Advances in Research on HIV Drug Resistance and Other Determinants of Treatment Success: 2nd Edition

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

Deadline for manuscript submissions: 31 August 2024 | Viewed by 4301

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Guest Editor
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 treatment-naïve and -experienced patients, alongside standard three-drug antiretroviral therapies. However, antiretroviral drug 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 the 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 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 advancing HIV Medicine relies on personalized, rather than standardized, treatment strategies, research should still focus on the role of drug resistance and other predictors of treatment success, in order to reach the goal of a patient-centered 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

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Published Papers (4 papers)

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14 pages, 1928 KiB  
Article
Factors Associated with Virological Failure in First-Line Antiretroviral Therapy in Patients Diagnosed with HIV-1 between 2010 and 2018 in Israel
by Tali Wagner, Itzchak Levy, Daniel Elbirt, Eduardo Shahar, Karen Olshtain-Pops, Hila Elinav, Michal Chowers, Valery Istomin, Klaris Riesenberg, Dikla Geva, Neta S. Zuckerman, Marina Wax, Rachel Shirazi, Yael Gozlan, Natasha Matus, Shirley Girshengorn, Rotem Marom, Ella Mendelson, Orna Mor and Dan Turner
Viruses 2023, 15(12), 2439; https://doi.org/10.3390/v15122439 - 15 Dec 2023
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Abstract
Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study [...] Read more.
Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study of individuals on first-line ART diagnosed with HIV-1 in 2010–2018 and followed-up for a median of two years was conducted. Demographics, baseline and longitudinal CD4 counts, treatment regimens, adherence and VF were recorded. The Cox proportional hazards regression and mixed models were used. A cohort of 1130 patients were included. Overall, 80% were males and 62% were Israeli-born individuals. Compared to individuals diagnosed in 2010–2014, when treatment was initiated according to CD4 levels, those diagnosed in 2015–2018 were older and had lower baseline CD4 counts. VF was recorded in 66 (5.8%) patients. Diagnosis with CD4 <200 cells/mmᶟ with AIDS-defining conditions (HR = 2.75, 95%CI:1.52–4.97, p < 0.001) and non-integrase strand transfer inhibitor regimens (non-INSTI, HR = 1.80, 95%CI:1.01–3.24, p = 0.047) increased VF risk. No impact of baseline resistance was observed. We concluded that the early detection of HIV-1 infection and usage of INSTI-based regimens are recommended to reduce VF. Full article
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14 pages, 3465 KiB  
Article
Web Service for HIV Drug Resistance Prediction Based on Analysis of Amino Acid Substitutions in Main Drug Targets
by Anastasiia Iu. Paremskaia, Anastassia V. Rudik, Dmitry A. Filimonov, Alexey A. Lagunin, Vladimir V. Poroikov and Olga A. Tarasova
Viruses 2023, 15(11), 2245; https://doi.org/10.3390/v15112245 - 11 Nov 2023
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Abstract
Predicting viral drug resistance is a significant medical concern. The importance of this problem stimulates the continuous development of experimental and new computational approaches. The use of computational approaches allows researchers to increase therapy effectiveness and reduce the time and expenses involved when [...] Read more.
Predicting viral drug resistance is a significant medical concern. The importance of this problem stimulates the continuous development of experimental and new computational approaches. The use of computational approaches allows researchers to increase therapy effectiveness and reduce the time and expenses involved when the prescribed antiretroviral therapy is ineffective in the treatment of infection caused by the human immunodeficiency virus type 1 (HIV-1). We propose two machine learning methods and the appropriate models for predicting HIV drug resistance related to amino acid substitutions in HIV targets: (i) k-mers utilizing the random forest and the support vector machine algorithms of the scikit-learn library, and (ii) multi-n-grams using the Bayesian approach implemented in MultiPASSR software. Both multi-n-grams and k-mers were computed based on the amino acid sequences of HIV enzymes: reverse transcriptase and protease. The performance of the models was estimated by five-fold cross-validation. The resulting classification models have a relatively high reliability (minimum accuracy for the drugs is 0.82, maximum: 0.94) and were used to create a web application, HVR (HIV drug Resistance), for the prediction of HIV drug resistance to protease inhibitors and nucleoside and non-nucleoside reverse transcriptase inhibitors based on the analysis of the amino acid sequences of the appropriate HIV proteins from clinical samples. Full article
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11 pages, 1429 KiB  
Article
Features of Tat Protein in HIV-1 Sub-Subtype A6 Variants Circulating in the Moscow Region, Russia
by Anna Kuznetsova, Kristina Kim, Alexander Tumanov, Iana Munchak, Anastasiia Antonova, Aleksey Lebedev, Ekaterina Ozhmegova, Elena Orlova-Morozova, Elena Drobyshevskaya, Alexander Pronin, Aleksey Prilipov and Elena Kazennova
Viruses 2023, 15(11), 2212; https://doi.org/10.3390/v15112212 - 04 Nov 2023
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Abstract
Tat, the trans-activator of transcription, is a multifunctional HIV-1 protein that can induce chronic inflammation and the development of somatic diseases in HIV-infected patients. Natural polymorphisms in Tat can impact the propagation of the inflammatory signal. Currently, Tat is considered an object for [...] Read more.
Tat, the trans-activator of transcription, is a multifunctional HIV-1 protein that can induce chronic inflammation and the development of somatic diseases in HIV-infected patients. Natural polymorphisms in Tat can impact the propagation of the inflammatory signal. Currently, Tat is considered an object for creating new therapeutic agents. Therefore, the identification of Tat protein features in various HIV-1 variants is a relevant task. The purpose of the study was to characterize the genetic variations of Tat-A6 in virus variants circulating in the Moscow Region. The authors analyzed 252 clinical samples from people living with HIV (PLWH) with different stages of HIV infection. Nested PCR for two fragments (tat1, tat2) with subsequent sequencing, subtyping, and statistical analysis was conducted. The authors received 252 sequences for tat1 and 189 for tat2. HIV-1 sub-subtype A6 was identified in 250 samples. The received results indicated the features of Tat1-A6 in variants of viruses circulating in the Moscow Region. In PLWH with different stages of HIV infection, C31S in Tat1-A6 was detected with different occurrence rates. It was demonstrated that Tat2-A6, instead of a functional significant 78RGD80 motif, had a 78QRD80 motif. Herewith, G79R in Tat2-A6 was defined as characteristic amino acid substitution for sub-subtype A6. Tat2-A6 in variants of viruses circulating in the Moscow Region demonstrated high conservatism. Full article
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Systematic Review
HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis
by Fei Ouyang, Defu Yuan, Wenjing Zhai, Shanshan Liu, Ying Zhou and Haitao Yang
Viruses 2024, 16(2), 239; https://doi.org/10.3390/v16020239 - 02 Feb 2024
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Abstract
Background: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. [...] Read more.
Background: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. As SGS is gradually replaced by next-generation sequencing (NGS), it is necessary to assess the levels of PDR using NGS in ART-naïve patients systematically. NGS can detect the viral variants (low-abundance drug-resistant HIV-1 variants (LA-DRVs)) of virus quasi-species at levels below 20% that SGS may fail to detect. NGS has the potential to optimize current HIV drug resistance surveillance methods and inform future research directions. As the NGS technique has high sensitivity, it is highly likely that the level of pretreatment resistance would be underestimated using conventional techniques. Methods: For the systematic review and meta-analysis, we searched for original studies published in PubMed, Web of Science, Scopus, and Embase before 30 March 2023 that focused exclusively on the application of NGS in the detection of HIV drug resistance. Pooled prevalence estimates were calculated using a random effects model using the ‘meta’ package in R (version 4.2.3). We described drug resistance detected at five thresholds (>1%, 2%, 5%, 10%, and 20% of virus quasi-species). Chi-squared tests were used to analyze differences between the overall prevalence of PDR reported by SGS and NGS. Results: A total of 39 eligible studies were selected. The studies included a total of 15,242 ART-naïve individuals living with HIV. The prevalence of PDR was inversely correlated with the mutation detection threshold. The overall prevalence of PDR was 29.74% at the 1% threshold, 22.43% at the 2% threshold, 15.47% at the 5% threshold, 12.95% at the 10% threshold, and 11.08% at the 20% threshold. The prevalence of PDR to INSTIs was 1.22% (95%CI: 0.58–2.57), which is the lowest among the values for all antiretroviral drugs. The prevalence of LA-DRVs was 9.45%. At the 2% and 20% detection threshold, the prevalence of PDR was 22.43% and 11.08%, respectively. Resistance to PIs and INSTIs increased 5.52-fold and 7.08-fold, respectively, in those with a PDR threshold of 2% compared with those with PDR at 20%. However, resistance to NRTIs and NNRTIs increased 2.50-fold and 2.37-fold, respectively. There was a significant difference between the 2% and 5% threshold for detecting HIV drug resistance. There was no statistically significant difference between the results reported by SGS and NGS when using the 20% threshold for reporting resistance mutations. Conclusion: In this study, we found that next-generation sequencing facilitates a more sensitive detection of HIV-1 drug resistance than SGS. The high prevalence of PDR emphasizes the importance of baseline resistance and assessing the threshold for optimal clinical detection using NGS. Full article
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