Viruses

Research

15 pages, 3656 KiB

Open AccessArticle

Cardiometabolic Differences in People Living with HIV Receiving Integrase Strand Transfer Inhibitors Compared to Non-nucleoside Reverse Transcriptase Inhibitors: Implications for Current ART Strategies

by Wilhelm A. J. W. Vos, Nadira Vadaq, Vasiliki Matzaraki, Twan Otten, Albert L. Groenendijk, Marc J. T. Blaauw, Louise E. van Eekeren, Kees Brinkman, Quirijn de Mast, Niels P. Riksen, Anton F. H. Stalenhoef, Jan van Lunzen, Andre J. A. M. van der Ven, Willem L. Blok and Janneke E. Stalenhoef

Viruses 2024, 16(4), 582; https://doi.org/10.3390/v16040582 - 10 Apr 2024

Viewed by 1476

Abstract

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to [...] Read more.

In people living with HIV (PLHIV), integrase strand transfer inhibitors (INSTIs) are part of the first-line combination antiretroviral therapy (cART), while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are alternatives. Distinct cART regimens may variably influence the risk for non-AIDS comorbidities. We aimed to compare the metabolome and lipidome of INSTI and NNRTI-based regimens. The 2000HIV study includes asymptomatic PLHIV (n = 1646) on long-term cART, separated into a discovery cohort with 730 INSTI and 617 NNRTI users, and a validation cohort encompassing 209 INSTI and 90 NNRTI users. Baseline plasma samples from INSTI and NNRTI users were compared using mass spectrometry-based untargeted metabolomic (n = 500) analysis. Perturbed metabolic pathways were identified using MetaboAnalyst software. Subsequently, nuclear magnetic resonance spectroscopy was used for targeted lipoprotein and lipid (n = 141) analysis. Metabolome homogeneity was observed between the different types of INSTI and NNRTI. In contrast, higher and lower levels of 59 and 45 metabolites, respectively, were found in the INSTI group compared to NNRTI users, of which 77.9% (81/104) had consistent directionality in the validation cohort. Annotated metabolites belonged mainly to ‘lipid and lipid-like molecules’, ‘organic acids and derivatives’ and ‘organoheterocyclic compounds’. In pathway analysis, perturbed ‘vitamin B1 (thiamin) metabolism’, ‘de novo fatty acid biosynthesis’, ‘bile acid biosynthesis’ and ‘pentose phosphate pathway’ were detected, among others. Lipoprotein and lipid levels in NNRTIs were heterogeneous and could not be compared as a group. INSTIs compared to individual NNRTI types showed that HDL cholesterol was lower in INSTIs compared to nevirapine but higher in INSTIs compared to doravirine. In addition, LDL size was lower in INSTIs and nevirapine compared to doravirine. NNRTIs show more heterogeneous cardiometabolic effects than INSTIs, which hampers the comparison between these two classes of drugs. Targeted lipoproteomic and lipid NMR spectroscopy showed that INSTI use was associated with a more unfavorable lipid profile compared to nevirapine, which was shifted to a more favorable profile for INSTI when substituting nevirapine for doravirine, with evidently higher fold changes. The cardiovascular disease risk profile seems more favorable in INSTIs compared to NNRTIs in untargeted metabolomic analysis using mass-spectrometry. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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8 pages, 739 KiB

Open AccessCommunication

Dolutegravir + Lamivudine vs. Dolutegravir + Tenofovir Disoproxil Fumarate/Emtricitabine: Very-Low-Level HIV-1 Replication through 144 Weeks in the GEMINI-1 and GEMINI-2 Studies

by Mark Underwood, Rimgaile Urbaityte, Ruolan Wang, Joe Horton, James Oyee, Brian Wynne, Dainielle Fox, Bryn Jones, Choy Man and Jörg Sievers

Viruses 2024, 16(3), 405; https://doi.org/10.3390/v16030405 - 6 Mar 2024

Viewed by 1591

Abstract

In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott’s RealTime HIV-1 assay provides quantitative VL (40–10,000,000 copies/mL) and qualitative target detected or target not [...] Read more.

In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott’s RealTime HIV-1 assay provides quantitative VL (40–10,000,000 copies/mL) and qualitative target detected or target not detected (TND) for VL < 40 copies/mL. This post hoc analysis assessed very-low-level viremia and “blips” through Week 144. Proportions with VL < 40 copies/mL and TND are presented overall and by baseline VL and CD4+ cell count. “Blips” (single VL ≥ 50 to <200 copies/mL with adjacent values < 50 copies/mL) were assessed from Day 1 after VL suppression and from Weeks 48 through to 144. Proportions with TND increased through Week 48 and were similar between groups at all visits (Week 144: dolutegravir + lamivudine, 451/716 [63%]; dolutegravir + TDF/FTC, 465/717 [65%]). By observed analysis, TND rates were similar between groups across baseline subgroups. Through Week 144, proportions with ≥1 “blip” were generally comparable for dolutegravir + lamivudine vs. dolutegravir + TDF/FTC from Day 1 (15% vs. 20%) and from Week 48 (7% vs. 11%). Through 144 weeks, the proportions with TND or “blips” were similar between dolutegravir + lamivudine and the three-drug comparator, reinforcing the efficacy and durability of dolutegravir + lamivudine. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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13 pages, 863 KiB

Open AccessArticle

DOLAMA 200: Effectiveness and Safety of a Dual Therapy with Dolutegravir Plus Lamivudine in Treatment-Experienced HIV-1 Infected Real World Participants in Spain

by Sergio Sequera-Arquelladas, Carmen Hidalgo-Tenorio, Luis López-Cortés, Alicia Gutiérrez, Jesús Santos, Francisco Téllez, Mohamed Omar, Sergio Ferra-Murcia, Elisa Fernández, Rosario Javier, Coral García-Vallecillos and Juan Pasquau

Viruses 2024, 16(2), 259; https://doi.org/10.3390/v16020259 - 6 Feb 2024

Cited by 1 | Viewed by 1432

Abstract

The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the setting of the viral suppression of treatment-experienced patients with the emerging evidence of the [...] Read more.

The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the setting of the viral suppression of treatment-experienced patients with the emerging evidence of the effectiveness and safety of dual therapies. The aim of this study is to determine the antiviral efficacy and safety of switching to Dolutegravir + Lamivudine in people living with HIV, and to analyze the rate of patients with virologic failure (VF). A total of 200 patients were included with a median age of 51 years, 189 cells/µL of nadir CD4+, 13 years on ART and four previous ART regimens. Among the 168 patients who completed a follow-up at 48 weeks, a total of five VFs occurred, resulting in a 2.98% (5/168) VF rate. The results of the intention-to-treat analysis were a VF rate of 2.54% (5/197), and the rate of patients/year with viral suppression was 98.3% (298/303) in the observed data analysis. We observed a significant improvement in mean CD4 lymphocytes, the CD4/CD8 ratio and lipid profiles. The optimization of ART to DTG plus 3TC is a cost-effective switch option for treatment-experienced HIV patients, and also improves their lipid profiles. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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12 pages, 574 KiB

Open AccessArticle

Virological Findings and Treatment Outcomes of Cases That Developed Dolutegravir Resistance in Malawi’s National HIV Treatment Program

by Hope Kanise, Joep J. van Oosterhout, Pachawo Bisani, John Songo, Bilaal W. Matola, Chifundo Chipungu, Katherine Simon, Carrie Cox, Mina C. Hosseinipour, Jean-Batiste Sagno, Risa M. Hoffman, Claudia Wallrauch, Sam Phiri, Kim Steegen, Andreas Jahn, Rose Nyirenda and Tom Heller

Viruses 2024, 16(1), 29; https://doi.org/10.3390/v16010029 - 23 Dec 2023

Cited by 2 | Viewed by 1803

Abstract

Millions of Africans are on dolutegravir-based antiretroviral therapy (ART), but few detailed descriptions of dolutegravir resistance and its clinical management exist. We reviewed HIV drug resistance (HIVDR) testing application forms submitted between June 2019 and October 2022, data from the national HIVDR database, [...] Read more.

Millions of Africans are on dolutegravir-based antiretroviral therapy (ART), but few detailed descriptions of dolutegravir resistance and its clinical management exist. We reviewed HIV drug resistance (HIVDR) testing application forms submitted between June 2019 and October 2022, data from the national HIVDR database, and genotypic test results. We obtained standardized ART outcomes and virological results of cases with dolutegravir resistance, and explored associations with dolutegravir resistance among individuals with successful integrase sequencing. All cases were on two nucleoside reverse transcriptase inhibitors (NRTIs)/dolutegravir, and had confirmed virological failure, generally with prolonged viremia. Among 89 samples with successful integrase sequencing, 24 showed dolutegravir resistance. Dolutegravir resistance-associated mutations included R263K (16/24), E138K (7/24), and G118R (6/24). In multivariable logistic regression analysis, older age and the presence of high-level NRTI resistance were significantly associated with dolutegravir resistance. After treatment modification recommendations, four individuals (17%) with dolutegravir resistance died, one self-discontinued ART, one defaulted, and one transferred out. Of the 17 remaining individuals, 12 had follow-up VL results, and 11 (92%) were <1000 copies/mL. Twenty-four cases with dolutegravir resistance among 89 individuals with confirmed virological failure suggests a considerable prevalence in the Malawi HIV program. Successful management of dolutegravir resistance was possible, but early mortality was high. More research on the management of treatment-experienced individuals with dolutegravir resistance is needed. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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12 pages, 397 KiB

Open AccessArticle

Uptake of Oral HIV Pre-Exposure Prophylaxis (PrEP) and Associated Factors among Female Sex Workers in Tanga, Tanzania

by Veronica O. Martin, Novatus A. Tesha and Bruno F. Sunguya

Viruses 2023, 15(10), 2125; https://doi.org/10.3390/v15102125 - 20 Oct 2023

Cited by 1 | Viewed by 1661

Abstract

Pre-exposure prophylaxis (PrEP) prevents HIV infection among female sex workers (FSW). WHO recommends the use of Tenofovir disoproxil fumarate for use in oral PrEP regimens (TDF). Emtricitabine (FTC) 200 mg/Tenofovir Disoproxil Fumarate (TDF) 300 mg (Truvada) daily is the approved PrEP regimen in [...] Read more.

Pre-exposure prophylaxis (PrEP) prevents HIV infection among female sex workers (FSW). WHO recommends the use of Tenofovir disoproxil fumarate for use in oral PrEP regimens (TDF). Emtricitabine (FTC) 200 mg/Tenofovir Disoproxil Fumarate (TDF) 300 mg (Truvada) daily is the approved PrEP regimen in Tanzania. Evidence is limited on oral PrEP uptake and its associated factors in countries with a high burden of HIV, such as Tanzania. This study aimed to examine the uptake of oral PrEP and its associated factors among FSW in the Tanga region of Tanzania. This community-based cross-sectional study was conducted among 428 FSW. Data were collected through face-to-face interviews and analysed using STATA version 17 and RDSAT. Logistic regression was used to examine the associations of independent factors and PrEP uptake among study participants. About 55% of the recruited FSW used oral PrEP. FSW with three or more children were 2.41 times more likely to take oral PrEP (AOR 2.41, 95% CI: 1.08–4.25, p < 0.05). Moreover, those with a positive attitude were more likely to use oral PrEP (AOR 2.8, 95% CI: 1.88–4.17, p < 0.05). Poor belief was a barrier to PrEP use, and side effects of the drugs were a reason for the discontinuation of PrEP services. Most of the participants preferred PrEP services to be provided in the community. Oral PrEP uptake was 55%. Efforts to scale up PrEP for FSW should address misconceptions regarding PrEP, PrEP sensitization, and improving access through community-based intervention. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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15 pages, 1309 KiB

Open AccessArticle

HIV Drug Resistance Patterns and Characteristics Associated with Clinically Significant Drug Resistance among Children with Virologic Failure on Antiretroviral Treatment in Kenya: Findings from the Opt4Kids Randomized Controlled Trial

by Lisa Abuogi, Patrick Oyaro, Garoma Wakjira, Katherine K. Thomas, Andrea J. Scallon, Irene Mukui, Bhavna H. Chohan, Evelyn Brown, Enericah Karauki, Nashon Yongo, Bilaal Ahmed, Shukri A. Hassan, James Wagude, Eunice Kinywa, Linda Otieno, Leonard Kingwara, Boaz Oyaro, Lisa M. Frenkel, Grace John-Stewart and Rena C. Patel

Viruses 2023, 15(10), 2083; https://doi.org/10.3390/v15102083 - 12 Oct 2023

Cited by 2 | Viewed by 2041

Abstract

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1–14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) [...] Read more.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1–14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for virologic failure (VF) (≥1000 copies/mL)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; the median age was 9 years (interquartile range (IQR) 7, 12), 344 (49%) were female, and the median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associated with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual-class resistance. A history of VF in the prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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11 pages, 550 KiB

Open AccessArticle

Retention in Care and Virological Failure among Adult HIV-Positive Patients on First-Line Antiretroviral Treatment in Maputo, Mozambique

by Leonid Joaquim, Mafalda N. S. Miranda, Victor Pimentel, Maria do Rosario Oliveira Martins, Tacilta Nhampossa, Ana Abecasis and Marta Pingarilho

Viruses 2023, 15(10), 1978; https://doi.org/10.3390/v15101978 - 22 Sep 2023

Cited by 2 | Viewed by 1483

Abstract

Introduction: Access to antiretroviral treatment (ART) is increasingly available worldwide; however, the number of patients lost to follow-up and number of treatment failures continue to challenge most African countries. Objectives: To analyse the retention in clinical care and the virological response and their [...] Read more.

Introduction: Access to antiretroviral treatment (ART) is increasingly available worldwide; however, the number of patients lost to follow-up and number of treatment failures continue to challenge most African countries. Objectives: To analyse the retention in clinical care and the virological response and their associated factors of HIV-1 patients from the Maputo Military Hospital (MMH). Methods: A cross-sectional observational study was conducted to analyse data from patients who started ART between 2016 and 2018 in the MMH. Results: At the end of 12 months, 75.1% of 1247 patients were active on clinical follow-up and 16.8% had suspected virologic failure (VL > 1000 copies/mm³). Patients younger than 40 years old were more likely to be lost to follow-up when compared to those aged >50 years old, as well as patients who were unemployed and patients with a CD4 count < 350 cells/mm³. Patients with haemoglobin levels lower than 10 g/dL and with a CD4 count < 350 cells/mm³ were more likely to have virological failure. Conclusions: We have identified clinical and sociodemographic determinants of loss to follow-up and in the development of virological failure for HIV-positive patients in clinical care in the MMH. Therefore, HIV programs must consider these factors to increase the screening of patients at high risk of poor outcomes and particularly to strengthen adherence counselling programs. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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12 pages, 1108 KiB

Open AccessArticle

Sensitive HIV-1 DNA Pol Next-Generation Sequencing for the Characterisation of Archived Antiretroviral Drug Resistance

by Johannes C. Botha, Matthew Byott, Moira J. Spyer, Paul R. Grant, Kathleen Gärtner, Wilson X. Chen, James Burton, Alasdair Bamford, Laura J. Waters, Carlo Giaquinto, Anna Turkova, Cindy L. Vavro and Eleni Nastouli

Viruses 2023, 15(9), 1811; https://doi.org/10.3390/v15091811 - 25 Aug 2023

Cited by 1 | Viewed by 1940

Abstract

Modern HIV-1 treatment effectively suppresses viral amplification in people living with HIV. However, the persistence of HIV-1 DNA as proviruses integrated into the human genome remains the main barrier to achieving a cure. Next-generation sequencing (NGS) offers increased sensitivity for characterising archived drug [...] Read more.

Modern HIV-1 treatment effectively suppresses viral amplification in people living with HIV. However, the persistence of HIV-1 DNA as proviruses integrated into the human genome remains the main barrier to achieving a cure. Next-generation sequencing (NGS) offers increased sensitivity for characterising archived drug resistance mutations (DRMs) in HIV-1 DNA for improved treatment options. In this study, we present an ultra-sensitive targeted PCR assay coupled with NGS and a robust pipeline to characterise HIV-1 DNA DRMs from buffy coat samples. Our evaluation supports the use of this assay for Pan-HIV-1 analyses with reliable detection of DRMs across the HIV-1 Pol region. We propose this assay as a new valuable tool for monitoring archived HIV-1 drug resistance in virologically suppressed individuals, especially in clinical trials investigating novel therapeutic approaches. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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15 pages, 2365 KiB

Open AccessArticle

High-Level Drug-Resistant Mutations among HIV-1 Subtype A6 and CRF02_AG in Kazakhstan

by Ainur Sanaubarova, Emma Pujol-Hodge, Natalya Dzissyuk, Philippe Lemey, Sten H. Vermund, Andrew J. Leigh Brown and Syed Ali

Viruses 2023, 15(7), 1407; https://doi.org/10.3390/v15071407 - 21 Jun 2023

Cited by 3 | Viewed by 2199

Abstract

HIV incidence in Kazakhstan increased by 73% between 2010 and 2020, with an estimated 35,000 people living with HIV (PLHIV) in 2020. The development of antiretroviral drug resistance is a major threat to effective antiretroviral therapy (ART), yet studies on the prevalence of [...] Read more.

HIV incidence in Kazakhstan increased by 73% between 2010 and 2020, with an estimated 35,000 people living with HIV (PLHIV) in 2020. The development of antiretroviral drug resistance is a major threat to effective antiretroviral therapy (ART), yet studies on the prevalence of drug resistance in Kazakhstan are sparse. In this study on the molecular epidemiology of HIV in Kazakhstan, we analyzed 968 partial HIV-1 pol sequences that were collected between 2017 and 2020 from PLHIV across all regions of Kazakhstan, covering almost 3% of PLHIV in 2020. Sequences predominantly represented subtypes A6 (57%) and CRF02_AG (41%), with 32% of sequences exhibiting high-level drug resistance. We further identified distinct drug-resistant mutations (DRMs) in the two subtypes: subtype A6 showed a propensity for DRMs A62V, G190S, K101E, and D67N, while CRF02_AG showed a propensity for K103N and V179E. Codon usage analysis revealed that different mutational pathways for the two subtypes may explain the difference in G190S and V179E frequencies. Phylogenetic analysis highlighted differences in the timing and geographic spread of both subtypes within the country, with A62V-harboring subtype A6 sequences clustering on the phylogeny, indicative of sustained transmission of the mutation. Our findings suggest an HIV epidemic characterized by high levels of drug resistance and differential DRM frequencies between subtypes. This emphasizes the importance of drug resistance monitoring within Kazakhstan, together with DRM and subtype screening at diagnosis, to tailor drug regimens and provide effective, virally suppressive ART. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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Review

Jump to: Research, Other

24 pages, 375 KiB

Open AccessReview

Treatment Management Challenges in Naïve and Experienced HIV-1-Infected Individuals Carrying the M184V Mutation

by Iordanis Mimtsoudis, Olga Tsachouridou, Karolina Akinosoglou and Symeon Metallidis

Viruses 2024, 16(9), 1392; https://doi.org/10.3390/v16091392 - 30 Aug 2024

Viewed by 704

Abstract

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in [...] Read more.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

21 pages, 370 KiB

Open AccessReview

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings

by Cassidy Henegar, Emilio Letang, Ruolan Wang, Charles Hicks, Dainielle Fox, Bryn Jones, Annemiek de Ruiter and Vani Vannappagari

Viruses 2023, 15(12), 2426; https://doi.org/10.3390/v15122426 - 14 Dec 2023

Cited by 3 | Viewed by 1900

Abstract

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on [...] Read more.

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

Other

Jump to: Research, Review

28 pages, 1573 KiB

Open AccessSystematic Review

Current ARTs, Virologic Failure, and Implications for AIDS Management: A Systematic Review

by Frank Eric Tatsing Foka and Hazel Tumelo Mufhandu

Viruses 2023, 15(8), 1732; https://doi.org/10.3390/v15081732 - 13 Aug 2023

Cited by 9 | Viewed by 3157

Abstract

Antiretroviral therapies (ARTs) have revolutionized the management of human immunodeficiency virus (HIV) infection, significantly improved patient outcomes, and reduced the mortality rate and incidence of acquired immunodeficiency syndrome (AIDS). However, despite the remarkable efficacy of ART, virologic failure remains a challenge in the [...] Read more.

Antiretroviral therapies (ARTs) have revolutionized the management of human immunodeficiency virus (HIV) infection, significantly improved patient outcomes, and reduced the mortality rate and incidence of acquired immunodeficiency syndrome (AIDS). However, despite the remarkable efficacy of ART, virologic failure remains a challenge in the long-term management of HIV-infected individuals. Virologic failure refers to the persistent detectable viral load in patients receiving ART, indicating an incomplete suppression of HIV replication. It can occur due to various factors, including poor medication adherence, drug resistance, suboptimal drug concentrations, drug interactions, and viral factors such as the emergence of drug-resistant strains. In recent years, extensive efforts have been made to understand and address virologic failure in order to optimize treatment outcomes. Strategies to prevent and manage virologic failure include improving treatment adherence through patient education, counselling, and supportive interventions. In addition, the regular monitoring of viral load and resistance testing enables the early detection of treatment failure and facilitates timely adjustments in ART regimens. Thus, the development of novel antiretroviral agents with improved potency, tolerability, and resistance profiles offers new options for patients experiencing virologic failure. However, new treatment options would also face virologic failure if not managed appropriately. A solution to virologic failure requires a comprehensive approach that combines individualized patient care, robust monitoring, and access to a range of antiretroviral drugs. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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9 pages, 675 KiB

Open AccessBrief Report

Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144

by Ruolan Wang, Jonathan Wright, Parminder Saggu, Mounir Ait-Khaled, Riya Moodley, Chris M. Parry, Thomas Lutz, Daniel Podzamczer, Richard Moore, Miguel Górgolas Hernández-Mora, Clifford Kinder, Brian Wynne, Jean van Wyk and Mark Underwood

Viruses 2023, 15(6), 1350; https://doi.org/10.3390/v15061350 - 11 Jun 2023

Cited by 2 | Viewed by 1987

Abstract

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance [...] Read more.

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society–USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144. Full article

(This article belongs to the Special Issue Current ART, Virologic Failure and Implications for HIV Drug Resistance)

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