Non-nucleotide Reverse Transcriptase Inhibitor Research Articles

A Sensitivity and Consistency Comparison Between Next-Generation Sequencing and Sanger Sequencing in HIV-1 Pretreatment Drug Resistance Testing

Next-generation sequencing (NGS) for HIV drug resistance (DR) testing has an increasing number of applications for the detection of low-abundance drug-resistant variants (LA-DRVs) in regard to its features as a quasi-species. However, there is less information on its detection performance in DR detection with NGS. To determine the feasibility of using NGS technology in LA-DRV detection for HIV-1 pretreatment drug resistance, 80 HIV-infected individuals who had never undergone antiretroviral therapy were subjected to both NGS and Sanger sequencing (SS) in HIV-1 drug resistance testing. The results reported in this study show that NGS exhibits higher sensitivity for drug resistance identification than SS at a 5% detection threshold. NGS showed a better consistency compared with that of SS for both protease inhibitors (PIs) and integrase inhibitors (INSTIs), with a figure amounting to more than 90%, but worse consistency in nucleotide reverse transcriptase inhibitors (NRTIs), with a consistency ranging from only 61.25% to 87.50%. The consistency of non-nucleotide reverse transcriptase inhibitors (NNRTIs) between NGS and SS was around 85%. NGS showed the highest sensitivity of 87.0% at a 5% threshold. The application of NGS technology in HIV-1 genotype resistance detection in different populations infected with HIV requires further documentation and validation.

Optimizing Patient Care through Analysis of HIV-1 Genotyping: Insights into Test Ordering Strategies, Clinical Relevance, and Implications for Managing Drug Resistance

Abstract Background Antiretroviral resistance can lead to treatment failure and disease progression, especially in HIV patients. HIV-1 sequencing/genotyping tests (e.g., GenoSure) can be ordered by clinicians to detect HIV drug resistance (HIVDR). Here, we investigated our institution’s ordering practices, clinical relevance, and rates of HIVDR. Methods A total of 94 patients positive for HIV-1 between 01/2019-08/2021 were included (n=46 pre-COVID-19 prior to 03/11/2020; n=48 post-COVID-19). Patients’ charts were reviewed for demographics, laboratory results, clinical presentation, and antiviral management. Student t-test and Fisher exact test were used for statistical analyses. Results HIV-1 genotyping was ordered most by Medicine (67%), Surgery, (7%), Emergency medicine (6%), Neurology and Obstetrics & Gynecology (5% each). Only 70% of patients with GenoSure ordered and sent out had sufficient viral loads for genotyping. Among the patients with insufficient viral loads, the GenoSure test was most ordered by Medicine (68%), Surgery (9%) and Ob/Gyn (9%) departments. Our HIV patient population was predominantly male (70%) and had a mean age of 49 years (range: 25 to 90 years). Lower viral loads (1.8x105 vs. 3.4x105 copies/mL, p=0.05), CD4 counts (174 vs. 196 cells/mcL, p=0.7), CD8 counts (555 vs. 800 cells/mcL, p=0.04), and higher CD4/CD8 ratio (0.312 vs. 0.266, p=0.57) were seen in our post-COVID-19 patients. The overall prevalence of HIVDR was 20%. There was a 9% increase in HIVDR, predominantly in non-nucleotide reverse transcriptase inhibitors (NNRTI), after the COVID-19 pandemic. For example, higher resistance was documented for antiviral drugs Efavirenz (16%), Nevirapine (16%), and Rilpivirine (13%). Increased prevalence of mutations in G190A, K101, K103, and E138 positions which confer resistance to NNRTIs was seen. The GenoSure test results helped optimize antiviral therapy in 47.8% (42/88) of total cases, with an increase of 12.5% in patients from post-COVID-19 era. Infectious disease consultations led to more actionable changes (16% increase) and ordering of the updated version of the GenoSure test that includes integrase inhibitors (20% increase, p=0.005). Conclusion We have implemented stringent clinical criteria including pathologist approval and changed our electronic health record ordering system to ensure GenoSure is appropriately ordered. Diagnostic stewardship of sequencing tests needs to be implemented to ensure actionable clinical changes in the right patient population and to control testing costs. Additionally, our findings revealed increased HIVDR in our patient population post-COVID-19. Continued surveillance and collaboration with antimicrobial stewardship are critical to managing HIVDR and improving patient outcomes, particularly given the significant strain that the COVID-19 pandemic has placed on our healthcare system.

Exploring the interplay between antiretroviral therapy and the gut-oral microbiome axis in people living with HIV

The gut and oral microbiome is altered in people living with HIV (PLWH). While antiretroviral treatment (ART) is pivotal in restoring immune function in PLWH, several studies have identified an association between specific antiretrovirals, particularly integrase inhibitors (INSTI), and weight gain. In our study, we explored the differences in the oral and gut microbiota of PLWH under different ART regimens, and its correlation to Body Mass Index (BMI). Fecal and salivary samples were collected from PLWH (n = 69) and healthy controls (HC, n = 80). We performed taxonomy analysis to determine the microbial composition and relationship between microbial abundance and ART regimens, BMI, CD4+T-cell count, CD4/CD8 ratio, and ART duration. PLWH showed significantly lower richness compared to HC in both the oral and gut environment. The gut microbiome composition of INSTI-treated individuals was enriched with Faecalibacterium and Bifidobacterium, whereas non-nucleotide reverse transcriptase inhibitor (NNRTI)-treated individuals were enriched with Gordonibacter, Megasphaera, and Staphylococcus. In the oral microenvironment, Veillonella was significantly more abundant in INSTI-treated individuals and Fusobacterium and Alloprevotella in the NNRTI-treated individuals. Furthermore, Bifidobacterium and Dorea were enriched in gut milieu of PLWH with high BMI. Collectively, our findings identify distinct microbial profiles, which are associated with different ART regimens and BMI in PLWH on successful ART, thereby highlighting significant effects of specific antiretrovirals on the microbiome.

Plasma Lipidomic Profiles in cART-Treated Adolescents with Perinatally Acquired HIV Compared to Matched Controls.

Children with perinatally acquired human immunodeficiency virus (PHIV) are growing into adulthood with HIV and treatment-associated comorbidities, such as dyslipidemia and insulin resistance. HIV is identified as independent risk factor for cardiovascular disease (CVD). The hypothesis behind increased CVD risk associated with HIV includes vascular inflammation, dyslipidemia and combination antiretroviral therapy (cART) metabolomic toxicity. To investigate differences in lipid profiles and pathophysiological mechanisms of CVD risk in adolescents with PHIV, we compared the plasma lipidome of PHIV adolescents and HIV-negative controls. We additionally investigated the influence of current cART regimens and increased lipoprotein(a) (Lp(a)) levels on the plasma lipidome. We included 20 PHIV-infected adolescents and 20 HIV-negative controls matched for age, sex, ethnic origin and socio-economic status. Plasma lipidome was measured using Thermo Scientific Ultimate 3000 binary high-performance liquid chromatography (HPLC)-mass spectrometry. We evaluated the plasma lipidome in PHIV adolescents using different cART regimens (including those known to be associated with lipid alterations). The median age was 17.5 years (15.5-20.7) and 16.5 years (15.7-19.8) for PHIV adolescents and controls, respectively. Of PHIV adolescents, 45% used a non-nucleotide reverse transcriptase inhibitor (NNRTI)-based (25%) or protease inhibitor (PI)-based (20%) cART regimen. In this pilot study, we observed no significant differences between lipidomic profiles between PHIV adolescents and controls. We observed no differences in the plasma lipidome in participants with increased versus normal Lp(a) levels. Different cART regimens appear to influence chain length differences in the plasma lipidome of PHIV adolescents; however, the significance and causality of this observation remains undetermined. Further research on the influence of cART on lipid composition could further identify these alterations.

HIV Type-1 Genotyping in the Context of the COVID-19 Pandemic: A Critical Tool for Identifying Antiretroviral Drug Resistance and Optimizing Treatment Strategies

Abstract Introduction/Objective The COVID-19 pandemic strained the healthcare system and the WHO recently reported increased rates of antibiotic resistance. Meanwhile, antiretroviral resistance can also lead to treatment failure and disease progression, especially in HIV patients. Here, we investigated the rates of HIV drug resistance (HIVDR) in our HIV population between pre and post-COVID-19 eras. Methods/Case Report The post-COVID-19 era began on 03/11/2020. Patients positive for HIV-1 between 01/2019- 08/2021 were included (total: 94 patients, 46 pre-COVID-19; 48 post-COVID-19). Patients’ charts were reviewed for demographics, laboratory results (including HIV-1 sequencing/genotyping (e.g., Genosure)), clinical presentation and management. Student t-test and Fisher exact test were calculated. Results (if a Case Study enter NA) Most patients were male (70%) and had a mean age of 49 years. 70% of patients had sufficient viral loads in samples reflexed to HIV genotyping. Post-COVID-19 patients harbored lower viral loads (1.8x105 vs. 3.4x105 copies/mL, p=0.05), CD4 counts (174 vs. 196 cells/mcL, p=0.7), CD8 counts (555 vs. 800 cells/mcL, p=0.04), and higher CD4/CD8 ratio (0.312 vs. 0.266, p=0.57). Overall, 20% of patients had HIVDR. Following COVID-19 pandemic, there was a 9% increase in HIVDR, predominantly seen in non-nucleotide reverse transcriptase inhibitors (NNRTI), although insignificant. Specifically, high resistance was documented for drugs Efavirenz (16%), Nevirapine (16%), and Rilpivirine (13%). We observed an increased prevalence of G190A, K101, K103, and E138 mutations conferring resistance to NNRTIs. Changes to therapy were observed in 47.8% (42/88) of total cases, with an increase of 12.5% in patients from post-COVID-19 era. Additionally, changes to therapy were observed more in patients with infectious diseases consultation (16% increase). Conclusion Increasing HIVDR was seen in our patient population post-COVID-19. Continued surveillance is critical to managing HIVDR and improving patient outcomes. The clinical utility of sequencing tests can outweigh the cost if results are appropriately acted upon which may involve the participation of other clinical teams and the antimicrobial stewardship committee.

Reasons, safety and efficacy analysis for conversion of HAART to TAF/FTC/BIC among HIV-infected patients.

This study aimed to determine the reasons for conversion and elucidate the safety and efficacy of transition to tenofovir alafenamide/emtricitabine/bictegravir sodium (TAF/FTC/BIC) in highly active antiretroviral therapy (HAART)-experienced HIV-infected patients in real-world settings. We conducted a retrospective cohort study. The treatment conversion rationales, safety, and effectiveness in 1684 HIV-infected patients with previous HAART experience who switched to TAF/FTC/BIC were evaluated at Beijing Ditan Hospital from September 2021 to Auguest 2022. Regimen simplification (990/1684, 58.79%) was the most common reason for switching, followed by osteoporosis or osteopenia (375/1684, 22.27%), liver dysfunction (231/1684, 13.72%), decline in tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat (TAF/FTC/EVG/c) with food restriction (215/1684, 12.77%), virological failure (116/1684, 6.89%), and renal dysfunction (90/1684, 5.34%). In patients receiving non-nucleotide reverse transcriptase inhibitors (NNRTI)-containing regimens, lipid panel changes 1year after switching indicated a difference of 3.27±1.10mmol/L vs . 3.40±1.59mmol/L in triglyceride ( P =0.014), 4.82±0.74mmol/L vs . 4.88±0.72mmol/L in total cholesterol ( P =0.038), 3.09±0.70mmol/L vs . 3.18±0.66mmol/L in low-density lipoprotein ( P <0.001), and 0.99±0.11mmol/L vs . 0.95±0.10mmol/L in high-density lipoprotein ( P <0.001). Conversely, among patients receiving booster-containing regimens, including TAF/FTC/EVG/c and lopinavir/ritonavir (LPV/r), lipid panel changes presented decreased trends. We also observed an improved trend in viral load suppression, and alanine transaminase (ALT), aspartate transaminase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine levels after the transition ( P <0.001). The transition to TAF/FTC/BIC demonstrated good treatment potency. Furthermore, this study elucidates the motivations behind the adoption of TAF/FTC/BIC in real-world scenarios, providing clinical evidence supporting the stable conversion to TAF/FTC/BIC for HAART-experienced patients.

Low Prevalence of Pre-Treatment and Acquired Drug Resistance to Dolutegravir among Treatment Naïve Individuals Initiating on Tenofovir, Lamivudine and Dolutegravir in Zimbabwe.

Dolutegravir (DTG) use in combination with tenofovir and lamivudine (TLD) is scaling up in Africa. However, HIV drug resistance (HIVDR) data to DTG remain scarce in Zimbabwe. We assessed the prevalence and genetic mechanisms of DTG resistance in people living with HIV initiating on TLD. A prospective cohort study was conducted between October 2021 and April 2023 among antiretroviral therapy (ART) naïve adults (≥18 years) attending care at an HIV clinic in Zimbabwe. Pre-treatment drug resistance (PDR) was assessed prior to TLD initiation and viral load (VL) outcome and acquired drug resistance (ADR) to TLD were described after 24 weeks follow-up. In total, 172 participants were enrolled in the study. The median (IQR) age and log10 VL were 39 (29-48) years and 5.41 (4.80-5.74) copies/mL, respectively. At baseline, no PDR to DTG was found. However, as previously reported, PDR to non-nucleotide reverse transcriptase inhibitor (NNRTI) was high (15%) whilst PDR to NRTI was low (4%). After a median duration of 27 (25-30) weeks on TLD, virological suppression (VL < 1000 copies/mL) was 98% and among the 2 participants with VL ≥ 1000 copies/mL, no ADR was found. HIVDR to DTG is rare among ART naïve individuals. DTG is more likely to address the problems of HIVDR in Africa.

HIV-1 Disease Progression and Drug Resistance Mutations among Children on First-Line Antiretroviral Therapy in Ethiopia.

Background: High rates of disease progression and HIV drug resistance (HIVDR) among adults taking highly active antiretroviral treatment (HAART) in Sub-Saharan Africa were previously documented. However, children were generally not considered despite their greater risk. Hence, this study was aimed to evaluate HIV-1 disease progression and drug resistance mutation among children on first-line antiretroviral therapy in Ethiopia. Method: A longitudinal study was conducted among 551 HIV-positive children (<15 years old) recruited between 2017 and 2019 at 40 antiretroviral treatment delivery sites in Ethiopia. Disease progression was retrospectively measured over a 12-year (2007-2019) follow-up as the progress towards immunosuppression. Two consecutive viral load (VL) tests were conducted in 6-month intervals to assess virologic failure (VF). For children with VF, HIV-1 genotyping and sequencing was performed for the pol gene region using in-house assay validated at the Chinese Center for Disease Control and Prevention, and the Stanford HIVDB v9.0 algorithm was used for identification of drug resistance mutations. The Kaplan-Meier analysis and Cox proportional hazards regression model were used to estimate the rate and predictors of disease progression, respectively. Results: The disease progression rate was 6.3 per 100 person-years-observation (95% CI = 4.21-8.53). Overall immunosuppression (CD4 count < 200 cells/mm3) during the 12-year follow-up was 11.3% (95% CI = 7.5-15.1). Immunosuppression was significantly increased as of the mean duration of 10.5 (95% CI = 10.1-10.8) years (38.2%) to 67.8% at 12 years (p < 0.001). Overall, 14.5% had resistance to at least one drug, and 6.2% had multi-drug resistance. A resistance of 67.8% was observed among children with VF. Resistance to non-nucleotide reverse transcriptase inhibitors (NNRTI) and nucleotide reverse transcriptase inhibitors (NRTI) drugs were 11.4% and 10.1%, respectively. Mutations responsible for NRTI resistance were M184V (30.1%), K65R (12.1%), and D67N (5.6%). Moreover, NNRTI-associated mutations were K103N (14.8%), Y181C (11.8%), and G190A (7.7%). Children who had a history of opportunistic infection [AHR (95% CI) = 3.4 (1.8-6.2)], vitamin D < 20 ng/mL [AHR (95% CI) = 4.5 (2.1-9.9)], drug resistance [AHR (95% CI) = 2.2 (1.4-3.6)], and VF [AHR (95% CI) = 2.82 (1.21, 3.53)] had a higher hazard of disease progression; whereas, being orphan [AOR (95% CI) = 1.8 (1.2-3.1)], history of drug substitution [(AOR (95% CI) = 4.8 (2.1-6.5), hemoglobin < 12 mg/dL [AOR (95% CI) = 1.2 (1.1-2.1)] had higher odds of developing drug resistance. Conclusions: Immunosuppression was increasing over time and drug resistance was also substantially high. Enhancing routine monitoring of viral load and HIVDR and providing a vitamin-D supplement during clinical management could help improve the immunologic outcome. Limiting HAART substitution is also crucial for children taking HAART in Ethiopia.

Characteristics of genotype, drug resistance, and molecular transmission network among newly diagnosed HIV-1 infections in Shenzhen, China.

The HIV-1 pandemic has persisted for four decades, and poses a major challenge to global public health. Shenzhen, a city with large number of migrant populations in China, is suffering HIV-1 epidemic. It is necessary to continuously conduct the molecular surveillance among newly diagnosed HIV-1 patients in these migrant population. In this study, plasma samples of newly diagnosed and ART-naive HIV-1 infections were collected from Shenzhen city in China. The partial genes of HIV-1 gag and pol were amplified and sequenced for the analysis of genotype, drug resistance, and molecular transmission network. Ninety-one sequences of pol gene were obtained from newly diagnosed HIV-1 infections in Shenzhen, and seven HIV-1 subtypes were revealed in this investigation. Among them, the circulating recombinant form (CRF) 07_BC was the mostly frequent subtype (53.8%, 49/91), followed by CRF01_AE (20.9%, 19/91), CRF55_01B (9.9%, 9/91), unique recombinant forms (URFs) (8.8%, 8/91), B (3.3%, 3/91), CRF59_01B (2.2%, 2/91), and CRF08_BC (1.1%, 1/91). The overall prevalence of pretreatment drug resistance (PDR) was 23.1% (21/91), and 52.38% (11/21) of the PDR was specific for the nonnucleotide reverse transcriptase inhibitors (NNRTIs). Furthermore, a total of 3091 pol gene sequences were used to generate 19 molecular transmission clusters, and then one growing cluster, a new cluster, and a cluster with growth reactivation were identified. The result revealed that more sexual partner, CRF_07BC subtype, and seven amino acid deletions in gag p6 region might be the influencing factors associated with the high risk of transmission behavior. Compared with CRF01_AE subtype, CRF07_BC subtype strains were more likely to form clusters in molecular transmission network. This suggests that long-term surveillance of the HIV-1 molecular transmission should be a critical measure to achieve a precise intervention for controlling the spread of HIV-1 in China.

Effects of Gender and Baseline CD4 Count on Post-Treatment CD4 Count Recovery and Outcomes in Patients with Advanced HIV Disease: A Retrospective Cohort Study.

Presentation to care with advanced HIV disease (AHD) is a significant problem in sub-Saharan Africa. We evaluated factors associated with immune recovery among individuals presenting to care with AHD in Zimbabwe. We conducted a retrospective evaluation of outcomes among adult (>18 years old) individuals with AHD (CD4 count ≤200 cells/mm3) receiving care at 18 outpatient primary care clinics in Harare, Zimbabwe. Baseline and 12-month CD4 count data were extracted from medical records. CD4 count recovery (defined as CD4 count >200 cells/mm3) after 12 months on non-nucleotide reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) regimen was determined and factors associated with CD4 count recovery were established using logistic regression. All statistical analysis was performed on SPSS v23. A total of 1,338 participant records were included in the analysis. The median interquartile range (IQR) age was 37 (30-43) years and 52% were females. The baseline median (IQR) CD4 count was 50 (28-75) cells/mm3 and was significantly lower among patients with history of cryptococcal meningitis compared to those without [25 (10-52) vs. 52 (32-77), respectively; p = .0009]. The median (IQR) CD4 count at 12 months after ART initiation increased from 50 (28-75) at baseline to 180 (92-290) cells/mm3. Immune recovery with a CD4 count >200 cells/mm3 was observed in 181/417 (43%). Male gender and low baseline CD4 count were strong predictors of poor immunological recovery on ART. Immunological recovery following ART initiation was 43% among individuals with AHD. Male patients are most vulnerable to persistent immunological failure. Clinical Trial Registration number: NCT02434172.

Prevalence of Primary Drug Resistance Among Newly Diagnosed HIV-1-Infected Individuals in Hunan Province, China.

At present, research on the prevalence of primary drug resistance (PDR) in Hunan Province is limited. Therefore, we explored the current status of HIV-1 PDR in Hunan to provide a basis for antiretroviral therapy (ART) and a theoretical foundation for prevention and control of the HIV/AIDS epidemic. Three hundred seventy newly diagnosed HIV-1-infected individuals who had not received ART in Hunan province, China, were enrolled in the study. Plasma samples were collected, RNA was extracted, two rounds of gene amplification were carried out with the in-house method, and subtype analysis and drug resistance analysis were carried out with relevant software. We found that the most prevalent subtypes of HIV-1 in Hunan Province are CRF_01AE (126/359, 35.1%) and CRF07_BC (85/359, 23.7%). The PDR rate among newly diagnosed HIV/AIDS patients was 10.0% (36/359). Among them, the drug resistance rates of protease inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, and integrase inhibitors were 0.3% (1/359), 3.3% (12/359), 8.36% (30/359), and 0.6% (2/359), respectively. The distribution of HIV-1 subtypes in Hunan Province is diverse and complex, and the PDR rate has exceeded the low-level warning line set by the World Health Organization (<5%). Therefore, we should conduct pretreatment drug resistance assays to determine the optimal primary ART so that patients can obtain better antiretroviral treatment outcomes and transmission of drug-resistant strains in the population can be blocked.

Transmission and Drug Resistance Characteristics of Human Immunodeficiency Virus-1 Strain Using Medical Information Data Retrieval System.

This study was aimed at exploring the transmission and drug resistance characteristics of acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus-1 (HIV-1). The query expansion algorithm based on Candecomp Parafac (CP) decomposition was adopted to construct a data information retrieval system for semantic web and tensor decomposition. In the latent variable model based on tensor decomposition, the three elements in the triples generated feature vectors to calculate the training samples. The HIV patient data set was selected to evaluate the performance of the system, and then, the HIV gene resistance of 213 patients was retrospectively analyzed based on the electronic medical records. 43 cases showed failure of ribonucleic acid drug resistance, the ART virological failure rate was 24.43% (43/213), and one case was not reported. There was 1 case of RNA hemolysis that could not be detected. There were 50 resistant cases of nonnucleotide reverse transcriptase inhibitors (NNRTI), accounting for 29.94% (50/167), and there were 17 resistant cases of nucleotide reverse transcriptase inhibitors (NRTI), accounting for 10.18% (17/167) of all mutation cases. Among the HIV-1 strains, 19 cases failed the detection of drug resistance sites in the integrase region, and mutations in the integrase region were significantly more than those in the protease region. There were 12 types of HIV-1 strains with drug-resistant mutations. The fusion technical scheme constructed in this study showed excellent performance in medical information retrieval. In this study, the characteristics of HIV-1 of AIDS patients were analyzed from different directions, and effective treatment was performed for patients, so as to provide reference for clinical diagnosis of AIDS patients.

Statewide Longitudinal Trends in Transmitted HIV-1 Drug Resistance in Rhode Island, USA.

BackgroundHIV-1 transmitted drug resistance (TDR) remains a global challenge that can impact care, yet its comprehensive assessment is limited and heterogenous. We longitudinally characterized statewide TDR in Rhode Island.MethodsDemographic and clinical data from treatment-naïve individuals were linked to protease, reverse transcriptase, and integrase sequences routinely obtained over 2004–2020. TDR extent, trends, impact on first-line regimens, and association with transmission networks were assessed using the Stanford Database, Mann-Kendall statistic, and phylogenetic tools.ResultsIn 1123 individuals, TDR to any antiretroviral increased from 8% (2004) to 26% (2020), driven by non-nucleotide reverse transcriptase inhibitor (NNRTI; 5%–18%) and, to a lesser extent, nucleotide reverse transcriptase inhibitor (NRTI; 2%–8%) TDR. Dual- and triple-class TDR rates were low, and major integrase strand transfer inhibitor resistance was absent. Predicted intermediate to high resistance was in 77% of those with TDR, with differential suppression patterns. Among all individuals, 34% were in molecular clusters, some only with members with TDR who shared mutations. Among clustered individuals, people with TDR were more likely in small clusters.ConclusionsIn a unique (statewide) assessment over 2004–2020, TDR increased; this was primarily, but not solely, driven by NNRTIs, impacting antiretroviral regimens. Limited TDR to multiclass regimens and pre-exposure prophylaxis are encouraging; however, surveillance and its integration with molecular epidemiology should continue in order to potentially improve care and prevention interventions.

Molecular transmission networks and pre-treatment drug resistance among individuals with acute HIV-1 infection in Baoding, China.

BackgroundHuman immunodeficiency virus type 1 (HIV-1) genetic diversity and pre-treatment drug resistance (PDR) are major barriers to successful antiretroviral therapy (ART). In China, sexual intercourse is the most frequent route of HIV-1 transmission. However, few studies have analyzed PDR and transmission networks in detail among individuals in China with acute HIV-1 infection and their sexual contacts.MethodsA cross-sectional study was conducted in Baoding City, Hebei Province, China from 2019–2020. CD4 T cell counts and viral loads were assessed and a HIV-1 genotypic PDR assay was developed in-house. Transmission networks were visualized using Cytoscape with a threshold genetic distance of 0.015 among HIV-1 subtypes.ResultsFrom 139 newly diagnosed and drug-naïve individuals with HIV-1, 132 pol gene sequences were obtained and revealed eight HIV-1 subtypes. Circulating recombinant form (CRF)01_AE was the most frequent subtype (53.0%, 70/132) followed by CRF07_BC (26.5%, 35/132), B (13.6%, 18/132), unique recombinant forms (2.3%, 3/132), CRF55_01B (1.5%, 2/132), CRF103_01B (1.5%, 2/132), CRF65_cpx (0.8%, 1/132), and C (0.8%, 1/132). A total of 47 pol gene sequences were used to generate 10 molecular transmission networks. The overall prevalence of PDR was 7.6% and that of PDR to non-nucleotide reverse transcriptase inhibitors was 6.1%. Of three transmission networks for PDR, two were closely associated with Beijing and Tianjin, while another was restricted to sequences determined in this study.ConclusionsThese results demonstrate that during acute HIV-1 infection, PDR is transmitted in dynamic networks. This suggests that early detection, diagnosis, surveillance, and treatment are critical to effectively control HIV-1 spread.

Metabolic Syndrome Prevalence and Cardiovascular Risk Assessment in HIV-Positive Men with and without Antiretroviral Therapy.

Treatment of HIV infection is a lifelong process and associated with chronic diseases. We evaluated the prevalence and predictors of metabolic syndrome (MetS) and cardiovascular diseases (CVDs) with individual antiretroviral drugs exposure among HIV-infected men in Taiwan. A total of 200 patients’ data were collected with a mean age of 32.9. Among them, those who had CD4 positive cell number less than 350/mL were eligible to have highly active antiretroviral therapy (HAART). Patients were divided into group-1 that contains 45 treatment-naïve participants, and group-2 that includes 155 HAART treatment-experienced participants. MetS prevalence between group-1 and group-2 was 18% and 31%, respectively. The Framingham Risk Score (FRS) for the naïve and experienced groups were 4.7 ± 4.2 and 3.87 ± 5.92, respectively. High triglyceride (TG > 150 mg/dL) in group-1 and group-2 were 15.6% and 36.6% (p < 0.05), whereas, lower high-density lipoprotein (HDL < 39 mg/dL) in group-1 and group-2 presented as 76.7% versus 51% (p < 0.05), respectively. In group-2, treatment with protease inhibitors (PIs) resulted in higher TG levels when compared with non-nucleotide reverse transcriptase inhibitors (NNRTIs) and integrase inhibitors (InSTIs). The prevalence of MetS in the treatment-naïve group was lower than that of the treatment-experienced group; high TG level resulted in higher MetS prevalence in the treatment-experienced group. In contrast, the cardiovascular risk of FRS in the treatment-naïve group was higher than that of the treatment-experienced group, which may result from the low HDL level. Although group-1 participants have a higher risk of developing CVDs, in group-2, an increasing TG level in PIs user indicated higher CVDs risk. TG and HDL are two significant biofactors that required regular evaluation in HIV-positive individuals.

Durability of non-nucleotide reverse transcriptase inhibitor-based first-line ART regimens after 7 years of treatment in rural Uganda: A prospective cohort study.

Most antiretroviral therapy (ART) programs in resource-limited settings have historically used non-nucleotide reverse transcriptase inhibitor (NNRTI)-based regimens with limited access to routine viral load (VL) testing. We examined the long-term success of these regimens in rural Uganda among participants with 1 measured suppressed VL.We conducted a prospective cohort study of participants who had been on NNRTI-based first-line regimens for ≥4 years and had a VL <1000 copies/mL at enrollment in Jinja, Uganda. We collected clinical and behavioral data every 6 months and measured VL again after 3 years. We quantified factors associated with virologic failure (VF) (VL ≥ 1000 copies/mL) using Wilcoxon Rank Sum, chi-square, and Fisher's Exact Tests.We enrolled 503 participants; 75.9% were female, the median age was 45 years, and the median duration of time on ART was 6.8 years (IQR = 6.0–7.6 years). Sixty-nine percent of participants were receiving nevirapine, lamivudine, and zidovudine regimens; 22.5% were receiving efavirenz, lamivudine, and zidovudine; and 8.6% were receiving other regimens. Of the 479 with complete follow-up data, 12 (2.5%) had VL ≥ 1000 copies/mL. VF was inversely associated with reporting never missing pills (41.7% of VFs vs 72.8% non-VFs, P = .034). There were differences in distribution of the previous ART regimens (P = .005), but no clear associations with specific regimens. There was no association between having a VL of 50 to 999 copies/mL at enrollment and later VF (P = .160).Incidence of VF among individuals receiving ART for nearly 7 years was very low in the subsequent 3 years. NNRTI-based regimens appear to be very durable among those with good initial adherence.

The optimum implementation of long-acting injectable cabotegravir–rilpivirine in sub-Saharan Africa

The optimum implementation of long-acting injectable cabotegravir–rilpivirine in sub-Saharan Africa

Design of Experiment (DoE)-Approach Based RP-HPLC Analytical Method Development and Validation for Estimation of Efavirenz in Bulk and Formulations

Present study reports design of experiment (DoE) based development and validation of a simple, rapid and sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) method for estimation of efavirenz (EFZ), a non-nucleotide reverse transcriptase inhibitor (NNRTs), used in the treatment of acquired immunodeficiency syndrome (AIDS). Plackett-Burman design was explored to screen the critical method variables (CMVs) for the RP-HPLC method. A response surface Box-Behnken design was employed to optimize the screened CMVs which affect the analytical responses (ARs) of RP-HPLC method. Using the optimized CMVs the HPLC method was developed and validated according to International Conference on Harmonization (ICH) guidelines. EFZ in marketed formulation was estimated using the validated method. Acetonitrile proportion, pH of the phosphate buffer and mobile phase flow rate were the CMVs and retention time and number of theoretical plates were the ARs for the study. The optimized chromatographic parameters were acetonitrile proportion in mobile phase: 51.17%v/v, pH of phosphate buffer: 4.04 and flow rate: 1.25mL/min. Use of these optimized parameters resulted in retention time of 11.031min and 9,498.787 number of theoretical plates as ARs of the HPLC method. The method was further validated in harmony with current ICH guidelines Q2 (R1). The method was capable of the successful estimation of EFZ in marketed formulation. The study depicts successful development and validation of a simple RP-HPLC method of EFZ using DoE approach.

Pretreatment HIV Drug Resistance Among Adults Initiating or Re-Initiating First-Line Antiretroviral Therapy in Zimbabwe: Fast-Tracking the Transition to Dolutegravir-Based First-Line Regimens?

Pretreatment drug resistance (PDR) can compromise antiretroviral therapy (ART) efficacy and undermine the WHO targets to end the AIDS epidemic as a public health threat by 2030. Thus, we examined the level of PDR in Harare, Zimbabwe. Eligible study participants were adults who were ART naive or individuals with previous ART exposure reinitiating treatment, recruited between October 2018 and February 2020 in a HIV ART treatment clinic, in Harare. HIV drug resistance tests were performed for all specimens with viral load ≥400 copies/mL and interpreted using the Stanford HIVDB Algorithm. Chi-square test or Fisher's exact test was used for comparison of proportions of PDR across ART-naive or prior ART-exposed participants. All statistical analyses were performed using Stata version 14. Overall, 120 samples were genotyped of whom 104 were ART naive and 16 reported previous ART exposure. The overall PDR frequency among all participants was 31% [95% confidence interval (CI): 22.5-39.6]. PDR to any non-nucleotide reverse transcriptase inhibitor (NNRTI) was reported in 29% (95% CI: 21.0-37.9). PDR to nucleotide reverse transcriptase inhibitors (NRTIs) and protease inhibitors were low, found in 3% (95% CI: 0.9-8.2) and 1% (95% CI: 0.02-4.52), respectively. PDR to NNRTIs [efavirenz/nevirapine (EFV/NVP)] was found in 17% (95% CI: 10.5-24.6) and was more than six times higher among people with previous ART exposure than ART-naive people: 63% versus 10%, p < .001. Our study shows that PDR to NNRTIs in Zimbabwe has remarkably increased from the 10.9% prevalence reported in the 2016 WHO survey. Addressing PDR at a national level is a critical need and will be facilitated by fast-tracking the transition to dolutegravir in first-line ART regimens.

Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

In HIV-1-infected patients, antiretroviral therapy (ART) is a key factor that may impact commensal microbiota and cause the emergence of side effects. However, it is not fully understood how long-term ART regimens have diverse impacts on the microbial compositions over time. Here, we performed 16S ribosomal RNA gene sequencing of the fecal and salivary microbiomes in patients under different long-term ART. We found that ART, especially conventional nucleotide/nucleoside reverse transcriptase inhibitor (NRTI)-based ART, has remarkable impacts on fecal microbial diversity: decreased α-diversity and increased ß-diversity over time. In contrast, dynamic diversity changes in the salivary microbiome were not observed. Comparative analysis of bacterial genus compositions showed a propensity for Prevotella-enriched and Bacteroides-poor gut microbiotas in patients with ART over time. In addition, we observed a gradual reduction in Bacteroides but drastic increases in Succinivibrio and/or Megasphaera under conventional ART. These results suggest that ART, especially NRTI-based ART, has more suppressive impacts on microbiota composition and diversity in the gut than in the mouth, which potentially causes intestinal dysbiosis in patients. Therefore, NRTI-sparing ART, especially integrase strand transfer inhibitor (INSTI)- and/or non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens, might alleviate the burden of intestinal dysbiosis in HIV-1-infected patients under long-term ART.