Search Results (186)

Objective: To characterize the profiles of resistance mutations to HIV reverse transcriptase inhibitors in Gabon. Design: Cross-sectional study conducted over 37 months, from October 2019 to October 2022, at the IST/HIV/AIDS Reference Laboratory, a reference center for the biological monitoring of people living with the human immunodeficiency virus (PWHIV) in Gabon. Methods: Plasma from 666 PWHIV receiving antiretroviral treatment was collected, followed by RNA extraction, amplification, and reverse transcriptase gene sequencing. Statistical analyses were performed using Stata^® 14.0 software (USA). Results: Six hundred and sixty-six (666) PWHIV plasma collected from 252 male and 414 female patients were analyzed and 1654 mutations were detected in 388 patients, including 849 (51.3%) associated with nucleoside reverse transcriptase inhibitors (NRTIs) and 805 (48.7%) with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Three of the most prescribed treatment regimens were associated to the appearance of both NRTIs and NNRTIs resistance mutations: TDF + 3TC + EFV (24.02%; 160/666); TDF + FTC + EFV) (17.2%; 114/666) and AZT + 3TC + EFV (14.6%; 97/666). Additionally, stage 3 of CD4 T-lymphocyte deficiency, the higher viral load, and treatment duration are risk factors influencing the appearance of virus mutations. Also, treatment containing TDF-3TC + DTG is more protective against mutations. Conclusions: Drug resistance mutations are common in Gabon and compromise the efficacy of ART. Further study must search for other causes of therapeutic failure in Gabon in PWHIV. Full article

Human Immunodeficiency Virus (HIV) infection remains a major global health issue, with effective antiretroviral therapy (ART) extending life expectancy but also increasing age-related issues like osteopenia and osteoporosis. This cross-sectional study examines bone mineral density (BMD) and related risk factors in Romanian HIV-positive patients, emphasizing regional and therapy influences. The patients varying in HIV infection duration underwent DXA scanning to measure BMD in the lumbar spine, femoral neck, and total femur. A high prevalence of low BMD, especially in the lumbar spine, was identified along with significant associations between reduced BMD and factors such as smoking, alcohol use, vitamin D deficiency and serum phosphorus levels. ART like Protease Inhibitors and Nucleoside Reverse Transcriptase Inhibitors were linked to increased bone loss, emphasizing the multifactorial nature of osteoporosis in HIV-infected individuals and underscore the importance of regular BMD assessments, lifestyle adjustments, and careful management of antiretroviral therapy to minimize fracture risk and enhance overall health and quality of life. Full article

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

The repurposing potential of Efavirenz (EFV), a clinically established non-nucleoside reverse transcriptase inhibitor, was comprehensively evaluated for its in vitro antibacterial effect either alone or in combination with other antibacterial agents on several Gram-positive clinical strains showing different antibiotic resistance profiles. The binding potential assessed by an in silico study included Penicillin-binding proteins (PBPs) and WalK membrane kinase. Despite the relatively high minimum inhibitory concentration (MIC) limiting the use of EFV as a single antibacterial agent, it exhibits significant synergistic activity at sub-MIC levels when paired with various antibiotics against Enterococcus species and Staphylococcus aureus. EFV showed restored sensitivity of β-lactams against Methicillin-resistant S. aureus (MRSA). It increased the effectiveness of antibiotics tested against Methicillin-sensitive S. aureus (MSSA). It also helped to overcome the intrinsic resistance barrier for several antibiotics in Enterococcus spp. In silico binding studies aligned remarkably with experimental antimicrobial testing results and highlighted the potential of EFV to direct the engagement of PBPs with moderate to strong binding affinities (pK_a 5.2–6.1). The dual-site PBP2 binding mechanism emerged as a novel inhibition strategy, potentially circumventing resistance mutations. Special attention should be paid to WalK binding predictions (pK_a = 4.94), referring to the potential of EFV to interfere with essential regulatory pathways controlling cell wall metabolism and virulence factor expression. These findings, in general, suggest the possibility of EFV as a promising lead for the development of new antibacterial agents. Full article

Rilpivirine (RPV, R278474) was highlighted in 2005, two years after the death of Dr. Paul Janssen, as the ideal non-nucleoside reverse transcriptase inhibitor (NNRTI) to treat HIV infections. For this purpose, it was subsequently combined with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), darunavir (boosted with ritonavir or cobicistat) or dolutegravir. Its wide-spread use is thanks to its combination with cabotegravir (CAB) in the form of a long-acting intramuscular injection once per month (QM), later twice per month (Q2M), for the treatment of adults, later extended to adolescents and pregnant women, with HIV infections. The long-acting CAB plus RPV should not be administered in patients treated with rifampicin or rifabutin, patients with virological failure or patients with resistance to CAB or RPV, or patients with hepatitis B virus (HBV) infection. Long-acting CAB+RPV may lead to pain at the site of injection which would diminish over time. Full article

In this study, we investigated the proportion of transmitted drug resistance (TDR) mutations and human immunodeficiency virus (HIV)-1 subtypes among 487 antiretroviral therapy (ART)-naïve individuals in South Korea from 2021 to 2024 to inform more effective treatment strategies. Consistent with previous reports, subtype B was most prevalent among HIV-1 subtypes at 50.7%; however, its proportion decreased annually (p = 0.047). Various subtypes of circulating recombinant forms (CRFs) were analyzed in this study, resulting in high genetic diversity. The subtype distributions of Korean and non-Korean patients differed, with subtype B (53.7%) and CRF01_AE (34.4%) being dominant in the former and latter, respectively. TDR across antiretroviral drug classes was approximately 3.5% in South Korea. Non-nucleoside reverse transcriptase inhibitors elicited the greatest drug resistance, which increased from 2021 to 2023, with a slight decrease in 2024. The integrase strand transfer inhibitor drugs, elvitegravir and raltegravir, most frequently exhibited high resistance scores. We provide a comprehensive overview of the HIV-1 genetic distribution and TDR patterns in South Korea from 2021 to 2024. Within the broader context of HIV-1 epidemiology in Asia and the Pacific, the findings contribute to a comprehensive understanding of the global distribution of HIV-1 resistance and genotypes, enabling the development of effective interventions. Full article

Background: Argentina has reported moderate to high levels of transmitted drug resistance in people living with HIV/AIDS (PLWHA), mostly to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Doravirine (DOR) has a unique resistance profile and retains potent antiviral activity in the presence of the most prevalent NNRTI-associated resistant viruses. Scarce data exist regarding the frequency of DOR resistance-associated mutations (RAMs) in Latin America. We describe the prevalence of DOR RAMs in samples from adults PLWHA in Buenos Aires, Argentina, in the context of a survey of transmitted drug resistance (TDR). Material and Methods: A cross-sectional study was undertaken utilizing samples collected between 2017 and 2021 at two reference HIV clinics. Samples were analyzed for RAMs using the World Health Organization (WHO) mutation list. Mutations to DOR were assessed with the Stanford and Agence Nationale de Recherches sur le SIDA (ANRS) algorithms. Rilpivirine (RPV) RAMs were assessed using the Stanford algorithm. Susceptibility to NNRTIs was evaluated using the HIVdb Program with Stanford and ANRS criteria. Results: Samples from 1667 PLWHA were analyzed: 81.2% were male, with 52.6% identifying as men who have sex with men. According to the WHO list, the overall TDR was 12.1% (n = 203). The prevalence of RAMs was 10.1% (170/1667) for NNRTIs, 4% (67/1667) for nucleoside reverse-transcriptase inhibitors (NRTIs), and 1.7% (30/1667) for protease inhibitors (PIs). The most frequent NNRTI mutations were K103N (5.6%), G190A (0.89%), and K103S (0.77%). The prevalence of DOR RAMs was <2%, with the most common being Y188L (0.53%). Rilpivirine RAM prevalence was 6%. Susceptibility to DOR, RPV, efavirenz, and nevirapine as given by the Stanford algorithm was 97.4%, 92%, 91.4%, and 90.4%, respectively. The ANRS criteria yielded susceptibility rates of 98.3%, 93.3%, 92.3%, and 90.8%, respectively. Regarding NRTIs, thymidine analog mutations (including T215 revertants) were the most frequent RAMs. Among PIs, the most prevalent RAMs were M46L (0.47%) and V82A (0.35%). Conclusions: Our study shows the persistence of moderate to high levels of resistance to first-generation NNRTIs. Despite this, prevalence was low for DOR. Surveillance of TDR remains critical for recommendations of ART initiation. Full article

Nucleoside reverse transcriptase inhibitors (NRTIs) and platinum-based chemotherapeutics are widely utilized in cancer treatment. Evidence suggests that drug plasma concentrations are closely linked to both therapeutic efficacy and the risk of adverse effects. Consequently, developing therapeutic drug monitoring (TDM) methods is essential. Here, an effective procedure utilizing QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) techniques for preparing samples and UPLC-MS/MS for simultaneously measuring eight NRTIs and platinum-based drugs in human plasma is described. Chromatographic separation was conducted with an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 μm) with acetonitrile with 0.1% formic acid as Phase A and 0.1% formic acid in water as Phase B, achieving complete separation within 10 min. The target analytes—lamivudine, telbivudine, emtricitabine, entecavir, tenofovir, nedaplatin, oxaliplatin, and adefovir dipivoxil—exhibited strong linearity within the 10–1000 ng/mL and 1–100 ng/mL ranges, showing correlations (r²) ≥ 0.9962. The method demonstrated excellent accuracy (−6.72% to 7.82%) and selectivity (84.53%–110.49%), as well as satisfactory recovery and stability. Overall, this analytical approach can be used to detect the combination of eight NRTIs and platinum-based drugs in human plasma. This method enables plasma drug-level monitoring in real time, with applications for individualized treatment approaches. Full article

By 2022, Bulgaria’s National Reference Laboratory had confirmed 4024 HIV cases. We analyzed 132 pol gene sequences to characterize the molecular epidemiology of HIV-1 subtypes A1, A6, and A7 (2001–2022). A1 accounted for 50.0% (66/132) of cases, increasing after 2014, with peaks in 2019 and 2022. A6 comprised 48.5% (64/132), dominating from 2005 to 2014 before stabilizing. A7 was rare (1.5%, 2/132), detected in 2003 and 2011. Transmission patterns varied: A1 was linked to men who have sex with men (MSM) (62.1%), while A6 was primarily heterosexual (HET) (82.8%) with a balanced gender distribution (56.3% male, 43.8% female). Resistance mutations were identified in 29.6% of cases, with A6 showing higher rates of nucleoside reverse transcriptase inhibitor (NRTI) (20.3%) and non-nucleoside reverse transcriptase inhibitor (NNRTI) (7.8%) resistance than A1. Phylogenetic analysis revealed that 13 Bulgarian sequences (9.8%) were involved in transmission clusters, including 10 (7.6%) from sub-subtype A1 and 3 (2.3%) from sub-subtype A6, highlighting distinct genetic diversity and transmission patterns. Despite significant migration from Ukraine in 2022, A6 prevalence remained unchanged, suggesting localized transmission dynamics. These findings highlight a shifting HIV-1 sub-subtype distribution in Bulgaria and emphasize the need for targeted prevention, diagnosis, and treatment strategies tailored to the evolving molecular landscape. Full article

The scale-up of antiretroviral therapy (ART) has markedly increased pretreatment drug resistance (PDR) among newly diagnosed HIV-infected individuals. This study aims to assess the prevalence and characteristics of PDR, infer the genetic transmission network, and evaluate the effect of PDR on ART in Nanning City, Guangxi. Methods: This study was conducted in the Fourth People’s Hospital of Nanning from 2019 to 2023. PDR was estimated using the Stanford algorithm. Genetic transmission networks were inferred by HIV-TRACE and visualized with Cytoscape. Logistic regression identified PDR-related factors. The Cox proportional hazards model assessed the impact of drug resistance on virological and immunological failure. Among 234 participants, the prevalence of PDR was 8.97%. CRF07_BC (35.9%), CRF-01AE (27.35%), and CRF08_BC (23.9%) were the top three HIV-1 strains. Resistance to non-nucleoside reverse-transcriptase inhibitors, protease inhibitors, nucleoside reverse-transcriptase inhibitors, and integrase strand-transfer inhibitors was 4.27%, 2.56%, 1.28%, and 0.43%, respectively. Overall, 21.37% of the participants exhibited drug resistance mutations (DRMs). Homosexuals were less likely to have PDR compared to heterosexuals ([aOR] 0.09, 95% CI 0.01–0.86). In the genetic network, V179D/E was also the most frequent DRM. Additionally, the incidence of virological failure (19.23%) and immune failure (20.09%) after one year of treatment did not show significant differences in different drug resistance groups. Conclusions: The prevalence of PDR in Nanning City is moderate, driven largely by the V179D and K103N mutations. The cross-transmission networks emphasize the imperative of PDR testing and targeted interventions. Full article

Background: Antiretroviral therapy has transformed HIV infection from a fatal disease to a chronic and manageable condition, but increasing health issues beyond acquired immunodeficiency syndrome, such as metabolic, liver, and cardiovascular diseases, have been observed. Furthermore, the increasing prevalence of HIV strains resistant to older antiretroviral regimens has necessitated a re-evaluation of treatment strategies. Methods: We performed a retrospective, observational study to evaluate the long-term outcomes of an antiretroviral switch from a non-nucleoside reverse transcriptase inhibitor-based to bictegravir-based regimen; this study aimed to assess the impact of this antiretroviral switch on treatment adherence, the safety profile, and virologic outcomes. The secondary objectives were to analyze the changes in lipid, kidney function, liver function, and anthropometric parameters after switching. Results: A total of 25 patients were included in this analysis; virologic suppression was maintained over time, with 100% of patients demonstrating undetectable viral loads at 6, 12, 24, and 36 months. In parallel, a significant increase in CD4+ cell count was observed after switching. No significant differences were observed compared to the previous therapy regarding anthropometric parameters or laboratory parameters. However, a significant reduction in liver steatosis, as assessed by Fibroscan, was observed. Conclusions: bictegravir-based regimens are a valid therapeutic option for people living with HIV, particularly for those with metabolic comorbidities. Full article

Acute HIV-1 infection (AHI) is a transient period where the virus causes evident damage to the immune system, including an extensive apoptosis of CD4+ T cells associated with a high level of activation and a major cytokine storm to fight the invading virus. HIV infection establishes persistence by integrating the viral genome into host cell DNA in both replicating and non-replicating forms, effectively hiding from immune surveillance within infected lymphocytes as cellular reservoirs. The measurement of total HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) is a reliable reflection of this reservoir. Initiating treatments during AHI with nucleoside reverse transcriptase inhibitors (NRTIs) and/or integrase strand transfer inhibitors (INSTIs) is essential to alter the dynamics of the global reservoir expansion, and to reduce the establishment of long-lived cellular and tissue reservoirs, while preserving and enhancing specific and non-specific immune responses. Furthermore, some of the patients treated at the AHI stage may become post-treatment controllers and should be informative regarding the mechanism of viral control, so patients treated during AHI are undoubtedly the best candidates to test innovative remission strategies toward a functional cure that could play a pivotal role in long-term HIV control. AHI is characterized by high levels of viral replication, with a significant increase in the risk of HIV transmission. Detecting AHI and initiating early treatment following diagnosis provides a window of opportunity to control the epidemic, particularly in high-risk populations. Full article

I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman’s group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2′,3′-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections. Full article

HIV subtype A6 with the L74I polymorphism, which increases the risk of cabotegravir/rilpivirine treatment failure, causes more and more infections in Poland. In this multicenter, observational, cross-sectional study (2023–2024), we analyzed viral subtypes and drug-resistance mutations to drugs used for long-acting injectable antiretroviral treatment and pre-exposure prophylaxis. Among 357 people with HIV, 247 (69%) were Polish nationals, and 102 (29%) were from former Soviet Union countries. Of the 357 people included, 159 (45%) had subtype B, and 177 (50%) had subtype A6 infections, with 165 (87%) of the latter characterized by the L74I polymorphism. Subtype A6 was more frequent in women (66% vs. 46% in men, p < 0.05) and among people from former Soviet countries (77% vs. 39% in Polish nationals, p < 0.05). About 40% of people had either drug-resistance mutations for cabotegravir/rilpivirine or HIV A6 subtype with the L74I polymorphism; 4.5% had both of these conditions. Compared to subtype B infections, subtype A6 infections were characterized by more frequent major transmitted drug-resistance mutations for non-nucleoside reverse transcriptase inhibitors (8.5% vs. 1.9%, p = 0.007) and rilpivirine (5.1% vs. 0.6%, p = 0.016). Due to the frequent occurrence of the L74I polymorphism and drug-resistance mutations in HIV A6 subtype infection, about 40% of people with HIV in Poland may be at risk of long-acting injectable treatment failure. Full article

HIV drug resistance (HIVDR) presents a significant challenge to antiretroviral therapy (ART) success, particularly in resource-limited settings like Ethiopia. This cross-sectional study investigated viral suppression rates and resistance patterns among patients on second-line ART across 28 Ethiopian health facilities. Blood samples collected from 586 participants were analyzed to measure CD4 count and viral load and assess HIVDR in patients experiencing virological failure (VF) (viral load ≥ 1000 copies/mL). Demographic and clinical data were analyzed using logistic regression to identify factors associated with VF. Results showed that 13.82% of participants experienced VF, with 67.57% of genotyped samples exhibiting at least one drug resistance mutation. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) was detected in 48.64%, 64.86%, and 18.92% of cases, respectively. Dual-class resistance was identified in 48.64% of patients, while triple-class resistance was detected in 18.92%. VF was more likely among students and those with CD4 counts below 200 cells/mm³, but less likely in patients on second-line treatment for 12 months or more. Our findings highlight a substantial HIVDR burden among patients on second-line ART with VF, emphasizing the need for comprehensive HIV care, including adherence support, regular viral load monitoring, and HIVDR testing. Full article