Transmitted Drug Resistance Mutations Research Articles

Prevalence of transmitted drug resistance and phylogenetic analysis of HIV-1 among antiretroviral therapy-naïve patients in Northern Vietnam from 2019 to 2022.

Since the rapid expansion of antiretroviral therapy (ART) for HIV, transmitted drug resistance (TDR) has become a major concern in Vietnam. HIV services there are transitioning to be covered by social insurance. Access to pre-exposure prophylaxis (PrEP) is being expanded to tackle the growing HIV epidemic among men who have sex with men. Therefore, a cross-sectional study was conducted at 10 ART facilities in Northern Vietnam from 9th December 2019 to 9th June 2022 to investigate the prevalence and pattern of TDR among ART-naïve people living with HIV (PLWH). TDR mutations were defined according to the World Health Organization 2009 List of Mutations for Surveillance of Transmitted Drug Resistant HIV Strains. Mutation transmission dynamics and TDR clusters were investigated via phylogenetic analysis. We enrolled 391 ART-naïve PLWH. The overall TDR prevalence was 4.6%, with an annual prevalence of 6.0% in 2019/2020, 4.8% in 2021, and 1.3% in 2022. TDR mutations to non-nucleoside reverse transcriptase inhibitors (2.8%), including K103N were the most common. Less commonly, the protease inhibitor-associated mutation M46I and mutations to nucleoside reverse transcriptase inhibitors, including M184V/ I, were observed. CRF01_AE was the most common subtype (77.0%). CRF07_BC (14.3%), which had been rare in Vietnam, was also observed. No genetic association was observed between HIV-1 sequences with TDR mutations. In conclusion, the overall prevalence of TDR was stably low in this region. The phylogenetic tree suggests that TDR clusters have not formed. Continuous monitoring of HIV TDR and strains is crucial to maintaining ART and PrEP efficacy.

MOLECULAR VIROLOGICAL ANALYSIS OF THE TRANSMISSION CLUSTERS AND RESISTANCE MUTATIONS OF HIV-1 SUBTYPE B IN BULGARIA (2012-2020)

HIV-1 infection in Bulgaria is known for its high level of genetic diversity. Previous studies have indicated that subtype B is the most common strain in Bulgaria, particularly among men who have sex with men, who are at a high risk of transmission. The primary objective of this study was to identify any transmission clusters and transmission resistance in individuals newly diagnosed with HIV-1 who have not yet received antiretroviral therapy (ART). To this end, we sequenced the HIV-1 pol gene in the samples from the study participants using either the Viroseq HIV-1 Genotyping Test (Abbott) and the Applied Biosystems 3130xl genetic analyzer or the TruGene DNA Sequencing System (Siemens Healthcare) and an OpenGene DNA sequencing system. We then subtyped the HIV-1 pol sequences, and further analyzed those that met the criteria for subtype B. The study included a total of 595 HIV-1 subtype B sequences. Our analysis revealed that the majority of those diagnosed with HIV-1 subtype B were male and lived in Sofia region. The most common transmission mode was through sexual intercourse among men who have sex with men, followed by heterosexual transmission. We also observed the presence of multiple transmission clusters , and a low percentage of transmitted drug resistance mutations (TDRMs). Overall, our study confirms that HIV-1 subtype B remains the most dominant strain in Bulgaria.

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

Virological 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. 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. 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. 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.

Increased prevalence of pretreatment drug resistance mutations in treatment-naïve people living with HIV-1 in Henan Province, China (2022/23)

Human deficiency virus type 1 (HIV-1) harboring drug resistance mutations (DRMs) before the initiation of antiretroviral therapy (ART) poses a serious threat to the efficacy of current ART regimens. Currently, the prevalence of pre-treatment drug resistance mutations (PDRMs) including transmitted DRMs (TDRMs) is not completely clear. Understanding this prevalence better should offer valuable data for clinical- and government-level decision-making. To closely monitor the PDRM trend in treatment-naïve people living with HIV/AIDS (PLWHA) in Henan Province, China, plasma samples from the patients seeking treatments at our hospital from January 2022 to February 2023 were collected for genotypic drug resistance testing. From the 645 patients whose samples were collected, partial pol and integrase gene sequences were obtained from 637 patients. Subtyping analysis indicated that the top-three most common subtypes, in descending order, were CRF07_BC (41.76%, 266/637), CRF01_AE (28.26%, 180/637), and B (20.41%, 130/637). PDRMs were observed in 5.18% (33/637), 6.28% (40/637), 0.31% (2/637), and 2.83% (18/637) cases for nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs), respectively; all these medications contributed to an overall PDRM prevalence of 11.93% (76/637). On analyzing individual PDRMs, we noted that the most commonly observed mutation(s) were K103S/N (3.77%, 24/637), M184I/V (3.14%, 20/637), followed by K65R (1.26%, 8/637), and V106A/M (1.10%, 7/637). PDRM prevalence in ART-naïve PLWHA of Henan Province is high and increased compared with that noted in previous years. However, evidence of cluster-linked outbreaks of PDRMs is lacking, suggesting that measures such as education about adherence and improved treatment strategies with a low incidence of failure can effectively reduce PDRM prevalence.

Full-spectrum HIV drug resistance mutation detection by high-resolution complete pol gene sequencing.

Drug resistance mutation testing is a key element for HIV clinical management, informing effective treatment regimens. However, resistance screening in current clinical practice is limited in reporting linked cross-class resistance mutations and minority variants, both of which may increase the risk of virological failure. To address these limitations, we obtained 358 full-length pol gene sequences from 52 specimens of 20 HIV infected individuals by combining microdroplet amplification, unique molecular identifier (UMI) labeling, and long-read high-throughput sequencing. We conducted a rigorous assessment of the accuracy of our pipeline for precision drug resistance mutation detection, verifying that a sequencing depth of 35 high-throughput reads achieved complete, error-free pol gene sequencing. We detected 26 distinct drug resistance mutations to Protease Inhibitors (PIs), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Strand Transfer Inhibitors (INSTIs). We detected linked cross-class drug resistance mutations (PI+NRTI, PI+NNRTI, and NRTI+NNRTI) that confer cross-resistance to multiple drugs in different classes. Fourteen different types of minority mutations were also detected with frequencies ranging from 3.2% to 19%, and the presence of these mutations was verified by Sanger reference sequencing. We detected a putative transmitted drug resistance mutation (TDRM) in one individual that persisted for over seven months from the first sample collected at the acute stage of infection prior to seroconversion. Our comprehensive drug resistance mutation profiling can advance clinical practice by reporting mutation linkage and minority variants to better guide antiretroviral therapy options.

Brief Report: Comparative Analysis of Pre-existing HIV Drug Resistance Mutations in Proviral DNA Using Next-Generation Sequencing and Routine HIV RNA Genotyping.

We investigated whether deep sequencing of archived HIV DNA of antiretroviral-naive persons with acute/early HIV infection could identify transmitted drug resistance mutations (DRM), per the IAS drug resistance algorithm, which are not detected by routine bulk (consensus) sequencing. Deep sequencing of HIV DNA from peripheral blood mononuclear cells and consensus sequencing from concurrent blood plasma (BP) was performed from antiretroviral (ART)-naive adults with recent infection. We compared the prevalence of low-frequency (2%-20%) and high-frequency (>20%) nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) DRM. Overall, 190 individuals were included, 72 (37.9%) with acute, 20 (10.5%) with very early, and 98 (51.6%) with recent HIV infection. Although all DRM detected in plasma appeared in archived proviral DNA, 9 high-frequency mutations were only detected in HIV DNA. These included 3 NRTI mutations, 4 NNRTI mutations, 1 PI mutation, and 1 H221Y (associated rilpivirine resistance) mutation. When considering DRM <20%, 11 NNRTI, 7 NRTI, 6 PI, and 3 F227L (associated doravirine resistance) mutations were found exclusively in HIV DNA. Interestingly, although 2 high-frequency M184V appeared in both DNA and RNA, low-frequency M184I were exclusive to HIV DNA (n = 6). No participants experienced virologic failure after initiating ART during the median 25.39 ± 3.13 months of follow-up on treatment. Although most high-frequency DRMs were consistently detected in HIV RNA and HIV DNA, the presence of low-frequency DRM in proviral DNA may be relevant for clinicians because these mutations could become dominant under drug selection pressure.

Identification of integrase inhibitor-related drug resistance mutations in newly diagnosed ART-naïve HIV patients

BackgroundIn China, the recommended treatment regimens for HIV-infected individuals were tenofovir in combination with lamivudine or emtricitabine as NRTIs, efavirenz or rilpivirine as NNRTIs, lopinavir/ritonavir as protease inhibitors, and raltegravir or dolutegravir as INSTIs. The development of drug resistance increases the risk of viral rebound, opportunistic infections, and ultimately treatment failure such that the early detection of resistance is ideal. This study was developed to explore primary drug resistance characteristics and genotypic distributions in newly diagnosed antiretroviral therapy (ART)-naïve HIV-1 patients in Nanjing with the goal of establishing a basis for their individualized treatment in the clinic. MethodsSamples of serum were collected from newly diagnosed ART-naïve HIV patients from the Second Hospital of Nanjing between May 2021 and May 2022. The HIV-1 integrase (IN), protease (PR), and reverse transcriptase (RT) gene coding sequences were amplified from these samples, sequenced, and assessed for drug resistance-related mutations. ResultsMajor integrase resistance-related mutations were detected in 4/360 amplified samples, with 5 other patient samples exhibiting accessory resistance mutations. The overall prevalence of PR and RT inhibitor-related transmitted drug resistance mutations (TDRMs) in this patient population was 16.99% (61/359). The most common mutations were non-nucleoside reverse transcriptase inhibitor-related mutations (51/359; 14.21%), followed by those associated with nucleoside reverse transcriptase inhibitors (7/359; 1.95%) and protease inhibitors (7/359; 1.95%). Dual-resistant strains were also observed in a subset of patients. ConclusionsIn summary, this study is the first to have surveyed the prevalence of integrase inhibitor resistance-related mutations and other drug resistance-related mutations among newly diagnosed ART-naïve HIV-positive patients in Nanjing, China. These results highlight the need for further molecular surveillance-based monitoring of the HIV epidemic in Nanjing.

Transmitted Drug Resistance Against Integrase Strand Transfer Inhibitors in Iranian HIV-Infected Naïve Patients.

Human Immunodeficiency Virus (HIV) has claimed the lives of millions of people during the past decades. While several antiretroviral drugs like Integrase Strand Transfer Inhibitors (INSTIs) have been introduced to control HIV, Transmitted Drug Resistance (TDR) in HIV genome caused failure in treatment. This study aimed to investigate TDR and natural occurring mutations (NOPs) in HIV integrase gene in Iranian HIV patients. In this cross-sectional study, blood samples of 30 HIV-positive patients who had never taken integrase inhibitors were considered for CD4 T cell count, RT real-time PCR, and, Nested PCR. The sequencing results were analyzed by CLC sequence viewer software and Stanford University HIV Drug Resistance Database. In all samples, nine NOPs with a high prevalence were found; however, we did not find any drug resistance mutations, except for a mutation in one sample, which showed a low resistance level. Subtype A1 was dominant in all samples. Based on the findings and compared to our previous study, all patients were sustainable to main integrase inhibitors, including bictegravir, raltegravir, bictegravir, elvitegravir and dolutegravir. It seems the resistant mutation pattern attributed to integrase inhibitors was not diffent among studied patients; hence, the prescription of such inhibitors helps physicians to control HIV infection in Iranian HIV-infected patients.

Increased prevalence and stable clustering rate of HIV-1 transmitted drug resistance strains after 'treat-all' in a megacity of China.

The 'treat-all' strategy was implemented in Shenzhen, China in 2016. The effect of this extensive treatment on transmitted drug resistance (TDR) of HIV is unclear. TDR analysis was performed, based on the partial HIV-1 pol gene obtained from the newly reported HIV-1 positive cases from 2011 to 2019 in Shenzhen, China. The HIV-1 molecular transmission networks were inferred to analyse the spread of TDR. Logistic regression was used to identify the potential risk factors with TDR mutations (TDRMs) to cluster. A total of 12 320 partial pol sequences were included in this study. The prevalence of TDR was 2.95% (363/12 320), which increased from 2.57% to 3.52% after 'treat-all'. The TDR prevalence was increased in populations with the characteristics of CRF07_BC, being single, educated to junior college level and above, MSM and male. The sensitivities of viruses to six antiretroviral drugs were decreased. The clustering rate of TDRMs remained stable, and the sequences in the three drug resistance transmission clusters (DRTCs) were mainly found during 2011-16. CRF07_BC and CRF55_01B were the factors associated with TDRMs clustering in the networks. The 'treat-all' strategy might have contributed to a small increase in TDR, while most of the TDRMs were distributed sporadically, which implies that the 'treat-all' strategy is helpful for the control of TDR in high-risk populations.

Prevalence of Transmitted Drug Resistance among HIV-1 Patients in the Aegean Region: Results from the Western part of Turkey.

This study aimed to analyze the antiretroviral drug resistance in antiretroviral treatment-naïve HIV-positive patients in the Aegean Region of Turkey from 2012 to 2019. The study included 814 plasma samples from treatment-naïve HIV-positive patients. Drug resistance analysis was performed by Sanger sequencing (SS) between 2012-2017 and by next-generation sequencing sequencing (NGS) between 2018-2019. SS was used to analyze resistance mutations in the protease (PR) and reverse transcriptase (RT) gene regions using a ViroSeq HIV-1 Genotyping System. PCR products were analyzed with an ABI3500 GeneticAnalyzer (Applied Biosystems). The sequencing of the HIV genome in the PR, RT, and integrase gene regions was carried out using MiSeq NGS technology. Drug resistance mutations and subtypes were interpreted using the Stanford University HIV-1 drug resistance database. Transmitted drug resistance (TDR) mutation was detected in 34/814 ( 4.1 %) samples. Non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) mutations were identified in 1.4 % (n =12), 2.4 % (n =20), and 0.3 % (n = 3) of samples, respectively. The most common subtypes were B (53.1 % ), A (10.9%), CRF29_BF (10.6%), and B + CRF02_AG (8,2%). The most common TDR mutations were E138A (3.4%), T215 revertants (1.7%), M41L (1.5%), and K103N (1.1%). Transmitted drug resistance rate in the Aegean Region is compatible with national and regional data. Routine surveillance of resistance mutations may guide the safe and correct selection of initial drug combinations for antiretroviral therapy. The identification of HIV-1 subtypes and recombinant forms in Turkey may contribute to international molecular epidemiological data.

Low rate of pre-exposure prophylaxis and post-exposure prophylaxis uptake and high prevalence of transmitted drug resistance among newly diagnosed primary HIV infections in Shenzhen, China: a real-world retrospective study.

Understanding the characteristics of newly diagnosed primary human deficiency virus-1 (HIV-1) infection in the context of the post-antiretroviral therapy era and HIV drug prophylaxis is essential for achieving the new target of 95-95-95-95 by 2025. This study reported the characteristics of newly diagnosed primary HIV-1 infection in Shenzhen. This is a real-world retrospective study. Eighty-seven newly diagnosed primary HIV-1-infected patients were recruited from January 2021 to March 2022 at the Third People's Hospital of Shenzhen. Demographic, epidemiological, diagnostic, drug resistance, and medical data were described and analyzed. Overall, 96.6% (84/87) of the newly identified primary HIV-1-infected patients were male, including 88.5% (77/87) men have sex with men (MSM), with a median age of 29.0 years (Q1-Q3: 24.0-34.0 years); of these, 85.1% (74/87) reported high-risk sexual behaviors with casual partners. The rate of condom usage was only 28.7% (25/87). The overall rate of pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) was 8.0% (7/87, including 4 PrEP and 3 PEP cases) around the potential exposure, although 41.4% of the patients had prior awareness of such interventions. Moreover, only 19.5% (17/87) had previously used PrEP or PEP. Of those, 58.8% (10/17) of the patients obtained drugs from the internet, and only 35.3% (6/17) reported good compliance. A total of 54.0% (47/87) of subjects were diagnosed by the HIV nucleic acid test. Acute retroviral syndrome appeared in 54.0% (47/87) of patients. The prevalence of transmitted drug resistance (TDR) mutation was 33.9% (19/56), including 6 (10.7%) against nucleoside reverse transcriptase inhibitor (NRTI) plus non-nucleoside reverse transcriptase inhibitor (NNRTI), 8 (14.3%) against NNRTI, and 5 (8.9%) against protease inhibitor (PI) only. Owing to the low utilization rate and incorrect usage of PrEP and PEP, massive efforts are needed to promote HIV-preventive strategies in the MSM population. The extremely high prevalence of TDR mutation in this population implies the need for future pretreatment drug resistance surveillance.

HIV-1 genetic diversity and transmitted drug resistance to integrase strand transfer inhibitors among recently diagnosed adults in Porto Alegre, South Brazil.

The HIV-1 genetic diversity and the presence of transmitted drug resistance mutations (TDRMs) against integrase strand transfer inhibitors (INSTIs) were assessed sequencing samples of antiretroviral (ARV)-naive HIV-1-infected individuals from South Brazil. Viral RNA from 42 ART-naive individuals was submitted to complete HIV-1 integrase gene amplification by RT-PCR and sequencing. Viral strains carrying TDRMs against INSTIs were not detected in the present study. However, the polymorphisms L74M and L74I were each observed in 4.8% of the individuals. These accessory mutations have been reported as putative causes of TDRMs in ART with raltegravir, but only when associated with additional major mutations. When submitted to HIV-1 subtyping, 50% were classified as subtype C, 21% as recombinant BC, 19% as subtype B, 4.8% as subtype F1 and 4.8% as recombinant CF1. All 42 ARV-naive individuals were apparently susceptible to INSTIs, included in the Brazilian therapeutic guideline since 2009. To the best of our knowledge, this is the first study to evaluate TDRMs against INSTIs in Brazil. The most prevalent HIV-1 subtypes were subtype C, followed by the recombinant BC and subtype B, which is in agreement with previous studies. However, the presence of subtype F1 and recombinant CF1 reported herein was not observed in previous studies.

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 Diversity and Drug Resistance in Treatment-Naïve Children and Adolescents from Rio de Janeiro, Brazil.

The human immunodeficiency virus type 1 (HIV-1) can be transmitted via parenteral, sexual, or vertical exposure routes. The number of HIV-1 cases detected yearly in children and adolescents in Brazil did not decrease over the last decade, representing ~5% of total cases described in the country. In recent years, the HIV-1 diversity and the prevalence of transmitted drug resistance mutations (TDRM) are moving toward a marked increase. In this study, we retrospectively evaluated the diversity of HIV-1 subtypes and the TDRM prevalence in 135 treatment-naïve HIV-1 vertically infected children and adolescents born in between 1993 and 2012. These children were assessed in either 2001–2007 or 2008–2012 when they were 0 to 17 years old. The individuals assessed in 2001–2007 (n = 38) had median CD4+ T cell counts of 1218 cells/mm3 (IQR: 738–2.084) and median HIV-1 plasma viral load of 4.18 log10 copies/mL (IQR: 3.88–4.08). The individuals (n = 97) evaluated in 2008–2012 showed median CD4+ T cell counts of 898.5 cells/mm3 (IQR: 591.3–1.821) and median HIV-1 plasma viral load of 4.69 log10 copies/mL (IQR: 4.26–5.33). A steady decrease in the median CD4 T+ cell counts was observed with age progression, as expected. The majority HIV-1 pol sequences (87%) were classified as pure HIV-1 subtypes (77% subtype B, 9% subtype F1 and 1.5% subtype C), while 13% of sequences were classified as recombinants (CRF45_cpx, n = 4; CRF28/29_BF1, n = 2; CRF02_AG, n = 1; CRF40_BF1, n = 1, CRF99_BF1, n = 1, URF_BF1, n = 8). The overall prevalence of TDRM was 14% (19/135), conferring resistance to the nucleoside reverse transcriptase inhibitors (NRTI, 13/135–9.6%), non-nucleoside reverse transcriptase inhibitors (NNRTI, 8/135–5.9%), and protease inhibitors (PI, 2/135–1.5%). The main TDRM observed for NNRTI was the K103N (n = 8), while the mutations T215I/Y/D/E (n = 7) and M184V (n = 4) were the main TDRM for NRTI. Only two TDRM were observed for PI in one individual each (M46I and V82A). Most TDRM were found in the HIV-1 subtype B (84%) sequences. This study reveals an HIV-1 epidemic with high diversity and moderate prevalence of TDRM in the pediatric population of Rio de Janeiro, indicating the existence of possible problems in the clinical management of prophylactic therapy to prevent mother-to-child transmission and future treatment options for the affected children.

Characterization of HIV-1 molecular epidemiology and transmitted drug-resistance in newly diagnosed HIV-infected patients in Sichuan, China

BackgroundSichuan province is one of the highest AIDS epidemic provinces in China, with a large number of floating population. The annual number of cases of HIV/AIDS reported in Sichuan has been the highest province in China for several successive years. There is a lack of widespread and representative data on the distribution of HIV genotypes in Sichuan. We aim to investigate the characteristics of HIV-1 molecular epidemiology and transmitted drug-resistance in newly diagnosed HIV-infected patients in Sichuan, China.MethodArchived plasma samples (n = 1524) from HIV-1 newly-diagnosed individuals in April 2019 were selected by cross-sectional investigation from all 21 cities in Sichuan province. Phylogenetic relationship, transmission cluster, and genotypic drug resistance analyses were performed using HIV-1 polymerase (pol) gene sequences. We also analysed the association of demographic and virological factors with transmitted drug-resistance (TDR) and transmission clusters.ResultsPartial pol gene sequences were obtained from 1297 cases. HIV-1 epidemic strains in Sichuan province: the majority of genotypes were circulating recombinant form (CRF) 07_BC (675, 52.04%), CRF01_AE (343, 26.45%), CRF08_BC (115, 8.87%), CRF85_BC (67, 5.17%), subtype B (33, 2.54%), the other genotypes only accounted for 4.93%, and unique recombinant forms (URFs) (23, 1.77%) were observed in the study, and the difference of age, ethnicity, education, occupation, region and transmission pathway of different genotypes were statistically significant. According to WHO HIVDR surveillance threshold, the level of TDR has reached a medium level, with 72 of 1297 (5.55%) cases carrying drug-resistance mutation sites, TDR mutation frequency to nonnucleoside reverse transcriptase inhibitors (NNRTIs, 3.85%) was much higher than nucleoside reverse transcriptase inhibitors (NRTIs, 0.31%) and protease inhibitors (PIs, 1.70%), and CRF08_BC was a risk factor for TDR (odds ratio, 8.32; 95% CI 4.38–15.80 for CRF07_BC, P < 0.05). The most common drug resistance HIV-1 mutation pattern for NNRTI was V106 (1.31%, 17/1297) and E138 (1.16%, 15/1297), and for PI was M46 (0.69%, 9/1297). A total of 205 (15.8%) pol sequences were involved in the genetic transmission network clusters, CRF01_AE (odds ratio, 2.369; 95% CI 1.659–3.382; P < 0.05), subtype B (odds ratio, 13.723; 95% CI 6.338–29.71; P < 0.05), drug resistance (odds ratio, 0.306; 95% CI 0.106–0.881; P < 0.05) and different levels of education (P < 0.05) were significantly associated to be in clusters.ConclusionThe distribution of HIV-1 genotypes in Sichuan is more diverse and complex, and the Men who have sex with men (MSM) is underrated, arguing for behavior scaling up intervention in this specific population besides the elderly people with heterosexual transmission risk groups. The risk of TDR mutation frequency increased in newly diagnosed patients highlights the significance of genotypic drug resistance monitoring and molecular surveillance of pretreatment HIV-1 drug resistance. The regimen composed of TDF, 3TC and EFV was still currently the preferred solution used free first-line therapy.

HIV Infection Progression Monitoring System Based on CD4 Counts and Wishart Distribution.

The human immunodeficiency virus (HIV) is a viral infection that destroys the human immune system, resulting in the acquired immunodeficiency syndrome (AIDS). The management and care of patients on antiretroviral therapy (ART) consumes a large portion of the health budget of many countries. ART improves the lives of the HIV patients. However, benefiting from the treatment remains to be low due to the nonadherence, adverse events, and treatment failure associated with the transmitted drug resistance mutations (TDRMs). Extra care is therefore required in prescribing switch of ART regimens for HIV-naive patients. We propose a disease monitoring system, which depends on how the HIV-naive patients respond to the ART regimen. We model cluster of differentiation 4 (CD4) counts data measured at every 3 months in a period of 48 weeks on a cohort of 87 HIV-naive patients on ART, from Zambia. We demonstrate how to apply the Bayesian Wishart distribution to model CD4 counts, leading to an informative HIV progression monitoring system. We found a steady increase in the average of the CD4 counts (from 219 to 315) for HIV-naive patients on the ART regimen. The average was still below the expected 500 CD4 counts for a normal person. The derived precision matrix shows an increase in probability of potency of the ART regimen, which ranges from 0.1261 to 0.8678. An early detection is crucial as it allows for timely switch of regimen from first to second line or to the third line. The proposed HIV disease progression monitoring system for HIV-naive patients on ART regimen that is based on CD4 counts could enable physicians make informed decisions on the management and care of the patients.

Molecular Network Analysis Reveals Transmission of HIV-1 Drug-Resistant Strains Among Newly Diagnosed HIV-1 Infections in a Moderately HIV Endemic City in China.

Since the implementation of the “treat all” policy in China in 2016, there have been few data on the prevalence of transmitted drug resistance (TDR) in China. In this study, we describe TDR in patients newly diagnosed with human immunodeficiency virus (HIV) infection between 2016 and 2019 in Shenyang city, China. Demographic information and plasma samples from all newly reported HIV-infected individuals in Shenyang from 2016 to 2019 were collected. The HIV pol gene was amplified and sequenced for subtyping and TDR. The spread of TDR was analyzed by inferring an HIV molecular network based on pairwise genetic distance. In total, 2,882 sequences including CRF01_AE (2019/2,882, 70.0%), CRF07_BC (526/2,882, 18.3%), subtype B (132/2,882, 4.6%), and other subtypes (205/2,882, 7.1%) were obtained. The overall prevalence of TDR was 9.1% [95% confidence interval (CI): 8.1–10.2%]; the prevalence of TDR in each subtype in descending order was CRF07_BC [14.6% (95% CI: 11.7–18.0%)], subtype B [9.1% (95% CI: 4.8–15.3%)], CRF01_AE [7.9% (95% CI: 6.7–9.1%)], and other sequences [7.3% (95% CI: 4.2–11.8%)]. TDR mutations detected in more than 10 cases were Q58E (n = 51), M46ILV (n = 46), K103N (n = 26), E138AGKQ (n = 25), K103R/V179D (n = 20), and A98G (n = 12). Molecular network analysis revealed three CRF07_BC clusters with TDR [two with Q58E (29/29) and one with K103N (10/19)]; and five CRF01_AE clusters with TDR [two with M46L (6/6), one with A98G (4/4), one with E138A (3/3), and one with K103R/V179D (3/3)]. In the TDR clusters, 96.4% (53/55) of individuals were men who have sex with men (MSM). These results indicate that TDR is moderately prevalent in Shenyang (5–15%) and that TDR strains are mainly transmitted among MSM, providing precise targets for interventions in China.

Epidemiology and Transmitted HIV-1 Drug Resistance among Treatment-Naïve Individuals in Israel, 2010-2018.

Despite the low prevalence of HIV-1 in Israel, continuous waves of immigration may have impacted the local epidemic. We characterized all people diagnosed with HIV-1 in Israel in 2010–2018. The demographics and clinical data of all individuals (n = 3639) newly diagnosed with HIV-1 were retrieved. Subtypes, transmitted drug-resistance mutations (TDRM), and phylogenetic relations, were determined in >50% of them. In 39.1%, HIV-1 transmission was through heterosexual contact; 34.3% were men who have sex with men (MSM); and 10.4% were people who inject drugs. Many (>65%) were immigrants. Israeli-born individuals were mostly (78.3%) MSM, whereas only 9% of those born in Sub-Saharan Africa (SSA), Eastern Europe and Central Asia (EEU/CA), were MSM. The proportion of individuals from SSA decreased through the years 2010–2018 (21.1% in 2010–2012; 16.8% in 2016–2018) whereas those from EEU/CA increased significantly (21% in 2010–2012; 27.8% in 2016–2018, p < 0.001). TDRM were identified in 12.1%; 3.7, 3.3 and 6.6% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively, with the overall proportion remaining stable in the studied years. None had integrase TDRM. Subtype B was present in 43.9%, subtype A in 25.2% (A6 in 22.8 and A1 in 2.4%) and subtype C in 17.1% of individuals. Most MSM had subtype B. Subtype C carriers formed small clusters (with one unexpected MSM cluster), A1 formed a cluster mainly of locally-born patients with NNRTI mutations, and A6 formed a looser cluster of individuals mainly from EEU. Israelis, <50 years old, carrying A1, had the highest risk for having TDRM. In conclusion, an increase in immigrants from EEU/CA and a decrease in those from SSA characterized the HIV-1 epidemic in 2010–2018. Baseline resistance testing should still be recommended to identify TDRM, and improve surveillance and care.

High prevalence of HIV-1 transmitted drug resistance and factors associated with time to virological failure and viral suppression in Taiwan.

Integrase strand transfer inhibitor (InSTI)-based regimens have become the major first-line treatment for HIV-1-infected patients in Taiwan. Transmitted drug resistance (TDR) and several clinical characteristics are associated with time to virological failure or viral suppression; however, these have not been investigated in Taiwan. To determine the impact of several factors on treatment outcomes in HIV-1-infected patients in Taiwan. The cohort included 164 HIV-1 treatment-naive patients in Taiwan from 2018 to 2020. Blood specimens were collected to determine the genotypic drug resistance using the Stanford University HIV drug resistance database. Cox proportional hazards models were used to identify factors associated with time to virological failure or viral suppression. The prevalence of TDR in Taiwan was 27.4% and an increasing trend was seen from 2018 to 2020. TDR mutations related to NNRTIs were the most prevalent (21%) while TDR to InSTIs remained at a relatively low level (1.3%). A baseline HIV-1 viral load of ≥100 000 copies/mL was associated with a shorter time to virological failure [multivariate hazard ratio (mHR) 7.84; P = 0.018] and longer time to viral suppression (mHR 0.46; P < 0.001). Time to viral suppression was shorter in patients receiving InSTI-based regimens (mHR 2.18; P = 0.006). Different InSTI-based regimens as initial treatment did not affect the treatment outcomes. This study found an increasing trend of HIV-1 TDR prevalence from 2018 to 2020 in Taiwan. Baseline HIV-1 viral load and receiving InSTI-based regimens are important factors associated with time to virological failure or viral suppression.

Brief Report: Prevalence Trend of Transmitted Drug Resistance in a Prospective Cohort of Thai People With Acute HIV Infection.

The greater availability of different antiretroviral therapy regimens in developing countries may influence the emergence of transmitted drug resistance (TDR). People with acute HIV infection (AHI) represent the best opportunity for real-time monitoring of TDR. This study assessed the TDR prevalence trends over time in a Thai cohort of predominantly men who have sex with men (MSM) with AHI. At the time of RV254/SEARCH010 study (NCT00796146) enrollment and before starting ART, HIV genotyping was used to identify mutations in the reverse transcriptase and protease genes. Testing for TDR mutations was obtained by a validated in-house method with TRUGENE assay in a subset. Genotype sequences were analyzed using the Stanford University HIV Drug Resistance Database. Genotyping was performed for 573 participants with AHI. Their median age was 26 years (interquartile range 22-31), 97.4% were men, and 94.1% were MSM. Overall TDR prevalence was 7.0%, declining from 12.5% in 2009-2010 to 4.8% in 2017-2018. A declining resistance prevalence to nonnucleoside reverse transcriptase inhibitor emerged from 9.4% in 2009-2010 to 3.5% in 2017-2018 and to nucleoside reverse transcriptase inhibitor from 6.3% to 2.1%. Protease inhibitor resistance showed a decreased TDR level from 3.1% in 2009-2010 to 1.4% in 2017-2018. We report an encouraging declining trend in TDR prevalence in a Thai cohort of mainly MSM from 2009 to 2018; in 2017-2018, we observed a low TDR prevalence according to the World Health Organization definition.