Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.

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Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

F1000Research ◽

10.12688/f1000research.15995.2 ◽

2019 ◽

Vol 7 ◽

pp. 1359 ◽

Cited By ~ 3

Author(s):

Gilles Wandeler ◽

Marta Buzzi ◽

Nanina Anderegg ◽

Delphine Sculier ◽

Charles Béguelin ◽

...

Keyword(s):

Drug Resistance ◽

Viral Load ◽

Maintenance Therapy ◽

Virologic Failure ◽

Meta Analysis ◽

Dual Therapy ◽

Undetectable Viral Load ◽

Resistance Mutations ◽

Hiv Viral Load ◽

Acquired Drug Resistance

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Detectable viral load among HIV -1 positive pregnant women on ART (Option B +) in northern Tanzania: Baseline results from the HIVDR study

East Africa Science ◽

10.24248/easci-d-20-00009 ◽

2021 ◽

Vol 3 (1) ◽

pp. 44-50

Author(s):

Nicholaus Steven Mazuguni ◽

Festo Mazuguni ◽

Eva Prosper Muro

Keyword(s):

Drug Resistance ◽

Viral Load ◽

Virological Failure ◽

Virologic Failure ◽

Resistance Mutation ◽

Resistance Testing ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Hiv 1 ◽

Level Resistance

Introduction: In Tanzania, the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDEC) has implemented the Option B+ as one of the strategies to facilitate achievement of elimination of mother to child transmission of HIV. To prevent emergence of drug resistance mutations early identification of option B+ failure is critical. The emergence of drug resistance mutation and subsequent treatment failure poses a major concern for HIV program in low- and middle-income resource settings where treatment options are limited. Methodology: We recruited treatment naïve, treatment experienced HIV-1 positive pregnant women and those who had prophylaxis in their previous pregnancy in Kilimanjaro, northern Tanzania August 2016 to February 2017. Whole blood (2ml) for biochemistry, viral load and drug resistance testing were taken at baseline. ARV drug resistance testing was done on women with VL ≥ 1000 copies/ml. We used descriptive statistic and logistic regression to determine the strength of association between virologic outcome (virologic failure) and independent predictors. Results: One hundred and forty eight (148) pregnant HIV-positive women were enrolled in the study with mean age of 29.82 years (SD=6.17) from August, 2016 to February, 2017. Virologic failure was demonstrated in 34 (23%) with viral load ≥ 1,000 copies/ml. Genotyping results were available from 26 women, mutations associated with ARV resistance were detected in 23.1% (n = 6/26). Among the six women with ARV resistance mutation 4(66.7%) had high level resistance and 2(33.3%) had low level resistance. Among the 26 samples genotyped 15(58%) viruses were subtype A, while eight were subtype C (31%) and three subtypes D (11%). The most dominant drug resistance mutations against the reverse transcriptase inhibitors for the women with high level resistance were K103N, Y188L, D67N, K70R, M184V, T215F, K219EQ, and the low-level resistance was E138A. The older age was associated with virological failure compared to those who were < 20 year of age. Conclusion: Viral load testing should be done on women who were already on antiretroviral treatment on their first antenatal visit to ensure early detection of virological failure and enable clinicians to take an appropriate course of action on their management. Educational intervention on adherence should be targeted at an early stage to women with virological failure during pregnancy to reduce the emergence of HIV-1 drug resistance mutations.

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Effectiveness, Safety, and Costs of a Treatment Switch to Dolutegravir Plus Rilpivirine Dual Therapy in Treatment-Experienced HIV Patients

Annals of Pharmacotherapy ◽

10.1177/1060028017728294 ◽

2017 ◽

Vol 52 (1) ◽

pp. 11-18 ◽

Cited By ~ 25

Author(s):

José Luis Revuelta-Herrero ◽

Esther Chamorro-de-Vega ◽

Carmen Guadalupe Rodríguez-González ◽

Roberto Alonso ◽

Ana Herranz-Alonso ◽

...

Keyword(s):

Drug Interaction ◽

Viral Load ◽

Dual Therapy ◽

Art Adherence ◽

Integrase Inhibitors ◽

Resistance Mutations ◽

Safe Strategy ◽

Treatment Switch ◽

Effectiveness Endpoint ◽

All Treatment

Background: Evidence about the use of dolutegravir (DTG) and rilpivirine (RPV) as an antiretroviral therapy (ART) in treatment-experienced patients is scarce. Objective: To explore the effectiveness, safety, and costs of switching to a DTG plus RPV regimen in this population. Methods: This observational, prospective study included all treatment-experienced patients who switched to DTG plus RPV between November 2014 and July 2016. Patients were excluded if resistance mutations to integrase inhibitors or RPV were found. The effectiveness endpoint was the proportion of patients who achieved virological suppression (viral load [VL] <50 copies/mL) at week 48 (W48). Safety (incidence of adverse events leading to discontinuation and laboratory abnormalities), adherence, and costs were analyzed. Results: A total of 35 patients were included, and 91.4% were virologically suppressed at baseline. Patients were treated with ART for a median of 14 years (interquartile range = 7-20). At W48, 91.4% of patients were virologically suppressed (95% CI = 77.0-98.2). Two of the 3 patients not suppressed at baseline achieved undetectable VL at W48, and 2 patients discontinued DTG plus RPV (intolerance and a drug-drug interaction). None of the virologically suppressed patients at baseline showed virological rebound through W48. There were no significant changes in lipid, liver, and renal profiles. The proportion of patients with an ART adherence >90% increased from 65.6% to 93.8% ( P = 0.004). The annual per-patient ART costs dropped by €665 ( P = 0.265). Conclusions: Switching to DTG plus RPV seems to be an effective and safe strategy. Significant improvements in patients’ adherence and costs were achieved.

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“I’m not that good with taking pills every day”

HIV ◽

10.1093/med/9780190088316.003.0004 ◽

2020 ◽

pp. 29-36

Author(s):

Blake Max

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Virologic Failure ◽

Undetectable Viral Load ◽

New Drugs ◽

Hiv Resistance ◽

Antiretroviral Drug ◽

Extensive Drug Resistance ◽

Drug Regimens ◽

Resistance Tests

The treatment goal of antiretroviral therapy is to achieve and maintain an undetectable viral load. Patients on antiretroviral therapy who do not achieve this goal can develop drug resistance to one or more drugs in the regimen. Poor medication adherence is the most likely reason for virologic failure and the development of drug resistance. Development of new drugs and clinical availability of HIV resistance tests has given providers more options for treatment-experienced patients with extensive drug resistance. Evaluating patients with extensive drug resistance requires knowledge of previous antiretroviral drug regimens, previous drug resistance tests, and interpretation of those tests. Managing treatment-experienced patients can be complex and may require consultation with an HIV expert.

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Performance of a high-throughput next-generation sequencing method for analysis of HIV drug resistance and viral load

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa352 ◽

2020 ◽

Vol 75 (12) ◽

pp. 3510-3516 ◽

Cited By ~ 1

Author(s):

Jessica M Fogel ◽

David Bonsall ◽

Vanessa Cummings ◽

Rory Bowden ◽

Tanya Golubchik ◽

...

Keyword(s):

Drug Resistance ◽

Viral Load ◽

Next Generation Sequencing ◽

High Throughput ◽

Whole Genome ◽

Hiv Viral Load ◽

Viral Loads ◽

Viral Load Assay ◽

Generation Sequencing ◽

Hiv 1

Abstract Objectives To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Methods Plasma samples (n = 145) were obtained from HIV-positive MSM (HPTN 078). Samples were analysed using clinical assays (the ViroSeq HIV-1 Genotyping System and the Abbott RealTime HIV-1 Viral Load assay) and a research assay based on whole-genome NGS (veSEQ-HIV). Results HIV protease and reverse transcriptase sequences (n = 142) and integrase sequences (n = 138) were obtained using ViroSeq. Sequences from all three regions were obtained for 100 (70.4%) of the 142 samples using veSEQ-HIV; results were obtained more frequently for samples with higher viral loads (93.5% for 93 samples with >5000 copies/mL; 50.0% for 26 samples with 1000–5000 copies/mL; 0% for 23 samples with <1000 copies/mL). For samples with results from both methods, drug resistance mutations (DRMs) were detected in 33 samples using ViroSeq and 42 samples using veSEQ-HIV (detection threshold: 5.0%). Overall, 146 major DRMs were detected; 107 were detected by both methods, 37 were detected by veSEQ-HIV only (frequency range: 5.0%–30.6%) and two were detected by ViroSeq only. HIV viral loads estimated by veSEQ-HIV strongly correlated with results from the Abbott RealTime Viral Load assay (R2 = 0.85; n = 142). Conclusions The NGS-based veSEQ-HIV method provided results for most samples with higher viral loads, was accurate for detecting major DRMs, and detected mutations at lower levels compared with a method based on population sequencing. The veSEQ-HIV method also provided HIV viral load data.

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Expanded Spectrum of Antiretroviral-Selected Mutations in Human Immunodeficiency Virus Type 2

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa026 ◽

2020 ◽

Vol 221 (12) ◽

pp. 1962-1972 ◽

Cited By ~ 1

Author(s):

Philip L Tzou ◽

Diane Descamps ◽

Soo-Yon Rhee ◽

Dana N Raugi ◽

Charlotte Charpentier ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Amino Acid ◽

Meta Analysis ◽

Multiple Comparisons ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract Background HIV-1 and HIV-2 differ in their antiretroviral (ARV) susceptibilities and drug resistance mutations (DRMs). Methods We analyzed published HIV-2 pol sequences to identify HIV-2 treatment-selected mutations (TSMs). Mutation prevalences were determined by HIV-2 group and ARV status. Nonpolymorphic mutations were those in <1% of ARV-naive persons. TSMs were those associated with ARV therapy after multiple comparisons adjustment. Results We analyzed protease (PR) sequences from 483 PR inhibitor (PI)-naive and 232 PI-treated persons; RT sequences from 333 nucleoside RT inhibitor (NRTI)-naive and 252 NRTI-treated persons; and integrase (IN) sequences from 236 IN inhibitor (INSTI)-naive and 60 INSTI-treated persons. In PR, 12 nonpolymorphic TSMs occurred in ≥11 persons: V33I, K45R, V47A, I50V, I54M, T56V, V62A, A73G, I82F, I84V, F85L, L90M. In RT, 9 nonpolymorphic TSMs occurred in ≥10 persons: K40R, A62V, K70R, Y115F, Q151M, M184VI, S215Y. In IN, 11 nonpolymorphic TSMs occurred in ≥4 persons: Q91R, E92AQ, T97A, G140S, Y143G, Q148R, A153G, N155H, H156R, R231 5-amino acid insertions. Nine of 32 nonpolymorphic TSMs were previously unreported. Conclusions This meta-analysis confirmed the ARV association of previously reported HIV-2 DRMs and identified novel TSMs. Genotypic and phenotypic studies of HIV-2 TSMs will improve approaches to predicting HIV-2 ARV susceptibility and treating HIV-2–infected persons.

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Prevalence of viral load suppression, predictors of virological failure and patterns of HIV drug resistance after 12 and 48 months on first-line antiretroviral therapy: a national cross-sectional survey in Uganda

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz561 ◽

2020 ◽

Vol 75 (5) ◽

pp. 1280-1289

Author(s):

Deogratius Ssemwanga ◽

Juliet Asio ◽

Christine Watera ◽

Maria Nannyonjo ◽

Faridah Nassolo ◽

...

Keyword(s):

Drug Resistance ◽

Viral Load ◽

Virological Failure ◽

Dried Blood Spots ◽

Viral Load Suppression ◽

First Line ◽

Hiv Viral Load ◽

Cross Sectional Survey ◽

Cross Sectional ◽

Weighted Prevalence

Abstract Objectives We implemented the WHO cross-sectional survey protocol to determine rates of HIV viral load (VL) suppression (VLS), and weighted prevalence, predictors and patterns of acquired drug resistance (ADR) in individuals with virological failure (VF) defined as VL ≥1000 copies/mL. Methods We enrolled 547 and 1064 adult participants on first-line ART for 12 (±3) months (ADR12) and ≥48 months (ADR48), respectively. Dried blood spots and plasma specimens were collected for VL testing and genotyping among the VFs. Results VLS was 95.0% (95% CI 93.4%–96.5%) in the ADR12 group and 87.9% (95% CI 85.0%–90.9%) in the ADR48 group. The weighted prevalence of ADR was 96.1% (95% CI 72.9%–99.6%) in the ADR12 and 90.4% (95% CI 73.6–96.8%) in the ADR48 group, out of the 30 and 95 successful genotypes in the respective groups. Initiation on a zidovudine-based regimen compared with a tenofovir-based regimen was significantly associated with VF in the ADR48 group; adjusted OR (AOR) 1.96 (95% CI 1.13–3.39). Independent predictors of ADR in the ADR48 group were initiation on a zidovudine-based regimen compared with tenofovir-based regimens, AOR 3.16 (95% CI 1.34–7.46) and ART duration of ≥82 months compared with <82 months, AOR 1.92 (95% CI 1.03–3.59). Conclusions While good VLS was observed, the high prevalence of ADR among the VFs before they underwent the recommended three intensive adherence counselling (IAC) sessions followed by repeat VL testing implies that IAC prior to treatment switching may be of limited benefit in improving VLS.

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