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Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 9384

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Dr. Alberto Borghetti

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Fondazione Policlinico Universitario Agostino Gemelli IRCCS, UOC Malattie Infettive, 00168 Rome, Italy
Interests: HIV; antiretroviral therapy; dual therapy; simplification antiretroviral therapy; HIV drug resistance; HIV-DNA
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Dear Colleagues,

The field of antiretroviral therapy has been steadily evolving in recent years. New potent antiretroviral drugs have allowed the use of two drugs-combinations for both naïve and treatment-experienced patients, alongside standard three-drug antiretroviral therapies. However, antiretroviral drugs-resistance and other viro-immunological factors (such as viral reservoir, viral subtypes, history of virological failure and therapeutic lines) can still play a role in influencing the risk of virological failure and therapy discontinuation. Moreover, since randomized trials typically exclude patients with those risk factors, clinicians involved in HIV field have few or no clues to safely optimize current antiretroviral therapies in a large proportion of patients with a long history of antiretroviral exposure (especially with previous virological failures), experiencing the burden of age-related, non-communicable diseases, toxicities from antiretroviral regimens and drug-drug interactions.

Besides clinical trials, cohort studies from the clinical practice, as well as in-vitro observations, are of paramount importance in characterizing the risk of virological failure with the newest treatment strategies. Since the advance of HIV Medicine relies on personalized, rather than standardized, treatment strategies, research should still focus on the role of drug resistances and other predictors of treatment success, in order to reach the goal of a patient-centred therapeutic approach.

Dr. Alberto Borghetti
Guest Editor

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Keywords

HIV
antiretroviral therapies
virological failure
HIV drug resistance
HIV reservoir
HIV viral subtype
predictors of virological failure

Related Special Issue

Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success: 2nd Edition in Viruses (4 articles)

Published Papers (7 papers)

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Research

10 pages, 614 KiB

Open AccessArticle

Low Prevalence of Pre-Treatment and Acquired Drug Resistance to Dolutegravir among Treatment Naïve Individuals Initiating on Tenofovir, Lamivudine and Dolutegravir in Zimbabwe

by Vinie Kouamou, Tendai Washaya, Chiratidzo Ellen Ndhlovu and Justen Manasa

Viruses 2023, 15(9), 1882; https://doi.org/10.3390/v15091882 - 05 Sep 2023

Cited by 2 | Viewed by 986

Abstract

Dolutegravir (DTG) use in combination with tenofovir and lamivudine (TLD) is scaling up in Africa. However, HIV drug resistance (HIVDR) data to DTG remain scarce in Zimbabwe. We assessed the prevalence and genetic mechanisms of DTG resistance in people living with HIV initiating on TLD. A prospective cohort study was conducted between October 2021 and April 2023 among antiretroviral therapy (ART) naïve adults (≥18 years) attending care at an HIV clinic in Zimbabwe. Pre-treatment drug resistance (PDR) was assessed prior to TLD initiation and viral load (VL) outcome and acquired drug resistance (ADR) to TLD were described after 24 weeks follow-up. In total, 172 participants were enrolled in the study. The median (IQR) age and log₁₀ VL were 39 (29–48) years and 5.41 (4.80–5.74) copies/mL, respectively. At baseline, no PDR to DTG was found. However, as previously reported, PDR to non-nucleotide reverse transcriptase inhibitor (NNRTI) was high (15%) whilst PDR to NRTI was low (4%). After a median duration of 27 (25–30) weeks on TLD, virological suppression (VL < 1000 copies/mL) was 98% and among the 2 participants with VL ≥ 1000 copies/mL, no ADR was found. HIVDR to DTG is rare among ART naïve individuals. DTG is more likely to address the problems of HIVDR in Africa. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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14 pages, 1854 KiB

Open AccessArticle

Laboratory Based Surveillance of HIV-1 Acquired Drug Resistance in Cameroon: Implications for Use of Tenofovir-Lamivudine-Dolutegravir (TLD) as Second- or Third-Line Regimens

by Joseph Fokam, Collins Ambe Chenwi, Desire Takou, Maria Mercedes Santoro, Valere Tala, George Teto, Grace Beloumou, Ezechiel Ngoufack Jagni Semengue, Beatrice Dambaya, Sandrine Djupsa, Etienne Kembou, Nounouce Pamen Bouba, Rogers Ajeh, Giulia Cappelli, Dora Mbanya, Vittorio Colizzi, Francesca Ceccherini-Silberstein, Carlo-Federico Perno and Alexis Ndjolo

Viruses 2023, 15(8), 1683; https://doi.org/10.3390/v15081683 - 02 Aug 2023

Cited by 1 | Viewed by 1117

Abstract

Increased HIV drug resistance (HIVDR) with antiretroviral therapy (ART) rollout may jeopardize therapeutic options, especially in this era of transition to fixed-dose tenofovir-lamivudine-dolutegravir (TLD). We studied acquired HIVDR (ADR) patterns and describe potentially active drugs after first- and second-line failure in resource-limited settings (RLS) like Cameroon. A laboratory-based study with 759 patients (≥15 years) experiencing virological failure was carried out at the Chantal Biya International Reference Centre (CIRCB), Yaoundé, Cameroon. Socio-demographic, therapeutic and immunovirological data from patient records were analysed according to HIV-1 genotypic profiles. Median (IQR) ART-duration was 63 (50–308) months. Median CD4 and viremia were 153 (IQR:50–308) cells/mm³ and 138,666 (IQR:28,979–533,066) copies/mL, respectively. Overall ADR was high (93.4% first-line; 92.9%-second-line). TDF, potentially active in 35.7% of participants after first-line and 45.1% after second-line, suggested sub-optimal TLD-efficacy in second-line (64.3%) and third-line (54.9%). All PI/r preserved high efficacy after first-line failure while only DRV/r preserved high-level efficacy (87.9%) after second-line failure. In this resource-limited setting (RLS), ADR is high in ART-failing patients. PI/r strategies remain potent backbones for second-line ART, while only DRV/r remains very potent despite second-line failure. Though TLD use would be preferable, blind use for second- and third-line regimens may be sub-optimal (functional monotherapy with dolutegravir) with high risk of further failure, thus suggesting strategies for selective ART switch to TLD in failing patients in RLS. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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17 pages, 1645 KiB

Open AccessArticle

Optimizing Antiretroviral Therapy in Heavily ART-Experienced Patients with Multi-Class Resistant HIV-1 Using Proviral DNA Genotypic Resistance Testing

by Dominic Rauschning, Ira Ehren, Eva Heger, Elena Knops, Gerd Fätkenheuer, Isabelle Suárez and Clara Lehmann

Viruses 2023, 15(7), 1444; https://doi.org/10.3390/v15071444 - 27 Jun 2023

Viewed by 923

Abstract

Resistance to multiple antiretroviral drugs among people living with HIV (PLWH) can result in a high pill burden, causing toxicity and drug interactions. Thus, the goal is to simplify treatment regimens while maintaining effectiveness. However, former resistance analysis data may not be current or complete. The use of proviral DNA genotyping may assist in selecting appropriate treatment options. A retrospective study was carried out on individuals belonging to the Cologne HIV cohort with a resistance history to two or more antiretroviral (ARV) classes and on non-standard antiretroviral therapy (ART). Patients required former viral RNA and a recent proviral DNA resistance test to be available prior to the switch to ART. Potential discrepancies between resistance test results obtained through RNA and proviral DNA methods and the consequent virological and clinical outcomes following ART adjustments were analyzed. Out of 1250 patients, 35 were eligible for inclusion in this study. The median length of known HIV infection was 27 years, and the median duration of ART was 22 years. Of the 35 participants, 16 had received all five ARV classes. Based on proviral DNA genotyping results, ART was simplified in 17 patients. At the last follow-up examination after changing therapy, 15 patients had HIV RNA <50 copies/mL (median 202 days, range 21–636). The mean number of pills per day decreased from eight to three, and the median intake frequency decreased from two to one time/day (ranges 1–2). Our study supports the use of proviral DNA genotyping as a safe strategy for switching to simplified ART regimens. However, the lack of extensive research on the advantages of proviral DNA genotyping makes it challenging to fully assess its benefits in terms of treatment selection. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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16 pages, 1986 KiB

Open AccessArticle

HIV-1 Drug Resistance among Treatment-Naïve Patients in Russia: Analysis of the National Database, 2006–2022

by Alina Kirichenko, Dmitry Kireev, Ilya Lapovok, Anastasia Shlykova, Alexey Lopatukhin, Anastasia Pokrovskaya, Marina Bobkova, Anastasiia Antonova, Anna Kuznetsova, Ekaterina Ozhmegova, Sergey Shtrek, Aleksej Sannikov, Natalia Zaytseva, Olga Peksheva, Michael Piterskiy, Aleksandr Semenov, Galina Turbina, Natalia Filoniuk, Andrey Shemshura, Valeriy Kulagin, Dmitry Kolpakov, Aleksandr Suladze, Valeriya Kotova, Lyudmila Balakhontseva, Vadim Pokrovsky and Vasiliy Akimkin Show full author list Hide full author list

Viruses 2023, 15(4), 991; https://doi.org/10.3390/v15040991 - 18 Apr 2023

Cited by 5 | Viewed by 1911

Abstract

In Russia, antiretroviral therapy (ART) coverage has significantly increased, which, in the absence of routine genotyping testing, could lead to an increase in HIV drug resistance (DR). The aim of this study was to investigate the patterns and temporal trends in HIV DR as well as the prevalence of genetic variants in treatment-naïve patients from 2006 to 2022, using data from the Russian database (4481 protease and reverse transcriptase and 844 integrase gene sequences). HIV genetic variants, and DR and DR mutations (DRMs) were determined using the Stanford Database. The analysis showed high viral diversity, with the predominance of A6 (78.4%), which was the most common in all transmission risk groups. The overall prevalence of surveillance DRMs (SDRMs) was 5.4%, and it reached 10.0% in 2022. Most patients harbored NNRTI SDRMs (3.3%). The prevalence of SDRMs was highest in the Ural (7.9%). Male gender and the CRF63_02A6 variant were association factors with SDRMs. The overall prevalence of DR was 12.7% and increased over time, primarily due to NNRTIs. Because baseline HIV genotyping is unavailable in Russia, it is necessary to conduct surveillance of HIV DR due to the increased ART coverage and DR prevalence. Centralized collection and unified analysis of all received genotypes in the national database can help in understanding the patterns and trends in DR to improve treatment protocols and increase the effectiveness of ART. Moreover, using the national database can help identify regions or transmission risk groups with a high prevalence of HIV DR for epidemiological measures to prevent the spread of HIV DR in the country. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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11 pages, 267 KiB

Open AccessArticle

Efficacy of Dolutegravir versus Darunavir in Antiretroviral First-Line Regimens According to Resistance Mutations and Viral Subtype

by Pierluigi Francesco Salvo, Damiano Farinacci, Arturo Ciccullo, Vanni Borghi, Stefano Rusconi, Annalisa Saracino, William Gennari, Bianca Bruzzone, Ilaria Vicenti, Annapaola Callegaro, Antonio Di Biagio, Maurizio Zazzi, Simona Di Giambenedetto and Alberto Borghetti

Viruses 2023, 15(3), 762; https://doi.org/10.3390/v15030762 - 16 Mar 2023

Cited by 1 | Viewed by 1248

Abstract

Background: Dolutegravir (DTG)-based first-line regimens have shown superior efficacy versus darunavir (DRV)-based ones in randomized trials. We compared these two strategies in clinical practice, particularly considering the role of pre-treatment drug resistance mutations (DRMs) and of the HIV-1 subtype. Materials and methods: The multicenter Antiretroviral Resistance Cohort Analysis (ARCA) database was queried to identify HIV-1-positive patients starting a first-line therapy with 2NRTIs plus either DTG or DRV between 2013 and 2019. Only adult (≥18 years) patients with a genotypic resistance test (GRT) prior to therapy and with HIV-1 RNA ≥1000 copies/mL were selected. Through multivariable Cox regressions, we compared DTG- versus DRV-based regimens in the time to virological failure (VF) stratifying for pre-treatment DRMs and the viral subtype. Results: A total of 649 patients was enrolled, with 359 (55.3%) and 290 (44.7) starting DRV and DTG, respectively. In 11 months of median follow-up time, there were 41 VFs (8.4 in 100 patient-years follow-up, PYFU) and 15 VFs (5.3 per 100 PYFU) in the DRV and DTG groups, respectively. Compared with a fully active DTG-based regimen, the risk of VF was higher with DRV (aHR 2.33; p = 0.016), and with DTG-based regimens with pre-treatment DRMs to the backbone (aHR 17.27; p = 0.001), after adjusting for age, gender, baseline CD4 count and HIV-RNA, concurrent AIDS-defining event and months since HIV diagnosis. Compared with patients harboring a B viral subtype and treated with a DTG-based regimen, patients on DRV had an increased risk of VF, both in subtype B (aHR 3.35; p = 0.011), C (aHR 8.10; p = 0.005), CRF02-AG (aHR 5.59; p = 0.006) and G (aHR 13.90; p < 0.001); DTG also demonstrated a reduced efficacy in subtypes C (versus B, aHR 10.24; p = 0.035) and CRF01-AE (versus B; aHR 10.65; p = 0.035). Higher baseline HIV-RNA and a longer time since HIV diagnosis also predicted VF. Conclusions: In line with randomized trials, DTG-based first-line regimens showed an overall superior efficacy compared with DRV-based regimens. GRT may still play a role in identifying patients more at risk of VF and in guiding the choice of an antiretroviral backbone. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

7 pages, 378 KiB

Open AccessCommunication

Women Living with HIV in Italian Prison Settings: Results from the Gender-Specific ROSE Network

by Elena Rastrelli, Vito Fiore, Roberto Ranieri, Emanuele Pontali, Tullio Prestileo, Giorgio Barbarini, Anna Maria Ialungo, Serena Dell’Isola, Andrea De Vito, Matteo Bolcato, Giordano Madeddu, Giulio Di Mizio, Giulio Starnini and Sergio Babudieri

Viruses 2023, 15(2), 497; https://doi.org/10.3390/v15020497 - 10 Feb 2023

Viewed by 1177

Abstract

Background: Incarcerated women are a minority in the Italian prison population. The lack of prevention and awareness of HIV infection and the lack of access to treatment make the treatment path difficult. Methods: we conducted a multi-center study including incarcerated women living with HIV (WLWH). Results: The study included 85 WLWH with a mean age of 41.7 ± 8.7 years, and 58.8% (50/85) of them were Italian. Principally, HIV transmission was related to sexual intercourse, 47% of all patients were PWIDs, and 62.5% of them were on opioid substitution therapy (OST). Overall, 56.4% of the included patients had a CD4+ cell count of >500 cells/mmc. Among the participants, 92.9% were on antiretroviral therapy, 87.3% had treatment before incarceration, and 83.5% were virologically suppressed. Among the 13 non-virally-suppressed patients, 53.8% were unaware of their serological status before incarceration and had started HAART but were still not virologically suppressed; 46.2% (6/13) had a lack of compliance or had suspended the treatment before incarceration and restarted it after admission. All patients with chronic hepatitis C underwent treatment with direct-acting antivirals and reached a sustained virological response. Conclusions: the detention of these women could represent an occasion for the patients’ healthcare provision and use, and the creation of a gender-specific network can be an effective strategy for reaching this population. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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13 pages, 2578 KiB

Open AccessArticle

Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART

by Maria Carolina Dos Santos Guedes, Wlisses Henrique Veloso Carvalho-Silva, José Leandro Andrade-Santos, Maria Carolina Accioly Brelaz-de-Castro, Fabrício Oliveira Souto and Rafael Lima Guimarães

Viruses 2023, 15(2), 440; https://doi.org/10.3390/v15020440 - 05 Feb 2023

Cited by 6 | Viewed by 1345

Abstract

Decades of studies in antiretroviral therapy (ART) have passed, and the mechanisms that determine impaired immunological recovery in HIV-positive patients receiving ART have not been completely elucidated yet. Thus, T-lymphocytes immunophenotyping and cytokines levels were analyzed in 44 ART-treated HIV-positive patients who had a prolonged undetectable plasma viral load. The patients were classified as immunological non-responders (INR = 13) and immunological responders (IR = 31), according to their CD4+ T cell levels. Evaluating pre-CD4+ levels, we observed a statistically significant trend between lower CD4+ T cell levels and INR status (Z = 3.486, p < 0.001), and during 18 months of ART, the CD4+ T cell levels maintained statistical differences between the INR and IR groups (WTS = 37.252, p < 0.001). Furthermore, the INRs were associated with an elevated age at ART start; a lower pre-treatment CD4+ T cell count and a percentage that remained low even after 18 months of ART; lower levels of recent thymic emigrant (RTE) CD4+ T cell (CD45RA + CD31+) and a naïve CD4+ T cell (CD45RA + CD62L+); higher levels of central memory CD4+ T cells (CD45RA-CD62L+); and higher immune activation by CD4+ expressing HLA-DR+ or both (HLA-DR+ and CD38+) when compared with IRs. Our study demonstrates that thymic exhaustion and increased immune activation are two mechanisms substantially implicated in the impaired immune recovery of ART-treated HIV patients. Full article

(This article belongs to the Special Issue Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success)

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