scholarly journals Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark J. Siedner ◽  
Michelle A. Moorhouse ◽  
Bryony Simmons ◽  
Tulio de Oliveira ◽  
Richard Lessells ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Integrase Inhibitor ◽  
Sub Saharan Africa ◽  
World Health ◽  
Virologic Suppression ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
The Impact

AbstractLittle is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.

scholarly journals Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

2020 ◽  
Author(s):  
Mark Siedner ◽  
Michelle Moorhouse ◽  
Brioni Simmons ◽  
Tulio de Oliveira ◽  
Richard Lessells ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Treatment Initiation ◽  
World Health ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
The Impact ◽  
Hiv 1

Abstract Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

scholarly journals Characterization of HIV-1 Integrase Gene and Resistance Associated Mutations Prior to Roll out of Integrase Inhibitors by Kenyan National HIV-Treatment Program in Kenya

2020 ◽  
Vol 30 (1) ◽  
Author(s):  
Mabeya Sepha ◽  
Nyamache Anthony ◽  
Ngugi Caroline ◽  
Nyerere Andrew ◽  
Lihana Raphael
Keyword(s):  
Drug Resistance ◽  
Direct Sequencing ◽  
Integrase Inhibitor ◽  
Hiv Treatment ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
Integrase Gene ◽  
Hiv 1

BACKGROUND: Antiretroviral therapy containing an integrase strand transfer inhibitor plus two Nucleoside Reverse Transcriptase inhibitors has now been recommended for treatment of HIV-1-infected patients. This thus determined possible pre-existing integrase resistance associated mutations in the integrase gene prior to introduction of integrase inhibitors combination therapy in Kenya.METHODS: Drug experienced HIV patients were enrolled at Kisii Teaching and Referral in Kenya. Blood specimens from (33) patients were collected for direct sequencing of HIV-1 polintegrase genes. Drug resistance mutations were interpreted according to the Stanford algorithm and phylogenetically analysed using insilico tools.RESULTS: From pooled 188 Kenyan HIV integrase sequences that were analysed for drug resistance, no major mutations conferring resistance to integrase inhibitors were detected. However, polymorphic accessory mutations associated with reduced susceptibility of integrase inhibitors were observed in low frequency; M50I (12.2%), T97A (3.7%), S153YG, E92G (1.6%), G140S/A/C (1.1%) and E157Q (0.5%). Phylogenetic analysis (330 sequences revealed that HIV-1 subtype A1 accounted for majority of the infections, 26 (78.8%), followed by D, 5 (15.2%) and C, 2 (6%).CONCLUSION: The integrase inhibitors will be effective in Kenya where HIV-1 subtype A1 is still the most predominant. However, occurring polymorphisms may warrant further investigation among drug experienced individuals on dolutegravir combination or integrase inhibitor treatment. 

scholarly journals Development of HIV drug resistance in a cohort of adults on first-line antiretroviral therapy in Tanzania during the stavudine era

2020 ◽  
Author(s):  
Raphael Z Sangeda ◽  
Perpétua Gómes ◽  
Soo-Yon Rhee ◽  
Fausta Mosha ◽  
Ricardo J. Camacho ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
One Year ◽  
Reverse Transcriptase Inhibitor

Abstract As more HIV patients start combination antiretroviral therapy (cART), the emergence of HIV drug resistance (HIVDR) is inevitable. This will have consequences for the transmission of HIVDR, the success of ART, and the nature and trend of the epidemic. We recruited a cohort of 223 patients starting or continuing their first-line cART in Tanzania during the stavudine era in 2010. Patients were then followed up for one year. From those with a viral load test at baseline and follow-up time, 34% were failing virologically at the one-year endpoint. From 41 patients, protease and reverse transcriptase genotyping were successful. Eighteen samples were from therapy-naïve patients and 23 samples were taken under therapy either baseline for patients already under cART at study entry, or follow-up sample. The isolates were mostly subtype A, followed by C and D at 41.5%, 22% and 12.2% of the patients, respectively. No transmitted HIVDR was detected, as scored using the surveillance drug resistance mutations (DRMs) list. However, in 3 of the 18 samples from therapy-naïve patients, the clinical Rega interpretation algorithm scored 44D or 138A as non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated polymorphisms. The most observed nucleoside reverse transcriptase inhibitor (NRTI) mutation was 184V. The mutation was found in 16 patients causing resistance to lamivudine and emtricitabine. Nineteen patients had NNRTI resistance mutations, the most common of which was 103N observed in 8 patients. These high levels of resistance calls for regular drug resistance surveillance in Tanzania to control the emergence and transmission of HIVDR.

scholarly journals Development of HIV Drug Resistance in a Cohort of Adults on First-Line Antiretroviral Therapy in Tanzania during the Stavudine Era

2021 ◽  
Vol 12 (4) ◽  
pp. 847-861
Author(s):  
Raphael Z. Sangeda ◽  
Perpétua Gómes ◽  
Soo-Yon Rhee ◽  
Fausta Mosha ◽  
Ricardo J. Camacho ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
One Year ◽  
Reverse Transcriptase Inhibitor

As more HIV patients start combination antiretroviral therapy (cART), the emergence of HIV drug resistance (HIVDR) is inevitable. This will have consequences for the transmission of HIVDR, the success of ART, and the nature and trend of the epidemic. We recruited a cohort of 223 patients starting or continuing their first-line cART in Tanzania towards the end of the stavudine era in 2010. Patients were then followed for one year. Of those with a viral load test at baseline and follow-up time, 34% had a detectable viral load at the one-year endpoint. For 41 patients, protease and reverse transcriptase genotyping were successful. Eighteen samples were from cART-naïve patients, and 23 samples were taken under therapy either at baseline for cART-experienced patients or from follow-up samples for both cART–naïve and cART–experienced patients. The isolates were subtype A, followed by C and D in 41.5%, 22%, and 12.2% of the patients, respectively. No transmitted HIVDR was detected, as scored using the surveillance drug resistance mutations (DRMs) list. However, in 3 of the 18 samples from cART-naïve patients, the clinical Rega interpretation algorithm scored 44D or 138A as non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated polymorphisms. The most observed nucleoside reverse transcriptase inhibitor (NRTI) mutation was 184V. The mutation was found in 16 patients, causing resistance to lamivudine and emtricitabine. Nineteen patients had NNRTI resistance mutations, the most common of which was 103N, observed in eight patients. These high levels of resistance call for regular drug resistance surveillance in Tanzania to inform the control of the emergence and transmission of HIVDR.

scholarly journals Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes

2020 ◽  
Author(s):  
Kara A. Moser ◽  
Rashid A. Madebe ◽  
Ozkan Aydemir ◽  
Mercy G. Chiduo ◽  
Celine I. Mandara ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Population Structure ◽  
Genetic Relatedness ◽  
Sub Saharan Africa ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Molecular Inversion Probes ◽  
Parasite Populations ◽  
The Impact

ABSTRACTHigh-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programs, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania country-wide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, roughly separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from geographically close districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts, and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.SIGNIFICANCEDocumenting dynamics of malaria parasite genomics in high-transmission settings at scale in sub-Saharan Africa is critical for policy and decision making to support ongoing malaria elimination initiatives. Using molecular inversion probes, we genotyped over 1,000 Tanzanian Plasmodium falciparum samples collected country-wide in 2017 at hundreds of variable polymorphic positions across the genome. Frequencies of known drug resistance mutations were higher in northern districts of the country compared to the south. Results also showed a distinct isolation-by-distance pattern (whereby increasing geographic distance was correlated with decreasing genetic relatedness), as well as signals of higher genetic sharing between several southern districts. These results provide, for the first time, a picture of current within-country diversity of Tanzanian P. falciparum populations.

scholarly journals An evolutionary-based approach to quantify the genetic barrier to drug resistance in fast-evolving viruses: an application to HIV-1 subtypes and integrase inhibitors

2019 ◽  
Author(s):  
Kristof Theys ◽  
Pieter Libin ◽  
Kristel Van Laethem ◽  
Ana B Abecasis
Keyword(s):  
Drug Resistance ◽  
Antiviral Treatment ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Viral Pathogens ◽  
Subtype B ◽  
Genetic Potential ◽  
The Impact ◽  
Hiv 1

AbstractViral pathogens causing global disease burdens are often characterised by high rates of evolutionary changes, facilitating escape from therapeutic or immune selective pressure. Extensive viral diversity at baseline can shorten the time to resistance emergence and alter mutational pathways, but the impact of genotypic background on the genetic barrier can be difficult to capture, in particular for antivirals in experimental stages, recently approved or expanded into new settings. We developed an evolutionary-based counting method to quantify the population genetic potential to resistance and assess differences between populations. We demonstrate its applicability to HIV-1 integrase inhibitors, as their increasing use globally contrasts with limited availability of non-B subtype resistant sequences and corresponding knowledge gap on drug resistance. A large sequence dataset encompassing most prevailing subtypes and resistance mutations of first- and second-generation inhibitors were investigated. A varying genetic potential for resistance across HIV-1 subtypes was detected for 15 mutations at 12 positions, with notably 140S in subtype B, while 140C was discarded to vary across subtypes. An additional analysis for HIV-1 reverse transcriptase inhibitors identified a higher potential for 65R in subtype C, on the basis of a differential codon usage not reported before. The evolutionary interpretation of genomic differences for antiviral treatment remains challenging. Our framework advances existing counting methods with an increased sensitivity that identified novel subtype dependencies as well as rejected previous statements. Future applications include novel HIV-1 drug classes as well as other viral pathogens.

scholarly journals Characterizing HIV-1 Genetic Subtypes and Drug Resistance Mutations among Children, Adolescents and Pregnant Women in Sierra Leone

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1314
Author(s):  
George A. Yendewa ◽  
Sulaiman Lakoh ◽  
Sahr A. Yendewa ◽  
Khadijah Bangura ◽  
Andrés Tabernilla ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pregnant Women ◽  
Sierra Leone ◽  
Integrase Inhibitor ◽  
Sub Saharan Africa ◽  
Success Rates ◽  
Resistance Mutations ◽  
Cross Sectional ◽  
Susceptibility Score ◽  
Hiv 1

Human immunodeficiency virus (HIV) drug resistance (HIVDR) is widespread in sub-Saharan Africa. Children and pregnant women are particularly vulnerable, and laboratory testing capacity remains limited. We, therefore, used a cross-sectional design and convenience sampling to characterize HIV subtypes and resistance-associated mutations (RAMs) in these groups in Sierra Leone. In total, 96 children (age 2–9 years, 100% ART-experienced), 47 adolescents (age 10–18 years, 100% ART-experienced), and 54 pregnant women (>18 years, 72% ART-experienced) were enrolled. Median treatment durations were 36, 84, and 3 months, respectively, while the sequencing success rates were 45%, 70%, and 59%, respectively, among children, adolescents, and pregnant women. Overall, the predominant HIV-1 subtype was CRF02_AG (87.9%, 95/108), with minority variants constituting 12%. Among children and adolescents, the most common RAMs were M184V (76.6%, n = 49/64), K103N (45.3%, n = 29/64), Y181C/V/I (28.1%, n = 18/64), T215F/Y (25.0%, n = 16/64), and V108I (18.8%, n = 12/64). Among pregnant women, the most frequent RAMs were K103N (20.6%, n = 7/34), M184V (11.8%, n = 4/34), Y181C/V/I (5.9%, n = 2/34), P225H (8.8%, n = 3/34), and K219N/E/Q/R (5.9%, n = 2/34). Protease and integrase inhibitor-RAMs were relatively few or absent. Based on the genotype susceptibility score distributions, 73%, 88%, and 14% of children, adolescents, and pregnant women, respectively, were not susceptible to all three drug components of the WHO preferred first-line regimens per 2018 guidelines. These findings suggest that routine HIVDR surveillance and access to better ART choices may improve treatment outcomes in Sierra Leone.

scholarly journals Acquired HIV drug resistance mutations on first-line antiretroviral therapy in Southern Africa: Bayesian evidence synthesis

2020 ◽  
Author(s):  
Anthony Hauser ◽  
Fardo Goldstein ◽  
Martina L. Reichmuth ◽  
Roger Kouyos ◽  
Nicola Low ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Southern Africa ◽  
Evidence Synthesis ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
Drug Resistance Mutations

Background: Until 2019, first-line antiretroviral therapy (ART) in Southern Africa consisted of one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI). As a response to the increasing level of NNRTI resistance, these drugs are being replaced by dolutegravir (DTG), an integrase inhibitor with a high barrier to resistance. Patients failing an NNRTI-based regimen might therefore start DTG-based therapy with preexisting NRTI resistance, potentially jeopardizing the long-term success of DTG-based ART. We performed a systematic review and meta-analysis to quantify the prevalence of NRTI drug resistance mutations (DRMs) in patients failing NNRTI-based ART in Southern Africa. Methods: We searched several bibliographic databases, including Embase and Medline, from inception to May 2019 to identify studies reporting NRTI DRMs observed among adult HIV-positive patients experiencing virological failure on first-line NNRTI-based regimens in countries of Southern Africa. After screening titles and abstracts, two independent reviewers assessed full manuscripts of potentially eligible studies and extracted data. We developed a hierarchical logistic meta-regression model to synthesize the effect of different ART regimen on the emergence of NRTI and NNRTI DRMs across studies, accounting for ART duration and study-specific effects. Analyses were performed in a Bayesian framework using the rstan package in R.Results: Of 7,579 studies, 3,247 were duplicates and 4,135 were excluded after initial screening. After assessing 194 full-texts, we included 15 studies with 17 study samples and 2,432 individuals from South Africa (13 studies), Mozambique (1), Botswana (1), Lesotho (1) and Zambia (1). We analyzed the dynamics of nine NRTI DRMs by ART regimen. Baseline levels of DRMs were low, ranging from 0.2% to 7.8%. The use of emtricitabine/lamivudine was associated with development of high levels of the M184V/I mutation (1.2% at baseline vs. 64% after 3 years on treatment). When emtricitabine/lamivudine was combined with tenofovir disoproxil fumarate, a substantial increase in the K65R mutation (0.8% at baseline vs. 69.5% after 3 years) was observed. We also analyzed the dynamics of seven NNRTI DRMs after 3 years. With a prevalence of 45.6% after 3 years of efavirenz, K103 was the most prevalent NNRTI resistance mutation, followed by V106 (35.5% after 3 years of efavirenz) and Y181 (14.7% after 3 years of nevirapine).Interpretation: In patients failing first-line ART in Southern Africa, the prevalence of NRTI DRM is high, suggesting that a substantial proportion of patients failing NNRTI-based regimen will switch to DTG-based regimen with non-working NRTIs. This could potentially impair the long-term efficacy of DTG-introduction in Southern Africa.

scholarly journals Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment

2010 ◽  
Vol 55 (3) ◽  
pp. 1114-1119 ◽  
Author(s):  
Jia Liu ◽  
Michael D. Miller ◽  
Robert M. Danovich ◽  
Nathan Vandergrift ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Low Frequency ◽  
Hiv Treatment ◽  
Viral Population ◽  
Virologic Suppression ◽  
Resistance Mutations ◽  
The Difference ◽  
Allele Specific Sequencing ◽  
Hiv 1

ABSTRACTRaltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients,n= 36) and those who experienced virologic rebound (failure patients,n= 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

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