Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure.

Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

The association between HIV pretreatment drug resistance and virological outcomes in children and adults in sub-Saharan Africa: A systematic review and meta-analysis.

INTRODUCTION: Pretreatment drug resistance (PDR) could occur in antiretroviral treatment (ART) naïve individuals, those previously exposed to ART, or individuals re-initiating ARV after a long period of interruption. Few studies have shown its association with virological outcomes, although inconsistent. The objective of this review was to provide a synthesis of the association between PDR and virological outcomes (virological failure or suppression). METHODS: This report is presented following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The method was subdivided into three main phases: record identification, screening, and report inclusion. Record identification consisted of an initial search with search term "HIV pretreatment drug resistance". Another search was done using terms "Pretreatment drug resistance OR pre-treatment drug resistance OR Pretreatment drug resist* OR pre-treatment drug resist* OR pretreatment antiretroviral resistance OR pretreatment medic* OR pretreatment medic* resist*" and a list of all the countries in sub-Saharan Africa. After the electronic search, studies were screened from full list based on their title and abstract and then full articles retrieved and studies were assessed based on set criteria. Inclusion criteria involved observational studies that report the association between PDR and virological failure. Data from trials that reported the association were also included. Published articles like modelling studies and reviews, and studies with data that had been previously included in the review were excluded. The Mantel Haenszel method with odds ratios was used for synthesis (meta-analyses) with the weights of each study which depends on the number of events and totals. RESULTS: A total of 733 records(studies) were obtained from all database search of which 74 reported on PDR, virological outcomes in sub-Saharan Africa (SSA). Out of the 74 articles, 11 were excluded and 26 did not explicitly report data needed, and 5 did not meet the inclusion criteria. Of the remaining 32 studies, 19 studies that had complete data on the number of participants with PDR and no PDR according to virological failure (VF) were included in the metanalyses. The pooled results from eleven (13) of these studies showed those with PDR had higher odds of virological failure compared to those without PDR OR 3.64[95% CI 2.93, 4.52]. The result was similar when stratified in adults and in children. In six (6) studies that had Virological suppression (VS) as outcome, there was a reduction in the odds of VS in those with PDR compared to those without PDR, OR 0.42 (95% CI 0.30, 0.58). CONCLUSION: In conclusion, this systematic review indicates that PDR increases the risk of virological failure in sub-Saharan Africa. The risk could be reduced by PDR monitoring for NNRTIs and INSTIs.

HIV protease resistance mutations in patients receiving second-line antiretroviral therapy in Libreville, Gabon.

INTRODUCTION: In 2022, the WHO reported that 29.8 million people around the world were living with HIV (PLHIV) and receiving antiretroviral treatment (ART), including 25| 375 people in Gabon (54% of all those living with HIV in the country). The literature reports a frequency of therapeutic failure with first-line antiretrovirals (ARVs) of between 20% and 82%. Unfortunately, data relating to the failure of second-line ARVs are scarce in Gabon. This study aims to determine the profiles of HIV drug resistance mutations related to protease inhibitors in Gabon. METHODOLOGY: Plasma from 84 PLHIV receiving ARVs was collected from 2019 to 2021, followed by RNA extraction, amplification, and sequencing of the protease gene. ARV resistance profiles were generated using the Stanford interpretation algorithm version 8.9-1 ( https://hivdb.stanford.edu ) and statistical analyses were performed using EpiInfo software version 7.2.1.0 (CDC, USA). RESULTS: Of 84 HIV plasma samples collected from 45 men and 39 women, 342 mutations were detected. Of these, 43.3% (148/342) were associated with nucleoside reverse transcriptase inhibitors (NRTIs), 30.4% (104/342) with non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 26.3% (90/342) with protease inhibitors (PIs). Most NRTI mutations were associated with thymidine analogues (TAMs) (50.7%; 75/148), including T215F/V (14.9%; 22/148), D67DN/E/G/N/T (10.1%; 15/148), M41L (9.5%; 14/148), and K70E/KN/S/R (9.5%; 14/148). Resistance mutations related to non-TAM NRTIs (33.1%; 49/148) were M184V (29.1%; 43/148), and L74I/V (8.1%; 12/148). NNRTI mutations were predominantly K103N/S (32.7%; 34/104), V108I (10.6%; 11/104), A98G (10.6%; 11/104), and P225H (9.6%; 10/104). Minor mutations associated with PIs (60.0%; 54/90) were predominantly K20I (15.6%; 14/90) and L10F/I/V (14.5%; 13/90). The major mutations associated with PIs (40.0%; 36/90) were M41L (12.2%; 11/90), I84V (6.7%; 06/90), and V82A (6.7%; 06/90). The four most prescribed therapeutic regimens were TDF + 3TC + LPV/r (20.3%; 17/84), ABC + DDI + LPV/r (17.9%; 15/84), TDF + FTC + LPV/r (11.9%; 10/84), and ABC + 3TC + LPV/r (11.9%; 10/84). CONCLUSION: This study revealed that HIV drug resistance mutations are common in Gabon. The major mutations associated with PIs were M41L, I84V, and V82A. There is a need for access to new NRTIs, NNRTIs, and PIs for a better therapeutic management of PLHIV in Gabon.

Prevalence of HIV Drug Resistance Mutations among Treatment-Naive People Living with HIV in a Tertiary Care Center in India.

India has the third-largest number of people living with HIV (PLHIV) in the world. A national program provides free access to standard uniform antiretroviral therapy. However, the program is not monitored by comprehensive drug resistance surveys. The aim of this study was to determine the prevalence of HIV drug resistance mutations (DRMs) among treatment-naive PLHIV in a large antiretroviral treatment center of the national program. This cross-sectional study was done in 2017 and involved 200 consecutive treatment-naive PLHIV. A target fragment of 1,306 bp in the reverse transcriptase and protease regions was amplified. Identification of mutations and drug resistance interpretation was done by HIV Genotypic Resistance Interpretation and International Antiviral Society-USA list. Sequencing was successful in 177 samples. The majority (98.8%; 175/177) belonged to subtype C. Nineteen of 177 patients (10.7%; 95% CI: 6.2%-15.3%) had at least one major DRM. The prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations was 10.2% (18/177). The most frequent mutations were E138A/K, A98G, K103N, V179D, and K101H/E. The prevalence of nucleoside reverse transcriptase inhibitor (NRTI) mutations was 1.1% (2/177). None of the samples had major protease inhibitor resistance mutations. The prevalence of NNRTI mutations in this study was >10%, crossing the threshold recommended by the WHO to change the NNRTI-based first-line regimen to non-NNRTI based. In 2021, the national program replaced efavirenz with dolutegravir in the first-line regimen of tenofovir, lamivudine, and efavirenz. As the majority (64%) of PLHIV in India are accessing free ART from the national program, this study highlights the need for regular nationally representative drug resistance surveys for optimizing antiretroviral regimens in the program.

Resistencia a los inhibidores de la integrasa en niños con el virus de la inmunodeficiencia humana por transmisión vertical: primeros casos en Uruguay / Resistance to integrase inhibitors in children with vertically-transmitted human immunodeficiency virus: First cases in Uruguay

La resistencia a los antirretrovirales (ARV) es un problema de salud pública. Con el uso de inhibidores de la integrasa (INSTI) en pediatría, también comienzan a aparecer resistencias. El objetivo de esta comunicación es describir 3 casos con resistencia a los INSTI. Se describen 3 pacientes pediátricos con transmisión vertical del virus de la inmunodeficiencia humana (VIH). Iniciaron ARV de lactantes y preescolares, con mala adherencia al tratamiento, cursaron con diferentes planes secundarios a comorbilidades asociadas y fallas virológicas por resistencia. Los 3 casos clínicos describen la rápida aparición de resistencia frente a la falla virológica y el compromiso de los INSTI. La adherencia debe ser supervisada para detectar precozmente el aumento de la viremia. La falla virológica en un paciente tratado con raltegravir obliga a un rápido cambio de esquema ARV, ya que continuar utilizándolo podría favorecer nuevas mutaciones y resistencia a los INSTI de segunda generación.

Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.

Viral rebound occurrence immediately after drug discontinuation involving neither drug resistance nor latent reservoir.

Some viruses exhibit "rebound" when the administration of antiviral drugs is discontinued. Viral rebound caused by resistance mutations or latent reservoirs has been studied mathematically. In this study, we investigated the viral rebound due to other causes. Since immunity is weaker during antiviral treatment than without the treatment, drug discontinuation may lead to an increase in the viral load. We analyzed the dynamics of the number of virus-infected cells, cytotoxic T lymphocytes, and memory cells and identified the conditions under which the viral load increased upon drug discontinuation. If drug is administered for an extended period, a viral rebound occurs when the ratio of viral growth rate in the absence to that in the presence of the antiviral drug exceeds the "rebound threshold." We analyzed how the rebound threshold depended on the patient's conditions and the type of treatment. Mathematical and numerical analyses revealed that rebound after discontinuation was more likely to occur when the drug effectively reduced viral proliferation, drug discontinuation was delayed, and the processes activating immune responses directly were stronger than those occurring indirectly through immune memory formation. We discussed additional reasons for drugs to cause viral rebound more likely.

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis.

BACKGROUND: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. As SGS is gradually replaced by next-generation sequencing (NGS), it is necessary to assess the levels of PDR using NGS in ART-naïve patients systematically. NGS can detect the viral variants (low-abundance drug-resistant HIV-1 variants (LA-DRVs)) of virus quasi-species at levels below 20% that SGS may fail to detect. NGS has the potential to optimize current HIV drug resistance surveillance methods and inform future research directions. As the NGS technique has high sensitivity, it is highly likely that the level of pretreatment resistance would be underestimated using conventional techniques. METHODS: For the systematic review and meta-analysis, we searched for original studies published in PubMed, Web of Science, Scopus, and Embase before 30 March 2023 that focused exclusively on the application of NGS in the detection of HIV drug resistance. Pooled prevalence estimates were calculated using a random effects model using the 'meta' package in R (version 4.2.3). We described drug resistance detected at five thresholds (>1%, 2%, 5%, 10%, and 20% of virus quasi-species). Chi-squared tests were used to analyze differences between the overall prevalence of PDR reported by SGS and NGS. RESULTS: A total of 39 eligible studies were selected. The studies included a total of 15,242 ART-naïve individuals living with HIV. The prevalence of PDR was inversely correlated with the mutation detection threshold. The overall prevalence of PDR was 29.74% at the 1% threshold, 22.43% at the 2% threshold, 15.47% at the 5% threshold, 12.95% at the 10% threshold, and 11.08% at the 20% threshold. The prevalence of PDR to INSTIs was 1.22% (95%CI: 0.58-2.57), which is the lowest among the values for all antiretroviral drugs. The prevalence of LA-DRVs was 9.45%. At the 2% and 20% detection threshold, the prevalence of PDR was 22.43% and 11.08%, respectively. Resistance to PIs and INSTIs increased 5.52-fold and 7.08-fold, respectively, in those with a PDR threshold of 2% compared with those with PDR at 20%. However, resistance to NRTIs and NNRTIs increased 2.50-fold and 2.37-fold, respectively. There was a significant difference between the 2% and 5% threshold for detecting HIV drug resistance. There was no statistically significant difference between the results reported by SGS and NGS when using the 20% threshold for reporting resistance mutations. CONCLUSION: In this study, we found that next-generation sequencing facilitates a more sensitive detection of HIV-1 drug resistance than SGS. The high prevalence of PDR emphasizes the importance of baseline resistance and assessing the threshold for optimal clinical detection using NGS.

Analysis of ART effects and drug resistance in adult HIV/AIDS patients in Meigu County, Liangshan Prefecture, China.

BACKGROUND OBJECTIVE: This study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed. METHODS: A total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels. RESULTS: A total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%). CONCLUSIONS: Compared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors.

The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19-0-14-3, 19-8-10-0, and 19-8-14-3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

Prevalence of acquired and transmitted HIV drug resistance in Iran: a systematic review and meta-analysis.

BACKGROUND: There is no systematic review on the prevalence of HIV drug resistance (HIVDR) in Iran. We aimed to estimate the prevalence of HIVDR among people living with HIV (PLHIV) in Iran. We assessed HIVDR prevalence in antiretroviral therapy (ART) naïve PLHIV (i.e., those without a history of ART) and PLHIV receiving ART. METHOD: We systematically searched Scopus, PubMed, Web of Science, Embase, Iranian databases (Iranian Medical Research Information System, Magiran, and Scientific Information Database), the references of studies, and Google Scholar until March 2023. A random-effects model was used to calculate a point estimate and 95% confidence interval (95% CI) for the prevalence of HIVDR in PLHIV. RESULTS: Among 461 potential publications, 22 studies were included in the meta-analysis. The pooled prevalence of acquired HIVDR in PLHIV receiving ART was 34% (95% CI: 19, 50) for nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 27% (95% CI: 15, 41) for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and 9% (95% CI: 3, 18) for protease inhibitors (PIs). The pooled prevalence of acquired HIVDR in treatment failure PLHIV was 50% (95% CI: 31, 69) for NRTIs, 49% (95% CI: 29, 69) for NNRTIs, 11% (95% CI: 2, 24) for PIs, and 1% (95% CI: 0, 4) for integrase inhibitors (INIs). The pooled prevalence of transmitted HIVDR in ART-naïve people was 3% (95% CI; 1, 6) for NRTIs, 5% (95% CI: 2, 9) for NNRTIs, and 0 for PIs and INIs. CONCLUSION: The prevalence of HIVDR was relatively high in both ART-naïve PLHIV and those receiving ART. Without universal pretreatment HIVDR testing and more frequent routine HIV viral load testing among PLHIV who are on ART, the HIVDR prevalence might increase in PLHIV in Iran.

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

BACKGROUND: Tackling 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. METHODS: We 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). RESULTS: A 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. CONCLUSIONS: Our accurate and affordable HIV drug resistance testing solution is adaptable for both individual patient care and large-scale surveillance initiatives.

Major Drug Resistance Mutations on Reverse Transcriptase Gene in Human Immunodeficiency Virus Type-1 in Indonesia: A Systematic Review.

PURPOSE OF REVIEW: The prevalence of HIV-1 in Indonesia is on a concerning upward trajectory, with a concurrent rise in the development of drug-resistant strains, challenging the efficacy of antiretroviral therapy (ART). Many mutations have been found in the pol gene that makes HIV resistant to ART. We aim to review the major drug resistance mutations (DRMs) of reverse transcriptase (RT) of pol gene in HIV-1 cases in Indonesia. RECENT FINDINGS: A total of eleven articles reporting DRMs in HIV-1 subjects from various regions between 2015-2020 in Indonesia are included. The prevalence of major DRMs on the RT gene in studies included varies from 3.4% to 34%. The CRF01_AE subtype stands out as the predominant variant. Notably, the prevalence of major DRMs in ART-experienced individuals is 22.1%, while ART-naïve individuals show a lower rate of 4.4%. Among the RT gene mutations, M184I/V emerges as the most prevalent (10.5%) within the nucleos(t)ide reverse transcriptase inhibitors (NRTI) group, while K103N leads among the non-NRTI (NNRTI) group, with a frequency of 6.4%. Regionally, North Sulawesi records the highest prevalence of major DRMs in the RT gene at 21.1%, whereas Riau and Central Papua exhibit the lowest rates at 3.4%. Significant variations in drug resistance mutations within the RT gene across Indonesian regions highlight the importance of closely monitoring and evaluating the effectiveness of current antiretroviral therapy (ART) regimens. Considerably, more studies are needed to understand better and overcome the emergence of DRMs on HIV-1 patients in Indonesia.

Transmitted Drug Resistance and HIV Diversity Among Adolescents Newly Diagnosed With HIV in Spain.

BACKGROUND: Virologic characterization of newly HIV-diagnosed adolescents could help to improve their specific needs. The objective was to describe the transmitted drug resistance mutations (TDR) and its transmission by clusters in this population in Spain. METHODS: TDR to retrotranscriptase and protease inhibitors included in the WHO TDR list 2009 implemented in the Calibrated Population Resistance tool v8.0 (Stanford) were studied in HIV pol sequences from all HIV-diagnosed adolescents (12-19-year-old) enrolled during 2004-2019 period in the Spanish pediatric and adult (CoRISpe-CoRIS) cohorts. The found TDR were compared with the provided by the Stanford algorithm v9.0 2021. HIV-1 variants and transmission clusters were also studied. RESULTS: Among 410 HIV-1 adolescents diagnosed, 141 (34.4%) had available ART-naive sequences. They were mostly male (81.6%), Spanish (55.3%) and with behavioral risk (92.2%), mainly male-to-male sexual contact (63.1%). TDR prevalence was significantly higher by Stanford versus WHO list (18.4% vs. 7.1%; P = 0.004). The most prevalent TDR by the WHO list was K103N (3.6%) and by Stanford E138A (6.6%), both at retrotranscriptase. E138A, related to rilpivirine/etravirine resistance, was absent in the WHO list. One in 4 adolescents carried HIV-1 non-B variants. We described 5 transmission clusters, and 2 carried TDR mutations. CONCLUSIONS: Our data suggest a high TDR prevalence in adolescents with a new HIV diagnosis in Spain, similar to adults, 2 active TDR transmission clusters, and the need for the WHO TDR list update. These findings could have implications for the options of the recently available rilpivirine-related long-acting treatment and in first-line regimen election.

Changes in Primary HIV-1 Drug Resistance Due to War Migration from Eastern Europe.

In recent years, especially as a result of war in Ukraine, enormous movements of migration to Poland from eastern European countries have been reported, including people living with Human Immunodeficiency Virus (HIV). We have conducted multi-center, prospective study, which aimed to establish HIV-1 subtype and assess the presence of primary drug resistance mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors in antiretroviral treatment naïve patients. The clinical trial recruited 117 individuals during 2 years period (2020-2022). The prevalence of HIV-1 subtype A was statistically significantly more frequent in Ukrainian, and HIV-1 subtype B in Polish patients (p < 0.05). Drug resistance mutations were detected in 44% of all cases and the comparison of presence of mutations in the analyzed groups, as well as in the subgroups of subtype A and B HIV-1 has not revealed any significant differences (p > 0.05), nevertheless Polish patients had multidrug resistance mutations more frequent (p < 0.05). The results from our trial show no increased risk of transmission of multidrug resistant HIV strains in our cohort of Ukrainian migrants.Clinical trials. Gov number NCT04636736; date of registration: November 19, 2020.