Nucleoside Reverse Transcriptase Inhibitor Mutations Research Articles

Trends and Patterns of HIV Transmitted Drug Resistance in China From 2018 to 2023.

National treatment guidelines of China evolving necessitates population-level surveillance of transmitted drug resistance (TDR) to inform or update HIV treatment strategies. We analyzed the demographic, clinical, and virologic data obtained from people with HIV (PWH) residing in 31 provinces of China who were newly diagnosed between 2018 and 2023. Evidence of TDR was defined by the World Health Organization list for surveillance of drug resistance mutations. Among the 22 124 PWH with protease and reverse transcriptase sequences, 965 (4.36%; 95% CI, 4.1-4.63) had at least 1 TDR mutation. The most frequent TDR mutations were nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.39%; 95% CI, 2.19%-2.59%), followed by nucleoside reverse transcriptase inhibitor mutations(1.35%; 95% CI, 1.2%-1.5%) and protease inhibitor mutations (1.12%; 95% CI, .98%-1.26%). The overall protease and reverse transcriptase TDR increased significantly from 4.05% (95% CI, 3.61%-4.52%) in 2018 to 5.39% (95% CI, 4.33%-6.57%) in 2023. A low level of integrase strand transfer inhibitor TDR was detected in 9 (0.21%; 95% CI, .1%-.38%) of 4205 PWH. Presently, the continued use of NNRTI-based first-line antiretroviral therapy regimen for HIV treatment has been justified.

Retrospective study of the prevalence of acquired drug resistance after failed antiretroviral therapy in Libya.

The increasing rate of drug-resistant HIV mutations in Libya and other African countries threatens the efficacy of antiretroviral therapy (ART), thus necessitating urgent regional strategies to combat resistance and improve treatment outcomes. To characterize the frequency and pattern of acquired HIV drug resistance mutations in patients showing ART failure while using non-nucleoside reverse transcriptase inhibitors (NNRTI) prescribed by the Department of Infectious Diseases at Tripoli University Hospital, Libya. We collated retrospective data on 128 people living with HIV, aged 18 years or above, who experienced firstline treatment failure at Tripoli University Hospital, Libya, from 2014 to 2017. We analysed the extant HIV amino acid sequences to identify resistance mutations using algorithms from the Stanford University HIV drug resistance database. All included cases had at least one resistance mutation (n = 128; 100%) and 119 (93%) had both nucleoside reverse transcriptase inhibitors (NRTI) and NNRTI mutations. M184V/I was the most common NRTI mutation (n = 119; 93%) while K103N was the most common NNRTI mutation (n = 100; 78%). Thymidine analog mutations were detected in 51 cases (40%); featuring T215Y, D67N and M41L. Predicted full susceptibility was highest for Tenofovir (66.4%), followed by Etravirine (60%). We detected high level drug resistance and associated mutations among people living with HIV. Implementing drug regimens with high genetic barriers to resistance, coupled with rigorous monitoring and surveillance of HIV resistance development, could help mitigate such resistance in the future.

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

IntroductionIn 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.MethodologyPlasma 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).ResultsOf 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).ConclusionThis 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.

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.

Анализ частоты формирования мутаций резистентности ВИЧ, ассоциированных с устойчивостью к антиретровирусным препаратам

Актуальность. В Украине проводится широкомасштабная антиретровирусная терапия (АРТ) больных ВИЧ-инфекцией. Необходимо постоянное наблюдение за развитием устойчивости ВИЧ к антиретровирусным препаратам (АРВП). Цель: проанализировать влияние продолжительности АРТ, возраста и пола пациентов на частоту формирования мутаций резистентности (МР) ВИЧ к АРВП разных классов. Материал и методы. Исследовали образцы плазмы крови ВИЧ-инфицированных пациентов с вирусологической неэффективностью АРТ. Секвенирование генома ВИЧ проводили на тест-системах ViroSeqTM Genotyping System v.2.1 (Celera Diagnostics, США) согласно инструкции производителя. Результаты. Достоверно чаще (р ≤ 0,05) МР ВИЧ к АРВП выявлялись у ВИЧ-инфицированных мужчин (59,70 %), чем у женщин (40,3 %). Установлено, что в 59,9 % случаев вирусологическая неэффективность АРТ была обусловлена формированием МР ВИЧ хотя бы к одному из АРВП. Среди МР ВИЧ к ненуклеозидным ингибиторам обратной транскриптазы наиболее распространенными были G190S (75,8 %); K101E (72,7%); Y181C (68,1 %); K103N (38,8 %); среди МР к нуклеозидным ингибиторам обратной транскриптазы преобладали: M184V (69 %), K65R (61 %), D67N (20 %). МР ВИЧ к ингибитору протеазы встречались редко. Выводы. Показано, что продолжительность АРТ и возраст пациентов существенного влияния на устойчивость ВИЧ к АРВП не оказывали. Решающее значение имел генетический барьер АРВП: на фоне приема препаратов с низким генетическим барьером частота выявления МР ВИЧ составляла 5,3 %; прием препаратов с высоким генетическим барьером сопровождался формированием МР ВИЧ значительно реже — в 1,1 % случаев. Доказано, что биоповеденческие особенности пациентов-мужчин являются фактором, ассоциирующимся с повышенным риском формирования МР ВИЧ к АРВП.

Transmitted Drug Resistance Among Human Immunodeficiency Virus (HIV)-1 Diagnoses in the United States, 2014-2018.

Transmitted human immunodeficiency virus (HIV) drug resistance can threaten the efficacy of antiretroviral therapy and pre-exposure prophylaxis (PrEP). Drug-resistance testing is recommended at entry to HIV care in the United States and provides valuable insight for clinical decision making and population-level monitoring. We assessed transmitted drug-resistance-associated mutation (TDRM) prevalence and predicted susceptibility to common HIV drugs among US persons with HIV diagnosed during 2014-2018 who had a drug resistance test performed ≤3 months after HIV diagnosis and reported to the National HIV Surveillance System and who resided in 28 jurisdictions where ≥20% of HIV diagnoses had an eligible sequence during this period. Of 50 747 persons in the analysis, 9616 (18.9%) had ≥1 TDRM. TDRM prevalence was 0.8% for integrase strand transfer inhibitors (INSTIs), 4.2% for protease inhibitors, 6.9% for nucleoside reverse transcriptase inhibitors (NRTIs), and 12.0% for non-NRTIs. Most individual mutations had a prevalence <1.0% including M184V (0.9%) and K65R (0.1%); K103N was most prevalent (8.6%). TDRM prevalence did not increase or decrease significantly during 2014-2018 overall, for individual drug classes, or for key individual mutations except for M184V (12.9% increase per year; 95% confidence interval, 5.6-20.6%). TDRM prevalence overall and for individual drug classes remained stable during 2014-2018; transmitted INSTI resistance was uncommon. Continued population-level monitoring of INSTI and NRTI mutations, especially M184V and K65R, is warranted amidst expanding use of second-generation INSTIs and PrEP.

Pretreatment and Acquired Antiretroviral Drug Resistance Among Persons Living With HIV in Four African Countries.

BackgroundEmerging HIV drug resistance (HIVDR) could jeopardize the success of standardized HIV management protocols in resource-limited settings. We characterized HIVDR among antiretroviral therapy (ART)-naive and experienced participants in the African Cohort Study (AFRICOS).MethodsFrom January 2013 to April 2019, adults with HIV-1 RNA >1000 copies/mL underwent ART history review and HIVDR testing upon enrollment at 12 clinics in Uganda, Kenya, Tanzania, and Nigeria. We calculated resistance scores for specific drugs and tallied major mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) using Stanford HIVDB 8.8 and SmartGene IDNS software. For ART-naive participants, World Health Organization surveillance drug resistance mutations (SDRMs) were noted.ResultsHIVDR testing was performed on 972 participants with median age 35.7 (interquartile range [IQR] 29.7–42.7) years and median CD4 295 (IQR 148–478) cells/mm3. Among 801 ART-naive participants, the prevalence of SDRMs was 11.0%, NNRTI mutations 8.2%, NRTI mutations 4.7%, and PI mutations 0.4%. Among 171 viremic ART-experienced participants, NNRTI mutation prevalence was 83.6%, NRTI 67.8%, and PI 1.8%. There were 90 ART-experienced participants with resistance to both efavirenz and lamivudine, 33 (36.7%) of whom were still prescribed these drugs. There were 10 with resistance to both tenofovir and lamivudine, 8 (80.0%) of whom were prescribed these drugs.ConclusionsParticipants on failing ART regimens had a high burden of HIVDR that potentially limited the efficacy of standardized first- and second-line regimens. Management strategies that emphasize adherence counseling while delaying ART switch may promote drug resistance and should be reconsidered.

ACQUIRED ANTIRETROVIRAL DRUG RESISTANCE MUTATIONS UPON TREATMENT FAILURE IN HIV-1 INFECTED PEDIATRIC PATIENTS IN CENTRAL BRAZIL

Antiretroviral drug-resistance mutations compromise the successful treatment of children and adolescents infected with human immunodeficiency virus type 1 (HIV-1). We describe the clinical, virological, and immunological follow-up of a cohort of children and adolescents perinatally infected with HIV-1 treated at Hospital Estadual de Doenças Tropicais Dr. Anuar Auad – HDT, in Central Brazil, after therapeutic failure related to drug resistance mutations.We analyzed the results of the genotypic test (protease codons 1–99 and reverse transcriptase codons 1–325) performed from 2003 to 2015. The ARV susceptibility profile was analyzed according to Stanford HIV drug resistance database. A total of 65 patients (median age of 10 years; range, 18 m–18 y) with therapeutic failure (after a median of 55 months of follow up; range, 9 m–13 y) and plasma levels of HIV-1 RNA greater than 1,000 copies/mL which were included and demonstrated mutations in: nucleoside reverse transcriptase inhibitors (NRTIs), 98.5%; non nucleoside reverse transcriptase inhibitors (NNRTIs), 75.4%; and protease inhibitors (PI), 44.6%. The most frequent NRTI mutations were found in codon T215 (83.1%) with a predominance of T215Y (56.9%), followed by M184V (69.3%). In the NNRTI class, mutations K103N (36.9%) and 190A (23.1%) were predominant, and, in the protease, mutations 54VL (35.4%) and 82ASTL (32.3%) were found in approximately the same proportion, with a predominance of the M54V mutation. These results demonstrate the high levels of resistance to different classes of antiretrovirals in HIV-infected children and adolescents and the importance of genotypic resistance tests in this population.KEY WORDS: HIV; drug resistance; genotypes; child; adolescent.

High Levels of Acquired HIV Drug Resistance Following Virological Nonsuppression in HIV-Infected Women from a High-Risk Cohort in Uganda.

HIV drug resistance (HIVDR) is of increasing health concern, especially among key populations. We investigated the prevalence of virological suppression (VS), prevalence and correlates of HIVDR in HIV-infected women, enrolled in a high-risk cohort. We enrolled 267 women initiated on first-line antiretroviral therapy (ART) between 2015 and 2018. Participants' plasma samples were analyzed for HIV RNA viral load (VL) and genotypic resistance testing was performed on those with VL nonsuppression (defined as VL ≥1,000 copies/mL). We used the Stanford HIVDR database-algorithm to assess HIVDR mutations and logistic regression to assess risk factors for VL nonsuppression and HIVDR. We observed an overall VS prevalence of 76.0% (203/267) and detected respective acquired drug resistance prevalence to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) of 81.3% [confidence interval (CI) 67.4-91.1] and 45.8% (CI 31.4-60.8) among the 48 successfully genotyped VL nonsuppressors. NNRTI mutations were observed in 81.3% (39/48) of the genotyped participants and 45.8% (22/48) had both NRTI and NNRTI mutations. The mutation K103N was detected in 62.5% (30/48) of participants, 41.7% (20/48) had M184V/I, 14.6% had K65R, and 12.5% (6/48) had thymidine analog mutations (TAMs). None of the analyzed potential risk factors, including age and duration on ART, was significantly correlated with VL nonsuppression or HIVDR. Although high levels of NNRTI mutations support the transition to dolutegravir, the presence of NRTI mutations, especially TAMs, may compromise dolutegravir-based regimens or other second-line ART options. The moderate VS prevalence and high HIVDR prevalence therefore call for timely ART switching and intensive adherence counseling.

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference.

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA <50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA >50 copies/mL or one HIV-RNA >1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12–78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96–0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.

Postmortem Molecular Epidemiology of HIV-1 Strains Isolated in Turkey

Human immunodeficiency virus (HIV) comprises two genotypes, namely HIV-1 (group M, N, O and P) and HIV-2 (group A to H), which differ in their envelope glycoproteins and other antigenic epitopes despite their morphological and biological resemblance.Group M of HIV-1 responsible for 95% of HIV infections worldwide is composed of nine subgroups. In addition to subgroups, group M contains also two recombinant forms, known as circulating recombinant form (CRF) and unique recombinant form (URF). The first case of HIV/acquired immun deficiency virus (AIDS) in Turkey was reported in 1985 and the current number of cases reached a total of 18.557 including 1736 with AIDS based upon the surveillance data of Ministry of Health between October 1985 and November 2018. The aim of this study was to determine the prevalence of HIV-1 strains isolated from HIV positive autopsy cases detected by HIV polymerase chain reaction (PCR) and determine drug resistance. Twenty eight cases [17 males, 11 female: age ranged between 3 months and 66 years (median: 35 years)] found to be HIV positive among the autopsy cases sent for HIV1 PCR study and serological screening between 2011-2017 were recruited in the study. For identification of subtypes in HIV-1 isolates, most-preferred analysis tool was used [HIVdb Stanford University Genotypic Resistance Interpretation Algorithm (www.hivdb.stanford.edu)]. Phylogenetic tree was made according to direct sequencing of HIV-1 reverse transcriptase (pol) region and phylogenetic analysis was evaluated in 23 cases. Los Alamos National Laboratory were trimmed from full-length genomes. Phylogenetic analysis of the 870 base pair of the pol gene region was performed using CLC Sequence Viewer v8.0 (Qiagen Aarhus A/S, www.qiagenbioinformatics.com) software. The phylogenetic tree was obtained according to the neighbor-joining method and the Jukes-Cantor nucleotide distance scale and bootstrap value was set at 1000. In our study, subtype B was found to be most frequent type (39.3%; 11/28). Subtype A (17.9%; 5/28), CRF02_AG (14.3%; 4/28), subtype C (10.7%; 3/28), B+CRF02_AG recombinant (3.6%; 1/28), CRF01_AE (3.6%; 1/28), subtype D (3.6%; 1/28), as well as subtype F (3.6%; 1/28) and subtype G (3.6%; 1/28) strains were also detected in the circulation. Analysis of our results showed that 32.1% (9/28) of the samples exhibited resistance mutations. Detected mutations were as follows: M41L, T215C, K65R, M184V, responsible for nucleoside reverse transcriptase inhibitor (NRTI) resistance; K103N, Y181C, G190A, responsible for non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance; D30N, M46I, responsible for protease inhibitor (PI) resistance. NRTI, NNRTI and PI mutation rates in the samples were found as 21.4%, 7.1% and 3.6%, respectively. Although number of samples analyzed in our study is low, we can propose that they resemble the strains circulating in Turkey. The results of our study; although the subtype B is still dominant in our country, it supports other studies reporting that there are non-B subtypes and an increase in CRF rates in recent years. Phylogenetic analysis is widely regarded as the gold standard technique to determine the subtypes of HIV-1. Molecular epidemiologic studies related to HIV may be important in monitoring HIV subtype patterns and spreading pathways in that country. As a result; the opportunity to collect postmortem HIV sequences in a database appears to have occurred, and as this database expands, its usability is available. Therefore, it is thought that HIV subtypes and mutation information may be useful.

Low rates of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drug resistance in Botswana.

Scale-up of antiretroviral therapy (ART) and introduction of treat-all strategy necessitates population-level monitoring of acquired HIV drug resistance (ADR) and pretreatment drug resistance (PDR) mutations. Blood samples were collected from 4973 HIV-positive individuals residing in 30 communities across Botswana who participated in the Botswana Combination Prevention Project (BCPP) in 2013-2018. HIV sequences were obtained by long-range HIV genotyping. Major drug-resistance mutations (DRMs) and surveillance drug resistance mutations (SDRMs) associated with nucleoside reverse transcriptase inhibitors (NRTI) and nonnucleoside reverse transcriptase inhibitors (NNRTI) were analyzed according to the Stanford University HIV Drug Resistance Database. Viral sequences were screened for G-to-A hypermutations. A threshold of 2% was used for hypermutation adjustment. Viral suppression was considered at HIV-1 RNA load ≤400 copies/ml. Among 4973 participants with HIV-1C sequences, ART data were available for 4927 (99%) including 3858 (78%) on ART. Among those on ART, 3435 had viral load data and 3297 (96%) were virologically suppressed. Among 1069 (22%) HIV-infected individuals not on ART, we found NRTI-associated and NNRTI-associated SDRMs were found in 1.5% (95% confidence interval [CI] 1.0-2.5%) and 2.9% (95% CI 2.0-4.2%), respectively. Of the 138 (4%) of individuals who had detectable HIV-1 RNA, we found NRTI-associated and NNRTI-associated drug resistance mutations in 16% (95% CI 10-25%) and 33% (95% CI 25-42%), respectively. We found a low prevalence of NRTI-associated and NNRTI-associated PDR-resistance mutations among residents of rural and peri-urban communities across Botswana. However, individuals on ART with detectable virus had ADR NRTI and NNRTI mutations above 15%.

Epidemiology of human immunodeficiency virus (HIV) drug resistance in HIV patients with virologic failure of first-line therapy in the country of Georgia.

Human immunodeficiency virus (HIV) drug resistance is a major threat to the sustained impact of antiretroviral therapy (ART). We studied the epidemiology of drug resistance in the country of Georgia. The study included all adult patients who experienced virologic failure on first line ART and received HIV drug resistance testing between 2005 and 2016. The Stanford HIV Sequence Database was used for interpretation of the resistance data. Patient-level data were extracted from the national AIDS health information system. Of the 447 patients included, 85.5% harbored the subtype A6 virus, 8.0% - subtype B, 2.9% - subtype G, and other subtypes were <1%. The most frequent first-line regimens were Tenofovir/Emtricitabine/Efavirenz (28.4%), Zidovudine/Lamivudine/Efavirenz (28.4%), and Abacavir/Lamivudine/Efavirenz (15.9%). A total of 85.0% of the patients with treatment failure developed at least one drug resistance mutation affecting their susceptibility to ART. The most frequent nucleoside reverse transcriptase inhibitor mutations were M184V (65.3%), K65R (19.7%) and L74V (17.0%). At least three thymidine analogue mutations were detected in 6.3% of the patients. From non-nucleoside reverse transcriptase inhibitor mutations, G190S was shown to be the most prevalent (49.4%), followed by K101E (27.10%) and K103N (24.4%). G190S and K101E were more common in subtype A as compared with non-A viruses (G190S: 54.9% vs 11.3%, P < 0.0001; K101E: 29.8% vs 11.3%, P = 0.005). On the other hand, K103N was more frequent in non-A subtypes (43.4%) compared with subtype A (22.2%), P = 0.0008. A majority of persons failing on ART had HIV drug resistance. Drug resistance patterns may vary by subtype. K65R mutation remains below 20%, but given the high use of Tenofovir in the country, continuing surveillance of drug resistance is needed.

Emergence of HIV-1 drug resistance mutations in mothers on treatment with a history of prophylaxis in Ghana

BackgroundAntiretrovirals have been available in Ghana since 2003 for HIV-1 positive pregnant women for prevention of mother-to-child transmission (PMTCT). Suboptimal responses to treatment observed post-PMTCT interventions necessitated the need to investigate the profile of viral mutations generated. This study investigated HIV-1 drug resistance profiles in mothers in selected centres in Ghana on treatment with a history of prophylaxis.MethodsGenotypic Drug Resistance Testing for HIV-1 was carried out. Subtyping was done by phylogenetic analysis and Stanford HIV Database programme was used for drug resistance analysis and interpretation. To compare the significance between the different groups and the emergence of drug resistance mutations, p values were used.ResultsParticipants who had prophylaxis before treatment, those who had treatment without prophylaxis and those yet to initiate PMTCT showed 32% (8), 5% (3) and 15% (4) HIV-1 drug resistance associated mutations respectively. The differences were significant with p value < 0.05. Resistance Associated Mutations (RAMs) were seen in 14 participants (35%) to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The most common NRTI mutation found was M184 V; K103 N and A98G were the most common NNRTI mutations seen. Thymidine Analogue Mutations (TAMs) such as M41 L, K70R and T215Y were found in all the groups; the most common of the TAMs found were M41 L and T215Y. Majority of the subtypes were CRF02_AG (82%).ConclusionIn Ghana initiation of uninterrupted treatment upon diagnosis, coupled with drug resistance testing, would produce a better treatment outcome for HIV-1 positive pregnant women.

HIV-1 Antiretroviral Resistance in Cuba, 2009-2014.

INTRODUCTION By the end of 2017, there were more than 28,000 individuals living with HIV in Cuba, over 80% receiving antiretroviral therapy, which dramatically reduces viral replication, improves immune status and decreases risk of transmission. These results could be jeopardized by emergence of HIV-1 drug resistance. In 2009, a test for HIV-1 genotypic resistance was introduced in routine clinical practice in Cuba. OBJECTIVE Investigate antiretroviral resistance and its relation to subtype distribution in HIV-1 treatment-naive and previously treated patients in Cuba. METHODS Resistance and HIV-1 subtype distribution were determined in 342 antiretroviral treatment-naive patients and 584 previously treated for HIV-1 whose blood specimens were sent to the Pedro Kouri Tropical Medicine Institute during 2009-2014. Transmitted drug resistance was determined using the Calibrated Population Resistance Tool v.6. Drug resistance analysis was conducted using the algorithm Rega v9.1.0. RESULTS Prevalence of transmitted drug resistance was 11.4%, and 41% of mutated viruses exhibited dual-class resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor. Overall, 84.9% of patients had ≥1 resistance mutation, 80% had ≥1 nucleoside reverse transcriptase inhibitor mutation, 71.4% had ≥1 non-nucleoside reverse transcriptase inhibitor mutation and 31.7% had ≥1 protease inhibitor mutation. K65R and K101E mutations were significantly more frequent in subtype C, L210W in CRF19_cpx, and M47V/I in CRF BGs (20, 23, 24). Full class resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and multidrug resistance were detected in 21.2%, 32.4%, 8% and 4.1% of patients, respectively. Average percentage resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor, full class resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor and multidrug resistance increased in patients failing two or more regimens. Nevertheless, after 2011, a declining trend was observed in the frequency of multidrug resistance and full class resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors. CONCLUSIONS Detected levels of transmitted drug resistance highlight the need for a national surveillance study in treatment-naive patients. Resistance prevalence is high in previously treated patients but appears to be decreasing over time. The frequency of resistance mutations in recombinant forms of HIV in Cuba needs further study. KEYWORDS Antiretroviral therapy, highly active antiretroviral therapy, HIV, anti-HIV agents, drug resistance, multiple drug resistance, Cuba.

Short Communication: Nucleoside Reverse Transcriptase Inhibitors with Reduced Predicted Activity Do Not Impair Second-Line Therapy with Lopinavir/Ritonavir or Darunavir/Ritonavir.

Second-line therapy randomized trials with lopinavir/ritonavir question the value of resistance testing to guide nucleoside reverse transcriptase inhibitor (NRTI) selection. In this study, we investigated the association between baseline drug resistance and treatment outcome after 104 weeks of second-line therapy with NRTIs and either darunavir/ritonavir or lopinavir/ritonavir in West-central Africa. We did an observational analysis of data from 387 individuals in a randomized, open-label 2LADY trial in Burkina Faso, Cameroon, and Senegal. We modeled the association between RTI drug resistance mutations (DRMs) and virological failure (VF) (viral load [VL] <50 copies/mL) at week 104 using logistic regressions. Covariates included baseline VL and CD4+ count, demographic, and adherence data. Overall, 193 (49.9%), 150 (38.8%), and 44 (11.4%) individuals had, respectively, low/none (genotypic susceptibility score [GSS] <1), intermediate (GSS = 1), and high predicted NRTI activity (GSS >1) in their prescribed second-line regimen. The average number of DRMs by drug class, the proportion of individuals by GSS category, and the duration of first-line therapy were not associated with VF (p > .05). High VL at switch was the only consistent prognostic factor for VF after multivariate adjustment (p < .01). Suboptimal adherence, high predicted RTI activity, or low NRTI mutations were associated with VF (p < .05) when using higher end points for VF or in the intention-to-treat analysis. In conclusion, the use of RTIs with predicted reduced activity does not impair second-line protease inhibitor-based therapy. Therefore, HIV care in resource-limited settings should prioritize strategies to improve adherence and targeted VL testing over drug resistance testing for selecting NRTIs during a protease-based second-line switch.

Effect of dolutegravir in combination with Nucleoside Reverse Transcriptase Inhibitors (NRTIs) on people living with HIV who have pre-existing NRTI mutations

Until the introduction of dolutegravir (DTG), people living with HIV (PLWH) who have developed nucleoside reverse transcriptase inhibitor (NRTI) mutations have had few other treatment options outside of regimens based on ritonavir-boosted protease inhibitors (PI/r). Here we report treatment results among PLWH in Sweden with pre-existing NRTI mutations on antiretroviral treatment (ART) with DTG and one to two NRTIs. All PLWH on ART with DTG and one to two NRTIs with pre-existing NRTI mutations were retrospectively identified from the National InfCare HIV database. As controls, PLWH on PI/r and one to two NRTIs, matched according to Genotypic Susceptibility Score and observation time, were included. Data were collected as long as the study population was on treatment with DTG; controls were monitored for the same interval. Outcome was classified as either treatment success or failure. In total, 244 participants (122 individuals treated with DTG and 122 individuals treated with PI/r) were included. Median observation time was 78 weeks (interquartile range 50–98 weeks) for participants on DTG and 75 weeks (50–101 weeks) for individuals on PI/r. Viral failure was detected in four individuals treated with DTG and three individuals treated with PI/r, resulting in similar success rates of 96.7% and 97.5%, respectively. No new mutations were found among participants with treatment failure. DTG in combination with one to two NRTIs was as efficient as PI/r in individuals with pre-existing NRTI mutations in this setting. It may be considered an alternative to PI/r-based ART even in the presence of NRTI resistance.

HIV-1 Antiretroviral Resistance in Cuba, 2009-2014.

INTRODUCTION By the end of 2017, there were more than 28,000 individuals living with HIV in Cuba, over 80% receiving antiretroviral therapy, which dramatically reduces viral replication, improves immune status and decreases risk of transmission. These results could be jeopardized by emergence of HIV-1 drug resistance. In 2009, a test for HIV-1 genotypic resistance was introduced in routine clinical practice in Cuba. OBJECTIVE Investigate antiretroviral resistance and its relation to subtype distribution in HIV-1 treatment-naïve and previously treated patients in Cuba. METHODS Resistance and HIV-1 subtype distribution were determined in 342 antiretroviral treatment-naïve patients and 584 previously treated for HIV-1 whose blood specimens were sent to the Pedro Kourí Tropical Medicine Institute during 2009-2014. Transmitted drug resistance was determined using the Calibrated Population Resistance Tool v.6. Drug resistance analysis was conducted using the algorithm Rega v9.1.0. RESULTS Prevalence of transmitted drug resistance was 11.4%, and 41% of mutated viruses exhibited dual-class resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor. Overall, 84.9% of patients had ≥1 resistance mutation, 80% had ≥1 nucleoside reverse transcriptase inhibitor mutation, 71.4% had ≥1 non-nucleoside reverse transcriptase inhibitor mutation and 31.7% had ≥1 protease inhibitor mutation. K65R and K101E mutations were significantly more frequent in subtype C, L210W in CRF19_cpx, and M47V/I in CRF BGs (20, 23, 24). Full class resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and multidrug resistance were detected in 21.2%, 32.4%, 8% and 4.1% of patients, respectively. Average percentage resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor, full class resistance to nucleoside reverse transcriptase inhibitor, protease inhibitor and multidrug resistance increased in patients failing two or more regimens. Nevertheless, after 2011, a declining trend was observed in the frequency of multidrug resistance and full class resistance to nucleoside reverse transcriptase inhibitors and protease inhibitors. CONCLUSIONS Detected levels of transmitted drug resistance highlight the need for a national surveillance study in treatment-naïve patients. Resistance prevalence is high in previously treated patients but appears to be decreasing over time. The frequency of resistance mutations in recombinant forms of HIV in Cuba needs further study. KEYWORDS Antiretroviral therapy, highly active antiretroviral therapy, HIV, anti-HIV agents, drug resistance, multiple drug resistance, Cuba.

Combination Therapy with Tenofovir Disoproxil Fumarate/Emtricitabine/Elvitegravir/Cobicistat Plus Darunavir Once Daily in Antiretroviral-Naive and Treatment-Experienced Patients: A Retrospective Review.

Background:Patients with drug-resistant HIV often require complex antiretroviral regimens. However, combining fixed-dose combination tablets such as tenofovir–disoproxil–fumarate, emtricitabine, and cobicistat-boosted elvitegravir (TDF/FTC/EVG/cobi) with darunavir (DRV) can provide a simple, once-daily (QD), 2-tablet regimen for patients with drug-resistant HIV. Primary objective was to determine the percentage of patients with HIV-1 RNA <40 copies/mL at 48 weeks.Methods:We performed a retrospective chart review of patients initiated on TDF/FTC/EVG/cobi plus DRV.Results:Among the 21 included patients, prior resistance showed a median of 2 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase mutation, and 1 protease inhibitor mutation. At week 48, 14 (67%) patients achieved HIV-1 RNA <40 copies/mL, 1 patient experienced viral rebound, and 6 (29%) had missing data or discontinued therapy. No patient discontinued for adverse events.Conclusion:According to this observational study, QD TDF/FTC/EVG/cobi plus DRV is considered safe, well tolerated, and generally effective in suppressing HIV drug-resistant virus.

Higher Frequency of HIV-1 Drug Resistance and Increased Nucleoside Reverse Transcriptase Inhibitor Mutations among the HIV-1 Positive Antiretroviral Therapy-Naïve patients Coinfected With Mycobacterium tuberculosis Compared With Only HIV Infection in India.

Background:Emergence of human immunodeficiency virus (HIV) drug resistance mutations prior to highly active antiretroviral therapy is a serious problem in clinical management of HIV/AIDS. Risk factors for appearance of drug resistance mutations are not known. We hypothesize that Mycobacterium tuberculosis infection may contribute to rapid emergence of such mutations in antiretroviral therapy–naïve patients.Methods:A total of 115 patients were recruited in this study of which 75 were HIV+TB+ coinfected (group 1) and 40 were HIV+TB− (group 2). Blood samples from all the patients were collected and CD4+ cell counts; HIV-1 plasma viral load and sequencing of protease and two-third region of reverse transcriptase of HIV-1 was performed and analyzed for drug resistance pattern.Results:For patients with HIV+TB+, 10.6% (8/75) had mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4% (3/75) to nucleoside reverse transcriptase inhibitors, and only 2.6% (2/75) patients had mutations to protease inhibitors. Interestingly, for group 2 (HIV+TB−), there were only NNRTI mutations found among these patients, and only 3 patients (7.5%) had these drug-resistant mutations. Clade typing and phylogenetic tree analysis showed HIV-1 subtype C predominance in these patients.Conclusions:Our study showed that higher percentage of HIV drug resistance mutations was found among HIV+TB+ individuals compared with tuberculosis-uninfected patients. Tuberculosis coinfection may be a risk factor for emergence of high frequency of drug resistance mutations. Studies with a larger sample size will help to confirm these findings from the Indian population.