Non-nucleoside Reverse Transcriptase Inhibitor Resistance Research Articles

HIV transmission dynamics and population-wide drug resistance in rural South Africa

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.

Case Series of People With HIV on the Long-Acting Combination of Lenacapavir and Cabotegravir: Call for a Trial.

Injectable cabotegravir (CAB)/rilpivirine (RPV) is the only combination long-acting (LA) antiretroviral regimen approved for HIV. RPV may not be effective among individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, which has >10% prevalence in many countries. Lenacapavir (LEN) is an LA capsid inhibitor given every 6 months, but has not been studied in combination with other LA agents. We assembled a case series from 4 US academic medical centers where patients with adherence challenges were prescribed LEN subcutaneously every 26 weeks/CAB (+/- RPV) intramuscularly every 4 or 8 weeks. Descriptive statistics, including viral load (VL) outcomes, were summarized. All patients (n = 34: 76% male; 24% cis/trans female; 41% Black; 38% Latino/a; median age [range], 47 [28-75] years; 29% and 71% on CAB every 4 or 8 weeks) reported challenges adhering to oral ART. The reasons for using LEN/CAB with or without RPV were documented or suspected NNRTI mutations (n = 21, 59%), integrase mutations (n = 5, 15%), high VL (n = 6, 18%), or continued viremia on CAB/RPV alone (n = 4, 12%). Injection site reactions on LA LEN were reported in 44% (32% grade I, 12% grade 2). All patients but 2 (32/34; 94%) were suppressed (VL <75 copies/mL) after starting LEN at a median (range) of 8 (4-16) weeks, with 16/34 (47%) suppressed at baseline. In this case series of 34 patients on LEN/CAB, high rates of virologic suppression (94%) were observed. Reasons for using LEN/CAB included adherence challenges and underlying resistance, mostly to NNRTIs. These data support a clinical trial of LEN/CAB among persons with NNRTI resistance.

Prevalence of pretreatment HIV resistance to integrase inhibitors in West African and Southeast Asian countries.

Integrase strand transfer inhibitors (INSTIs) have been recently recommended as the preferred first-line option for antiretroviral treatment initiators in low- and middle-income countries (LMICs) in response to the growing circulation of resistant HIV to non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, we estimated the frequency of pretreatment drug resistance (PDR) to INSTIs in West Africa and Southeast Asia. Using samples collected from 2015 to 2016, and previously used to assessed PI, NRTI and NNRTI resistance, we generated HIV integrase sequences and identified relevant INSTI PDR mutations using the Stanford and ANRS algorithms. We generated 353 integrase sequences. INSTI PDR frequency was low, 1.1% (4/353) overall, ranging from 0% to 6.3% according to country. However, frequency of PDR to any drug class was very high, 17.9% (95% CI: 13.9%-22.3%), and mostly associated with a high level of NNRTI PDR, 9.7%, and a moderate level of NRTI PDR, 5.3%. Our results support the recent introduction of INSTIs in LMICs to improve treatment outcome in these settings, but also stress the need for effective actions to prevent uncontrolled emergence of drug resistance to this drug class.

Growth of infants delivered by mothers with HIV in Guangxi, China: An 18-month longitudinal follow-up study, 2015-2021.

The prevention of mother-to-child transmission of HIV has been a global success. But little is known about the growth parameters of infants delivered by mothers with HIV or the drug resistance of infants with HIV in China. The study aimed to assess growth parameters and drug resistance in Chinese infants exposed to HIV. We conducted an 18-month longitudinal follow-up study of 3283 infants (3222 without HIV; 61 with HIV) born to mothers with HIV in the Guangxi Zhuang Autonomous Region between January 2015 and December 2021. The weight and length of all participants was recorded. In addition, genetic subtypes and drug resistance analysis were performed for infants with HIV. Compared with infants without HIV, those with HIV had significantly lower weight/length Z-scores, except at 18 months of age. The length/age Z-scores of infants with HIV was significantly reduced, except at 1 month of age. The weight/age Z-scores of infants with HIV were significantly lower at all follow-up time points. The weight/length Z-scores of male infants without HIV were significantly lower than for female infants without HIV at all follow-up time points. Male infants without HIV had lower length/age and weight/age Z-scores than female infants at the remaining follow-up points, except at 1 month of age. Of a total of 61 infants with HIV, subtype and drug-resistance data were obtained from 37 (60.66%) samples. Infants with HIV were dominated by the CRF01_AE genotype and showed a diversity of mutation sites dominated by non-nucleoside reverse transcriptase inhibitor resistance. Our study demonstrates the growth of infants exposed to HIV in southwest China and provides detailed information on subtype distribution and drug resistance of those with HIV. Nutritional support and drug-resistance surveillance for infants exposed to HIV need to be strengthened.

HIV-1 drug resistance and genetic diversity in people with HIV-1 in Cape Verde, 2019-2021.

To characterize the genetic diversity and drug resistance profiles of people with HIV-1 failing ART in Cape Verde (CV). Cross- sectional study conducted between January 2019 and December 2021 in 24 health centres on the islands of Santiago and São Vicente. The HIV-1 pol gene was sequenced in individuals with a detectable viral load (VL). HIV-1 genetic diversity was determined by phylogenetic analysis. Drug resistance mutation patterns and resistance phenotypes were estimated using the Stanford algorithm. VL was detected in 73 of 252 (29%) enrolled participants and sequencing data were produced for 58 (79%) participants. CRF02_AG strains predominated (46.5%), followed by subtype G (22.4%). Most patients (80%) had mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) (67%), nucleoside reverse transcriptase inhibitors (55%), integrase inhibitors (10%) and/or protease inhibitors (7%) used in CV, a significant increase compared to a study conducted in 2010-2011. The most common mutations were M184 V/I (43%), K103N/S (36%) and G190A/S (19%). NNRTI resistance was associated with younger age and exposure to two or more drug regimens. The HIV-1 epidemic in Cape Verde is mainly driven by CRF02_AG and subtype G. Resistance to NNRTIs and/or NRTIs is highly prevalent and resistance to LPV/r and DTG is emerging. Our results support the use of DTG-based first-line ART and PI-based regimens for patients with virological failure, but emerging resistance to LPV/r and DTG is a concern. Continued monitoring of drug resistance is essential to ensure adequate health care for PLWH in Cape Verde.

Portable Nanopore sequencing solution for next-generation HIV drug resistance testing

BackgroundTackling HIV drug resistance is one of major challenges for ending AIDS epidemic, but the elevated expense of cutting-edge genomics hampers the advancement of HIV genotype testing for clinical care. MethodsWe developed a HIV genotype testing pipeline that centers on a cost-efficient portable Nanopore sequencer. Accuracy verification was conducted through comparison with parallel data obtained via fixed-site Pacbio sequencing. Our complete pol-gene sequencing strategy coupled with portable high-throughput sequencing was applied to identify drug resistance mutations across 58 samples sourced from the ART-treated Los Angeles General Medical Center Rand Schrader Clinic (LARSC) cohort (7 samples from 7 individuals) and the ART-naïve Center for HIV/AIDS Vaccine Immunology (CHAVI) cohort (51 samples from 38 individuals). ResultsA total of 472 HIV consensus sequences, each tagged with a unique molecular identifier, were produced from over 1.4 million bases acquired through portable Nanopore sequencing, which matched those obtained independently via Pacbio sequencing. With this desirable accuracy, we first documented the linkage of multidrug cross-resistance mutations across Integrase Strand Transfer inhibitors (INSTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from an individual failing a second-generation INSTI regimen. By producing more than 500 full-length HIV pol gene sequences in a single portable sequencing run, we detected Protease Inhibitor (PI), Nucleoside Reverse Transcriptase Inhibitor (NRTI), NNRTI and INSTI resistance mutations. All drug resistance mutations identified through portable sequencing were cross-validated using fixed-site Pacbio sequencing. ConclusionsOur accurate and affordable HIV drug resistance testing solution is adaptable for both individual patient care and large-scale surveillance initiatives.

The Burden of Pretreatment HIV Drug Resistance in Trinidad and Tobago.

Strategies to improve the scale-up of antiretroviral therapy (ART) for patients with HIV in Trinidad and Tobago, including the adoption of the "Test and Treat All" policy, have accompanied an increase in the number of patients with pretreatment HIV drug resistance (PDR) in the country. However, the scale of this public health problem is not well established. The objective of this study was to estimate the prevalence of PDR and evaluate its impact on viral suppression among patients with HIV receiving care at a large HIV treatment center in Trinidad and Tobago. We retrospectively analyzed data from the Medical Research Foundation of Trinidad and Tobago of patients newly diagnosed with HIV who had HIV genotyping performed. PDR was defined as having at least one drug-resistant mutation. We assessed the impact of PDR on achieving viral suppression within 12 months of ART initiation, using a Cox extended model. Among 99 patients, 31.3% had PDR to any drug, 29.3% to a non-nucleoside reverse transcriptase inhibitor (NNRTI), 3.0% to a nucleoside reverse transcriptase inhibitor, and 3.0% to a protease inhibitor. Overall, 67.1% of the patients who initiated ART (n = 82) and 66.7% (16/24) of patients with PDR achieved viral suppression within 12 months. We found no significant association between PDR status and achieving viral suppression within 12 months [adjusted hazard ratio: 1.08 (95% confidence interval: 0.57-2.04)]. There is a high prevalence of PDR in Trinidad and Tobago, specifically driven by NNRTI resistance. Although we found no difference in virologic suppression by PDR status, there is an urgent need for an effective HIV response to address the many drivers of virologic failure. Accelerating access to affordable, quality-assured generic dolutegravir and adopting it as the preferred first-line ART therapy are critical.

Transitioning to Dolutegravir in a Programmatic Setting: Virological Outcomes and Associated Factors Among Treatment-Naive Patients With HIV-1 in the Kilombero and Ulanga Antiretroviral Cohort in Rural Tanzania.

Virological outcome data after programmatic transition from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based to dolutegravir (DTG)-based antiretroviral therapy (ART) regimens in sub-Saharan Africa (SSA) outside of clinical trials are scarce. We compared viral suppression and associated factors in treatment-naïve people living with HIV (PLHIV) starting DTG- based versus NNRTI-based ART. We compared virological suppression at 12 months, after treatment initiation in the two cohorts of participants aged ≥15 years, initiating DTG- and NNRTI-based ART. Drug resistance was assessed among participants with viremia ≥50 copies/mL on DTG. Viral suppression was achieved for 165/195 (85%) and 154/211 (73%) participants in the DTG- and NNRTI- cohorts, respectively (P = 0.003). DTG-based ART was associated with >2 times the odds of viral suppression versus NNRTI-based ART (adjusted odds ratio, 2.10 [95% confidence interval {CI}, 1.12-3.94]; adjusted risk ratio, 1.11 [95% CI, 1.00-1.24]). HIV-1 genotypic resistance testing (GRT) before ART initiation was done in 14 of 30 viremic participants on DTG, among whom nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and protease inhibitors resistance was detected in 0 (0%), 2 (14%) and 1 (7%), respectively. No resistance was found in the 2 of 30 participants with available GRT at the time of viremia ≥50 copies/mL. Virological suppression at 1 year was higher in participants initiating DTG- versus NNRTI-based ART. In those with viremia ≥50 copies/mL on DTG-based ART, there was no pretreatment or acquired resistance to the DTG co-administered NRTIs, although the number of samples tested was small.

Resistance rates among antiretroviral regimens in pregnant people living with HIV.

To update nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) resistance rates and describe the frequency of HIV subtypes in a cohort of pregnant people living with HIV (PPLH) at a national Prevention of Mother-To-Child HIV Transmission (PMTCT) centre. We evaluated genotypic resistance among PPLH during prenatal care who were antiretroviral therapy-naïve or experienced. We determined mutations by the Surveillance of Drug Resistance Mutations (SDRM) dataset and also focused on studying participants with intermediate or high resistance defined through the Stanford score. From 2018 to 2021, 1170 PPLH received prenatal care at the centre and 550 were genotyped. Among the 295 SDRMs, with respect to NRTI resistance mutations, there were 27/295 (9.2%) M184V/I, 14/295 (4.7%) T215Y/C/D/E/F/V/I/S and 12/295 (4.1%) M41L. For NNRTI, there were 75/295 (25.4%) K103N, 18/295 (6.1%) M230L and 14/295 (4.7%) G190A/E/S mutations. For PI, the most frequent mutations were 13/295 (4.4%) V82A/S/F/T, 12/295 (4.1%) M46I/L and 10/295 (3.4%) D30N. Based on the Stanford score, 36/224 (16%) naïve participants had one or more antiretroviral resistance mutations, 81% of whom had NNRTI resistance. In the treatment-experience group, 108/326 (33%) had one or more mutations, 91% of whom had NNRTI resistance. The most frequent HIV subtype was B (82.5%). Our findings suggest that continuous surveys of HIV genotype appear to be important tools to map the distribution and evolution of HIV subtypes and resistance to provide information to support treatment policies. Furthermore, concerns about the use of rilpivirine-containing regimens underscore the importance of resistance surveillance.

Genetic Diversity and Characteristics of Drug Resistance Among Treatment-Naive People Living with HIV in Xi'an, China.

The genetic diversity and genetic predisposition for drug resistance mutations are the primary features of human immunodeficiency virus type 1 (HIV-1), which could cause the incidence of failure of antiretroviral therapy (ART). This study investigates the distribution of various HIV-1 genotypes and the incidence of pretreatment drug resistance (PDR) in the antiretroviral-naive HIV-1 infected participants in Xi'an, China. In this study, a cross-sectional analysis was carried out at the Xi'an Eighth Hospital between January 2020 and December 2021 among newly-diagnosed ART-naive HIV-1 infected participants. A nested PCR technique was used for amplifying the target segment of 1.3 kb present in the pol gene that spanned the reverse transcriptase and the protease regions. HIV-1 genotypes and the PDR-associated mutations were identified using the Stanford HIV Drug Resistance Database. A total of 317 pol gene sequences were retrieved, amplified, and sequenced. The circulating recombinant form (CRF), CRF07_BC (51.7%) was seen to be the most prevalent HIV-1 genotype, followed by other genotypes like CRF01_AE (25.9%), B (14.2%), and CRF55_01B (4.7%). PDR was found in 18.3% of the population. The PDR mutation frequency in the non-nucleoside reverse transcriptase inhibitor (NNRTI) (16.1%) was significantly higher compared to that of the nucleoside reverse transcriptase inhibitor (NRTI) (4.4%) and the protease inhibitor (0.9%). V179D/E (both were 4.4%) was seen to be the most predominant type of NNRTI mutation. K65R and M184V (1.3%) were the most frequent NRTI-associated mutations. About half (48.3%) of the sequenced HIV-1 strains that had mutations could show a potential low-level NNRTI resistance owing to V179D/E. Multivariate regression analysis revealed one PDR mutation associated with subtype CRF01_AE (p=0.002) and CRF55_01B (p<0.001) as a higher risk mutation. Diverse and complex HIV-1 genotypes are distributed in Xi'an, China. Considering new evidence, it is necessary to screen for baseline HIV-1 drug resistance among the newly-diagnosed HIV-1 individuals.

Resistance Trends of Antiretroviral Agents in People with Human Immunodeficiency Virus in Korea, 2012 - 2020.

Domestic data on antiretroviral drug (ARV) resistance are limited, while alterations in ARV resistance are expected as the incidence of human immunodeficiency virus (HIV) infection increases. We evaluated the ten-year change in ARV resistance in people with HIV (PWH) in Korea. Adults aged ≥19 years and diagnosed with HIV infection between January 2010 and December 2020 at a 750-bed municipal hospital were retrospectively reviewed. Data on clinical characteristics and resistance mutation test results were collected. The study population was divided into three-year intervals according to diagnosed year and their clinical characteristics were compared. A total of 248 PWH were analyzed, and ARV resistance was detected in 30 of them (12.1%). Resistance was detected most frequently in PWH aged ≤29 years (16, 6.5%), and the median percentage of resistance detection per year was 14.3% (interquartile range, 12.7 - 16.1). The trend of the overall prevalence of ARV resistance mutations slightly decreased and then increased over time (15.3% in 2012 - 2014, 9.6% in 2015 - 2017, and 12.9% in 2018 - 2020). The prevalence of the non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance markedly decreased over time (15.3% in 2012 - 2014, 8.7% in 2015 - 2017, and 2.4% in 2018-2020), while that of protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) increased from 0 until 2018 to 3.5% and 8.2% in 2018 - 2020, respectively. The trend of NNRTI resistance has decreased over time, and resistance to PIs and INSTIs increased from 2018. Therefore, continuous monitoring of ARV resistance pattern is necessary.

Changes in HIV-1 Subtypes/Sub-Subtypes, and Transmitted Drug Resistance Among ART-Naïve HIV-Infected Individuals - China, 2004-2022.

The efficacy of treatment and clinical outcomes may be jeopardized by factors such as transmitted drug resistance (TDR) and the genetic diversity of the human immunodeficiency virus type 1 (HIV-1). This comprehensive study aims to examine the alterations in HIV-1 subtypes or sub-subtypes and TDR among Chinese individuals, who have been diagnosed with HIV infection and are previously untreated with antiretroviral therapy (ART), across the span of 2004 to 2022. Sequences of the HIV-1 pol gene region were obtained from ART-naïve HIV-positive individuals across 31 provincial-level administrative divisions between 2004 and 2022. To predict susceptibility to 12 antiretroviral drugs, the research utilized the Stanford HIV Drug Resistance Database. The Cochran-Armitage trend test facilitated the analysis of changes in HIV-1 subtype/sub-subtype prevalence and TDR. This analysis was conducted in alignment with the progression of the National Free Antiretroviral Treatment Program's stages between 2004 and 2022. Among the 57,902 ART-naïve individuals infected with HIV, there was a notable decline in the prevalence of CRF01_AE, B, and C from 37.3%, 24.1%, and 1.3% respectively in 2004-2007 to 29.4%, 7.3%, and 0.2% respectively in 2020-2022. Simultaneously, a significant increase was observed in the proportions of CRF07_BC, CRF08_BC, CRF55_01B, other CRFs, and URFs, from 24.1%, 11.5%, 0.1%, 0.4%, and 0.9% respectively in 2004-2007 to 40.8%, 11.5%, 3.8%, 3.7%, and 2.8% respectively in 2020-2022 (all P<0.001 for trend). The prevalence of TDR to overall, non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, and nevirapine also significantly increased from 2.6%, 1.8%, 1.6%, and 1.8% respectively in 2004-2007 to 7.8%, 6.7%, 6.3%, and 6.7% respectively in 2020-2022 (all P<0.001 for trend). However, there were no meaningful changes in the TDR prevalence of nucleoside reverse transcriptase inhibitor and protease inhibitor. Notably, in 2020-2022, the overall TDR prevalence exceeded 15% in Xinjiang. The total prevalence of TDR in China has achieved a moderate level (7.8%) from 2020 to 2022, with NNRTI resistance standing prominently at 6.7%. Consequently, measures to curb TDR are urgently required, particularly among ART-naïve HIV-infected individuals in China.

Nevirapine plasma concentration is associated with virologic failure and the emergence of drug-resistant mutations among HIV patients in Kenya: A cross sectional study

This study aimed to determine the association between the plasma concentration of nevirapine (NVP) and clinical outcomes. In this cross-sectional study, sociodemographic and clinical data were collected from 233 HIV patients receiving NVP-based first-line antiretroviral therapy (ART) regimens in Nairobi, Kenya. The mean age was 41.2 (SD ± 11.9) years. Fifty-four (23.2%) patients had virological failure (>1000 copies/mL), whereas 23 (9.9%) were infected with drug-resistant HIV strains. Eleven patients had nucleoside reverse transcriptase inhibitor resistance mutations, including M184V and T215Y, whereas 22 had non-nucleoside reverse transcriptase inhibitor resistance mutations, including G190A, K103N, V106A, Y181C, A98G, and Y188L. The median NVP plasma concentration was 6180 ng/mL (IQR 4444-8843 ng/mL), with 38 (16.3%) patients having suboptimal NVP plasma levels of <3400 ng/mL. The majority 23 of the 38 (60.5%) patients with NVP Cmin < 3400 ng/mL were significantly infected with drug-resistant HIV virus (P = .001). In the multivariate analysis, the time taken to arrive at the ART clinic (β -11.1, 95% CI -21.2 to -1.1; P = .031), higher HIV viral load (β -2008, 95% CI -3370.7 to -645.3; P = .004), and the presence of HIV drug resistance mutation (β 3559, 95% CI 2580.8-4537.2; P = .0001) were associated with NVP plasma concentration. A significant proportion of patients receiving the NVP-based regimen had supra- and sub-therapeutic plasma concentrations. Higher HIV viral load and the presence of HIV drug-resistant mutations are important factors associated with NVP plasma concentrations.

Single-center experience evaluating and initiating people with HIV on long-acting cabotegravir/rilpivirine.

To describe our experience evaluating and initiating individuals on long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) and evaluate factors associated with starting LAI CAB/RPV and reasons for not starting. We conducted a retrospective single-center study at the UC San Diego Owen Clinic. We included all individuals who expressed interest in treatment with LAI CAB/RPV between April 2021 and June 2022 who had a definitive decision made on starting LAI CAB/RPV. In total, 383 individuals were included with 201 (52.5%) initiating LAI CAB/RPV. Those who initiated LAI CAB/RPV were younger ( P  = 0.02) and were more likely to be on a two-drug regimen or first-generation integrase inhibitor regimen and less likely to be on a protease inhibitor or multiclass regimen. The most common reasons for not starting LAI CAB/RPV were inconsistent clinic attendance or difficulty being contacted and patient choice not to start. Of those who had a proviral DNA resistance test as workup for LAI CAB/RPV ( n  = 135), 18.5% had a resistance mutation identified that may have impacted the activity of LAI CAB/RPV. Despite novel challenges over half of our cohort initiated LAI CAB/RPV. Evaluating for potential non-nucleoside reverse transcriptase inhibitor resistance is an important part of the workup for LAI CAB/RPV and proviral DNA resistance testing can be an additional tool to identify potential resistance.

Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) induce pyroptosis of HIV-1-infected CD4+ T cells through induction of intracellular HIV-1 protease activity, which activates the CARD8 inflammasome. Because high concentrations of NNRTIs are required for efficient elimination of HIV-1-infected cells, it is important to elucidate ways to sensitize the CARD8 inflammasome to NNRTI-induced activation. We show that this sensitization can be achieved through chemical inhibition of the CARD8 negative regulator DPP9. The DPP9 inhibitor Val-boroPro (VbP) can kill HIV-1-infected cells without the presence of NNRTIs and act synergistically with NNRTIs to promote clearance of HIV-1-infected cells in vitro and in humanized mice. More importantly, VbP is able to enhance clearance of residual HIV-1 in CD4+ T cells isolated from people living with HIV (PLWH). We also show that VbP can partially overcome NNRTI resistance. This offers a promising strategy for enhancing NNRTI efficacy in the elimination of HIV-1 reservoirs in PLWH.

Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase.

In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment.

Low Prevalence of Transmitted HIV-1 Antiretroviral Resistance in Pregnant Women from Rio de Janeiro, Brazil

Background: HIV screening during antenatal care is being expanded in Brazil for early diagnosis of HIV-1 infection during pregnancy and prevention of vertical transmission. HIV genotyping in pregnant women is crucial to reduce the risk of vertical transmission in those carrying resistant strains and may also be used for Transmitted Drug Resistance (TDR) surveillance purpose. We evaluated prevalence and patterns of HIV-1 TDR and HIV subtype distribution in recently diagnosed ARV naïve pregnant women from Rio de Janeiro, Brazil. Methods: 299 blood samples of recently diagnosed HIV-1-infected pregnant women from four reference antenatal care public health units in Rio de Janeiro were consecutively collected and analyzed from 2005 to 2015.ViroseqTM (Abbott) and TrugeneTM HIV-1 Genotyping Systems (Siemens) were used for genotyping and the Standford Algorithm for Interpretation of HIV-1 Resistance for TDR and subtype identification. Results: The most prevalent HIV-1 subtype was the subtype B (77%), followed by subtype F (15%), BF recombinant forms (4%), subtype C (2%) and the recombinant forms: CRF02_AG, CRF31_BC and DF identified in one subject each. Overall, the TDR mutations was 11.7%, 2.7% associated to the Nucleoside Reverse Transcriptase Inhibitors (NRTIs) of the samples, 2.7% to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and 1% to Protease Inhibitors (PIs). Mutations associated with NRTI resistance were TAMs, F77L, M184V; associated with NNRTI resistance were K103N, Y188H and L100I and. mutations associated to PIs were D30N, M46I, and V82L. Conclusions: HIV-1 subtype B was the most prevalent subtype observed in our study. For the first time infections with the circulating recombinant forms CRF02_AG and CRF31_BC were described in a pregnant woman, suggesting the spread of African derived virus in Brazil and the introduction in Rio de Janeiro of the CRF31_BC coming from South Brazil. Our results strongly suggest the need of establishing a regular surveillance system for transmitted HIV-1 drug resistance in pregnant women in Brazil and its integration in antenatal care management policies for HIV-1 infected women should be considered.

HIV-1 pretreatment drug resistance and genetic transmission network in the southwest border region of China

BackgroundHIV drug resistance increased with the widespread use of antiretroviral drugs, and posed great threat to antiretroviral therapy (ART). Pu’er Prefecture, lying in the southwest of Yunnan Province, China, borders Myanmar, Laos and Vietnam, is also the area where AIDS was discovered earlier, however, in which there has been no information on HIV drug resistance.MethodsA cross-sectional survey of pretreatment drug resistance (PDR) was conducted in Pu’er Prefecture in 2021. Partial pol gene sequences were obtained to analyze drug resistance and construct genetic transmission network. HIV drug resistance was analyzed using the Stanford University HIVdb algorithm.ResultsA total of 295 sequences were obtained, among which 11 HIV-1 strain types were detected and CRF08_BC (62.0%, 183/295) was the predominant one. Drug resistance mutations (DRMs) were detected in 42.4% (125/295) of the sequences. The prevalence of PDR to any antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 10.8% (32/295), 9.5% (28/295), 1.0% (3/295) and 0.3% (1/295), respectively. The risk of PDR occurrence was higher among individuals with CRF01_AE strain types. HIV-1 molecular network was constructed, in which 56.0% (42/75) of links were transregional, and 54.7% (41/75) of links were associated with Lancang County. Among the sequences in the network, 36.8% (35/95) harbored DRMs, and 9.5% (9/95) were drug resistance strains. Furthermore, 8 clusters had shared DRM.ConclusionThe overall prevalence of PDR in this study was in a moderate level, but NNRTIs resistance was very approaching to the threshold of public response initiation. PDR was identified in the transmission network, and DRMs transmission was observed. These findings suggested that the consecutive PDR surveillance should be conducted in this region.

Molecular Epidemiology and Trends in HIV-1 Transmitted Drug Resistance in Mozambique 1999-2018.

HIV drug resistance (HIVDR) can become a public health concern, especially in low- and middle-income countries where genotypic testing for people initiating antiretroviral therapy (ART) is not available. For first-line regimens to remain effective, levels of transmitted drug resistance (TDR) need to be monitored over time. To determine the temporal trends of TDR in Mozambique, a search for studies in PubMed and sequences in GenBank was performed. Only studies covering the pol region that described HIVDR and genetic diversity from treatment naïve patients were included. A dataset from seven published studies and one novel unpublished study conducted between 1999 and 2018 were included. The Calibrated Population Resistance tool (CPR) and REGA HIV-1 Subtyping Tool version 3 for sequences pooled by sampling year were used to determine resistance mutations and subtypes, respectively. The prevalence of HIVDR amongst treatment-naïve individuals increased over time, reaching 14.4% in 2018. The increase was most prominent for non-nucleoside reverse transcriptase inhibitors (NNRTIs), reaching 12.7% in 2018. Subtype C was predominant in all regions, but a higher genetic variability (19% non-subtype C) was observed in the north region of Mozambique. These findings confirm a higher diversity of HIV in the north of the country and an increased prevalence of NNRTI resistance among treatment naïve individuals over time.

High Prevalence of Doravirine Resistance in HIV-1-Infected Patients with Virological Failure to an NNRTI-Based Single-Tablet Regimen.

PurposeThis study aimed to investigate the prevalence of resistance to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-tablet regimen (STR) in Taiwanese patients and clarify the clinical implications of using doravirine in patients who fail NNRTI treatment.Patients and MethodsTaiwanese patients infected with HIV-1 who failed NNRTI-based STR treatment were enrolled in this retrospective cohort study from 2015 to 2020. Mutations associated with drug resistance were identified using the 2019 International Antiviral Society-USA list of drug-resistant mutations in HIV, and drug susceptibility was assessed according to the Stanford HIV Drug Resistance Database version 9. Median values of continuous variables were compared between two groups using the Mann–Whitney U-test, and categorical variables were compared using the chi-square test or Fisher’s exact test.ResultsA total of 107 patients were included, of whom 29 were treatment failure to the initial STRs, and 78 failed treatment after switching to an STR. Seventy-four patients failed treatment with TDF/FTC/EFV (Atripla), 30 with TDF/FTC/RPV (Complera) and 3 with TAF/FTC/RPV (Odefsey). The prevalence rates of resistance to nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) were 76%, 86%, 3% and 2%, respectively. Among the 29 patients failure to the initial STRs, 62% developed doravirine resistance, compared to 64% of the 78 the patients who failed treatment after switching to an STR. There were no significant differences in the prevalence of specific NNRTI or doravirine resistance-associated mutations between these two groups. The patients with K65R mutations were more likely to have NNRTI resistance (p = 0.037) and doravirine resistance (p < 0.001).ConclusionOur findings showed a high rate of doravirine cross-resistance in patients with NNRTI-based STR treatment failure. Doravirine should be used cautiously as a salvage regimen in patients who fail NNRTI treatment.