral load measurements, with nearly 95% of patients achieving virologic suppression. However, incomplete viral load monitoring, particularly among patients initiating ART in later years, limits the evaluation of treatment outcomes at the program level. Strengthening routine viral load monitoring and long-term follow-up will improve the future real-world evaluation of ART effectiveness. Full article

Background/Objectives: People living with HIV (PLWH) who undergo prolonged antiretroviral therapy (ART) may experience weight gain as a potential side effect. Many of these individuals are prescribed glucagon-like peptide 1 (GLP-1) receptor agonists (RAs), or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RAs, which are known for their weight-reducing effects and positive impact on metabolic health. However, studies investigating their effects on PLWH are limited. Methods: We conducted a retrospective study at a public hospital in the Bronx, New York, among PLWH with obesity and/or type 2 diabetes mellitus (T2DM) prescribed GLP-1 or dual GLP-1/GIP RAs between August 2020 to March 2024. We collected baseline measurements of weight, body mass index (BMI), glycated hemoglobin (HbA1c), and lipid panel, before and after initiation of treatment, to assess the potential metabolic changes associated with the therapy. Logistic regression was used to analyze the factors associated with reductions in HbA1c and weight. Results: A total of 202 patients were included in the final study, with a mean duration of 24.2 months of GLP-1 or GLP-1/GIP RA therapy. A mean HbA1c reduction of 1.0% (p < 0.001), a mean BMI reduction of 0.7 kg/m² (p < 0.001), and an average mean weight loss of 3.55% were observed. In the univariate analysis, the duration of GLP-1 or GLP-1/GIP RA use was the only factor independently associated with HbA1c reduction greater than 1% (p = 0.027). However, no correlation was found between the duration of their use and the percentage of weight loss (p = 0.126). Insulin use was associated with less weight loss (p = 0.048), while younger age was associated with greater weight loss (p = 0.048). No significant differences in weight loss were observed when the population was stratified by sex, race, comorbidities, type of GLP-1 RA therapy, or other antidiabetic or ART regimens. Conclusions: Use of GLP-1 RAs among PLWH with obesity and/or T2DM is associated with reductions in HbA1c and BMI. In this diverse cohort, which predominantly consists of Black and Hispanic individuals, longer duration of treatment was associated with reductions in HbA1c greater than 1%. These findings encourage GLP-1 RA-related treatment for PLWH with obesity and/or T2DM. Further prospective studies with larger cohorts are needed to confirm these benefits and better define their effects on long-term metabolic health. Full article

Lenacapavir (LEN) is the first-in-class capsid inhibitor that inhibits HIV capsid function in vitro with picomolar activity. LEN has been approved for the treatment of HIV in combination with other antiretroviral agents (ARVs), as well as for the prevention of acquisition of HIV-1 in people who may benefit from pre-exposure prophylaxis (PrEP). In vitro investigations of the resistance profile of LEN have identified resistance-associated mutations (RAMs) at six residues in the HIV-1 capsid protein (CA), all found in the CA structural pocket where LEN binds and conferring LEN-resistance with various degrees of loss of susceptibility. LEN was initially evaluated in a clinical study (CAPELLA) of heavily treatment-experienced (HTE) people with HIV (PWH), in which 14 of 72 participants had emergence of in vitro-predicted LEN RAMs. Despite the presence of LEN RAMs in these participants with viral rebound, treatment with LEN led to viral suppression in a large majority of HTE PWH in CAPELLA. In treatment-naïve participants receiving subcutaneous LEN + asynchronous oral ARVs (CALIBRATE) 4 of 157 participants had emergence of LEN RAM after >2 years of study. In contrast, no cases of viral rebound with resistance to LEN have been observed in virologically suppressed PWH switching to the once-daily single-tablet regimen (STR) combining LEN with the integrase strand-transfer inhibitor (INSTI) bictegravir after up to 48 weeks in two Phase 3 studies, and for >3 years in Phase 2. Similarly, no resistance to LEN has been observed after up to 96 weeks in the Phase 2 study of once-weekly regimen of the deoxyadenosine analog RT inhibitor islatravir + LEN. Finally, in the Phase 2 study of the 6-monthly injectable LEN + 2 broadly neutralizing antibodies (bNAbs) combination, only one instance of resistance to LEN was observed in conjunction with loss of susceptibility to one of the bNAbs through 1 year of treatment. Overall, resistance to LEN in regimens using synchronous dosing (daily or weekly oral, or 6-monthly injectable) has been rare in clinical studies. As the use of LEN is predicted to increase in the near future with these potential new combinations, capabilities to test for capsid resistance are being developed through global commercial options as well as through regional health institutions. Full article

Antiretroviral therapy (ART) is essential for preventing HIV transmission and improving the health outcomes of people living with HIV (PLHIV). However, many barriers limit PLHIV from starting and adhering to ART, which explains why HIV responses in many settings, including Indonesia, have produced limited gains. This qualitative phenomenological study explored multilevel barriers to ART adherence in urban Yogyakarta (locally known as Jogja) and rural Belu, Indonesia, from the perspectives of PLHIV and healthcare professionals (HCPs). Data were collected through one-on-one in-depth interviews with 92 PLHIV and 20 HCPs. Participants were recruited using the snowball sampling technique. Data were analysed using framework analysis informed by the Access to Healthcare Framework. The findings showed that PLHIV in Belu and Jogja had different experiences in terms of the provision of and ability to access and adhere to ART or HIV treatment. In rural Belu, ART was less available and visible, harder to approach, often unaffordable, less aligned with patients’ needs, and strongly influenced by the widespread use of traditional medicine. PLHIV in Belu also reported a more limited ability to perceive the need for ART, reach services, pay costs, engage in care, and seek ART than those in urban Jogja. Personal, psychological, and social barriers were also reported to hinder PLHIV’s ART adherence in both settings. These findings highlight the need for HIV policies that promote the equitable distribution of ART services and targeted interventions to improve understanding and acceptance of HIV care among PLHIV and the wider community. Full article

As critical geopolitical and migratory hubs in Eastern Europe, the Azov and Donbas regions represent an epidemiological melting pot for HIV-1 trafficking, exacerbating the global trend of rising dolutegravir (DTG) resistance through the cross-border dissemination of drug-resistant strains. This study presents a comprehensive molecular epidemiological analysis of HIV-1 in these regions in 2025 (N = 1666), focusing on drug resistance and cross-border transmission networks using phylogenetic and molecular network approaches. The study cohort was predominantly female (53.33%) and had heterosexual transmission (78.77%). Most patients (87.64%) received antiretroviral therapy (ART). Sub-subtype A6 predominated, with the radiation’s origin traced to September 1994. Molecular network analysis identified the study area as a significant node, demonstrating viral exports towards the Russian Federation and Belarus, alongside multiple imports from Ukraine, Poland, and Russia. The overall resistance prevalence was 4.49% to integrase strand transfer inhibitors (INSTIs), 2.49% to protease inhibitors (PIs), 12.19% to nucleoside reverse transcriptase inhibitors (NRTIs), and 16.07% to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Surveillance drug resistance mutations in treatment-naive individuals stood at 0.89% (INSTIs), 4.90% (PIs), 4.90% (NRTIs), and 8.82% (NNRTIs). Crucially, intermediate or high-level DTG resistance and key mutations (G118R, R263K, and Y143R) were detected in individuals without prior DTG exposure. This 4.49% integrase inhibitor resistance cannot be considered low; combined with intense cross-border viral dissemination, it may indicate the formation of a stable pool of resistant variants, potentially posing a risk of dolutegravir-based regimen failure and highlighting the need for enhanced regional molecular surveillance. Full article

Background: Doravirine (DOR) is a new-generation non-nucleoside reverse transcriptase inhibitor, which has emerged as an option for people living with HIV (PLWH) owing to its favorable efficacy and safety profile, unique resistance pathway and limited potential for drug-drug interactions. Methods: This retrospective chart review study aimed to better understand DOR-based treatment use in Greece, PLWH characteristics, and drivers of treatment switch. Eligible individuals were adult PLWH who were switched to a DOR-based regimen based on the physician’s decision. Individuals exposed to DOR at any time prior to switching to the DOR-based regimen were excluded. Results: From 12 July 2023 to 31 October 2023, 110 PLWH were consecutively enrolled across 6 public hospital clinics. At baseline (closest prior to or on the date of first DOR prescription), the mean age of PLWH was 49.3 years, 90.9% were males, 88.2% were asymptomatic, 86.5% were virologically suppressed, 33.6% were suffering from multimorbidity (excluding infections/infestations), 45.5% were receiving comedications for their comorbidities, and 5.5% were co-infected with Hepatitis C virus. Most PLWH (98.2%) were prescribed DOR plus two nucleoside reverse transcriptase inhibitors; 87.3% were prescribed DOR/Lamivudine/Tenofovir Disoproxil Fumarate fixed-dose combination. PLWH started DOR a median of 11.7 years after first-ever antiretroviral therapy initiation, corresponding to 2nd/3rd/≥4th antiretroviral line in 33.6%/33.6%/32.7% of participants, respectively; 60.9% of them were proactively switched to a DOR-based regimen. The most common reasons for switching were ‘regimen simplification’ (42.7%), ‘tolerability’ (26.4%) and ‘prevention of toxicities’ (18.2%). Conclusions: This study highlights the patterns of DOR use in real-life clinical practice in Greece among treatment-experienced PLWH. Physicians switch HIV-1-infected individuals from prior ART to DOR-based regimens to offer a simplified regimen or to avoid or prevent toxicity. Full article

Antiretroviral therapy (ART) has proven effective in suppressing HIV-1 replication, but further development of HIV-1 inhibitors is continually driven by the challenge of drug resistance and viral adaptation. The HIV-1 capsid is a promising target for treatment due to its high sequence conservation as well as its crucial role in the viral life cycle. Recently, we have developed a novel capsid-targeting biologic that prevents HIV-1 replication by efficient degradation of newly synthesized capsid. Here, we have investigated the sensitivity to viral escape as well as the breadth of this biologic against HIV-1 subtypes. The capsid-targeting biologic efficiently blocked replication of different primary HIV-1 isolates, and continuous exposure of these viruses to the biologic resulted in viral breakthrough of two out of ten primary HIV-1 isolates tested. Notably, the breakthrough variants did not have amino acid changes in the nanobody epitope but primarily in the matrix region. The breakthrough variants remained sensitive to the biologic albeit to a lesser extent. In the absence of the biologic, breakthrough variants showed increased replication kinetics when compared to their parental virus, suggesting that adaption to the biologic is likely due to the increased viral production and that the target area of the biologic is too conserved for actual escape. This is further underscored by the broad specificity of the biologic as importantly the biologic blocked infection of different HIV-1 subtypes that occur worldwide (A, B, C, D, CRF01_AE, CRF02_AG). These results demonstrate the broad neutralization potential of anti-capsid biologics with a high barrier to resistance, making capsid-targeting inhibitors important for novel antiretroviral drug strategies worldwide. Full article