Open research questions in HIV/AIDS drug development and treatment

What the literature leaves open

• engine based on WHO 2021 consolidated treatment guidelines which links resistance probability profiles to named regimens using an ordered rule layer, and is fully auditable and traceable. Patient- level explanations are created using SHAP TreeExplainer waterfall plots for specific predictions and counterfactual analysis which highlights the minimum changes in the modifiable clinical features required to move a resistant prediction to one of susceptibility. Unlike static classifiers, the system has a temporal dimension as it allows to track visit data longitudinally over time for modeling the trend of CD4 and viral load over the course of treatment. The system generates auxiliary clinical parameters in addition to predicting resistance and recommending treatment, which helps to make the system more interpretable. The level of HIV disease is classified according to the CD4 count thresholds established by the WHO, which put patients into the following disease stages: asymptomatic, mild, advanced, and severe (AIDS). In addition, an estimated HIV subtype is inferred by a rule- based scoring mechanism based on known mutation patterns reported in the literature in the Stanford HIV Drug Resistance Database. Because they were not explicitly annotated as subtypes in the dataset, these predictions are considered estimates and associated with a level of confidence. A. Data Sources and Overview ViralGuide's data was gathered from multiple existing and independently managed data sources to provide both breadth and reliability of both the source data and the data being represented. The primary resource of genotype information that was utilized was a database of curated genome sequences maintained by Stanford University, HIV Drug Resistance Database (HIVDR) [10] that included mutation data for individual patients collected from various clinical settings. This data was augmented with HIV Sequence Database (HIVdb) data [11] from Los Alamos National Laboratory, a large database that includes sequencing data for virus strains and mutations that exist in genetically distinct populations. Thus, this source provided additional variability in the training dataset as compared to a single isolated population dataset. Data on clinical and behavior were obtained from the databases of WHO and CDC. The data was further enriched with observational data from public health cohort studies conducted in resource-limited settings, so that the data was not just from controlled clinical trial populations. The dataset comes in assembled patient records, each represented by three types of data. Patient characteristics comprise unique identifier, age and gender. Clinical measurements cover viral load, CD4 cell count and adherence level recorded as a normal

  Viralguide: Drug-Class-Level HIV Resistance Prediction using Bidirectional LSTM, Xgboost Ensemble and Cross-Modal Attention Fusion · 2026 · DOI

• Another similar study had conflicting findings with a lower overall prevalence of adverse drug reaction with the most common adverse drug being lipodystrophy [26].

  Evaluation of time to first adverse drug reaction among treatment-experienced adult persons living with HIV/AIDS: a retrospective cohort study · 2026 · DOI

• Despite the advent of newer NNRTIs with improved safety and higher resistance barriers (e.g., rilpivirine, doravirine) and integrase strand transfer inhibitors (INSTIs), nevirapine retains relevance in certain settings due to cost and into optimized combination strategies, especially in resource-limited regions, and pharmacogenomics to predict adverse risk could refine its clinical utility. availability. Continued research CONCLUSION Nevirapine is the first representative of a new class of antiretroviral compounds, non-nucleoside reverse transcriptase inhibitors, approved for use in HW-1 -infected individuals. Although clinical endpoint data were not completed, analysis of surrogate marker data indicates that nevirapine is therapy in combination with nucleosides is rapid and common when intravenously. When used associated with sustained antiviral and CD4 cell counts. Nevirapine is synergistic, and can be used safely with nucleoside analogs. Resistance to is nevirapine in administered combination with one or more nucleosides at the recommended dose, the development of clinically reduced or delayed. relevant Nevirapine is a stable and bioavailable substance that penetrates most tissues, including the central favorable nervous pharmacokinetics, allowing to be administered twice daily, except for the predictable and usually mild to moderate rash, nevirapine is safe and very well tolerated with few other side effects. resistance system. has is

  Nevirapine In Antiretroviral Therapy: A Concise Overview · 2026 · DOI

• Other CCD polymorphisms, including G134N and K136Q, may similarly affect DTG binding stability in non-B subtypes, however, their specic effects remain to be investigated.

  Effect of naturally occurring polymorphisms on HIV-1 integrase structure and dolutegravir binding in subtypes A1 and D · 2026 · DOI

• 32 Although our cohort was relatively young, the number of children was insufficient to draw firm conclusions regarding outcomes in those weighing < 14 kg.

  Early outcomes of South African children with persistent viral non-suppression following switch to dolutegravir-based antiretroviral therapy · 2026 · DOI

• ICH Q2(R2) accordance with confirmed excellent specificity, linearity, precision, accuracy, robustness, and sensitivity, demonstrating its suitability for quantitative pharmaceutical analysis. The forced degradation studies further established the stability-indicating capability of the method by effectively resolving the analytes from their degradation products under various stress conditions. In addition, the successful assay of the marketed formulation verified the applicability of the method for routine analysis. Owing to its rapid analysis, low solvent consumption, high reproducibility, and regulatory compliance, the proposed UPLC method represents a reliable and efficient analytical tool for routine quality control, stability evaluation, formulation development, and batch release tes. REFERENCES 1. Karunakaran A, Kamarajan K, Thangarasu V. Development and validation of first-derivative spectrophotometric method for the simultaneous estimation of Lamivudine and Tenofovir Disoproxil Fumarate in pure and tablet dosage form. Der Pharm Lett, 2010; 2(5): 221–228. 2. Bennetto-Hood C, Tabolt G, Savina P, Acosta EP. A sensitive and selective LC–MS/MS method for the determination of Dolutegravir in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci, 2014; 945–946: 225–232. 3. Hamrapurkar PD, Phale MD, Shah NS. Quantitative estimation of Efavirenz by high-performance thin- layer chromatography. J Young Pharm, 2009; 1(4): 356–361. 4. Sentenac S, Fernandez C, Thuillier A, Lechat P, Aymard G. Sensitive determination of Tenofovir in human liquid chromatography. J Chromatogr B, 2003; 793(2): 317–324. reversed-phase plasma by 5. Delahunty T, Bushman L, Fletcher CV. Sensitive

  DEVELOPMENT AND VALIDATION OF A STABILITY-INDICATING UPLC METHOD FOR THE SIMULTANEOUS ESTIMATION OF LAMIVUDINE AND DOLUTEGRAVIR IN BULK AND PHARMACEUTICAL DOSAGE FORMS · 2026 · DOI

• Notably, individuals aged ≥ 50 years constituted a substantial proportion of clustered cases, but the age–clustering association was attenuated in multivariate analysis, indicating that older populations may represent an underrecognized prevention priority rather than an independent driver of clustering.

  Genetic diversity, drug resistance, and molecular transmission networks of HIV-1 in Zunyi: implications for precision prevention · 2026 · DOI

• In contrast to HIV-1, few data exist to guide second-line therapy decisions for PLWH2, and the existing HIV-2 genotypic resis- tance algorithms are not supported by robust clinical or phenotypic resistance datasets.

  Phenotypic impacts of treatment-selected mutations in HIV-2 protease on darunavir and lopinavir susceptibility: Evaluating genotypic HIV-2 drug resistance tools · 2026 · DOI

• The first challenge of limited sampling and insufficient data can profoundly impact efforts to characterize HIV-1 genetic diversity in the MENA region.

  Challenges in Elucidating HIV-1 Genetic Diversity in the Middle East and North Africa: A Review Based on a Systematic Search · 2025 · DOI

• however, data on the efficacy and safety of transitioning virologically suppressed patients to DtG/3tc are lacking.

  Efficacy and metabolic outcomes of switching from an INSTI-based triple-drug regimen to dolutegravir/lamivudine in treatment-experienced HIV-1-infected patients: a 48-week real-world study · 2026 · DOI

• However, given the small sample size and observational study design, generalisabilty of the data is limited.

  Early outcomes of South African children with persistent viral non-suppression following switch to dolutegravir-based antiretroviral therapy · 2026 · DOI

• Valganciclovir, an oral prodrug of ganciclovir, treats CMV in immunocompromised patients, but pharmacokinetic data in infants living with HIV are lacking.

  Pharmacokinetics and pharmacodynamics of valganciclovir in infants with severe HIV-associated pneumonia in Africa: a sub-study of the EMPIRICAL randomised controlled trial · 2026 · DOI

• People with HIV-1 have higher risk for rejection after kidney transplantation but the mechanism is poorly understood.

  Allograft Rejection and the Latent HIV Reservoir in Kidney Transplant Recipients With HIV · 2026 · DOI

• Reverse transcriptase (RT) of retroviruses orchestrates viral replication, yet its structural diversity remains poorly understood.

  Protease‐mediated maturation of M‐ PMV reverse transcriptase into a functional heterodimer · 2026 · DOI

• Background: Certain antiretroviral drugs, including efavirenz, have been associated with mitochondrial and oxidative effects in hepatic cells, but quantitative translation from nominal in vitro concentrations to an in vivo effect-site concentration remains uncertain.

  Integrating PBPK Simulation and In Vitro Pharmacodynamics to Model Efavirenz-Associated Hepatic Oxidative Stress in Pregnancy · 2026 · DOI

• Real-world use has revealed occasional adverse events occurring almost immediately after injection, including vasovagal and presyncopal reactions, for which the underlying mechanism remains unclear.

  Initiating lenacapavir with increased dosing in a patient on rifabutin: Efficacy and TDM results · 2026 · DOI

• However, after applying IPTW, there was insufficient evidence for a difference in mortality in the full cohort (hazard ratio (HR) 1.

  Mortality using raltegravir versus other integrase strand-transfer inhibitors in people with HIV in Europe and Australia: a prospective multicentre study · 2025 · DOI

• BACKGROUND: There are limited data on how historical nucleoside reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs) other than M184V/I, affect the activity of B/F/TAF.

  Outcomes of switching from protease inhibitor-based antiretroviral therapy to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in virologically suppressed adults with nucleos(t)ide analogue resistance– a phase IV randomised, open-label study (PIBIK study) · 2025 · DOI

• Long-acting injectable (LA) ART with cabotegravir (CAB) and rilpivirine (RPV), administered once every 8 weeks (Q8W), has shown promising efficacy and acceptability in adults and adolescents, but limited data are available for adolescents in African settings.

  Pharmacokinetics of long‐acting cabotegravir and rilpivirine in virologically suppressed adolescents living with HIV‐1 in Sub‐Saharan Africa: Data from the LATA trial · 2025 · DOI

• The utility of therapeutic drug monitoring (TDM), particularly in paediatrics, remains understudied.

  Therapeutic drug monitoring of dolutegravir in children and adolescents living with HIV: A retrospective study · 2025 · DOI

• It remains unclear if these high DTG Ctau are clinically relevant in this population.

  Therapeutic drug monitoring of dolutegravir in children and adolescents living with HIV: A retrospective study · 2025 · DOI

• Background/Objectives: The impact of virion maturation on neutralizing antibody responses in HIV treatment is not fully understood.

  Antiretroviral Therapy with Ritonavir-Boosted Atazanavir- and Lopinavir-Containing Regimens Correlates with Diminished HIV-1 Neutralization · 2024 · DOI

• BACKGROUND: Limited data are available regarding the susceptibility of the reverse transcriptase V106 polymorphism to doravirine.

  Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes · 2024 · DOI

• Reduced susceptibility seems to occur at increased frequency in subtype F1; however, the clinical impact remains to be investigated.

  Prevalence and Phenotypic Susceptibility to Doravirine of the HIV-1 Reverse Transcriptase V106I Polymorphism in B and Non-B Subtypes · 2024 · DOI

• Furthermore, recent discoveries unveiled that IN has an under-studied yet equally vital second function.

  Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions · 2024 · DOI

Most-cited papers in HIV/AIDS drug development and treatment

• Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment · New England Journal of Medicine · 1994 · 2,813 citations
• A Controlled Trial of Two Nucleoside Analogues plus Indinavir in Persons with Human Immunodeficiency Virus Infection and CD4 Cell Counts of 200 per Cubic Millimeter or Less · New England Journal of Medicine · 1997 · 2,095 citations
• CD4+ Count–Guided Interruption of Antiretroviral Treatment · New England Journal of Medicine · 2006 · 1,833 citations
• The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex · New England Journal of Medicine · 1987 · 1,819 citations
• Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral Therapy · New England Journal of Medicine · 1997 · 1,508 citations
• Efficacy and Safety of Tenofovir DF vs Stavudine in Combination Therapy in Antiretroviral-Naive Patients<SUBTITLE>A 3-Year Randomized Trial</SUBTITLE> · JAMA · 2004 · 1,067 citations
• Antiretroviral Therapy in Adults · JAMA · 2000 · 814 citations
• Antiretroviral Treatment of Adult HIV Infection · JAMA · 2012 · 622 citations
• Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. · American Journal of Public Health · 1996 · 512 citations
• HIV-1 Antiretroviral Resistance · Drugs · 2012 · 281 citations

Most recent work

• Cabotegravir plus Rilpivirine for Persons with HIV and Adherence Challenges · New England Journal of Medicine · 2026
• Lenacapavir treatment–emergent HIV-1 capsid resistance mutations are frequently associated with replication defects · Science Translational Medicine · 2026
• Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial · The Lancet · 2026
• Switch to fixed-dose doravirine (100 mg) and islatravir (0·25 mg) once daily in virologically suppressed adults with HIV-1 on oral antiretroviral therapy: 48-week results of a phase 3, multicentre, randomised, open-label, non-inferiority trial · The Lancet · 2026
• Switch to single-tablet bictegravir–lenacapavir from a complex HIV regimen (ARTISTRY-1): a randomised, open-label, phase 3 clinical trial · The Lancet · 2026
• Phase 3 Trial of Weekly Oral Islatravir–Lenacapavir for HIV-1 Treatment · New England Journal of Medicine · 2026
• Virological Failure on Long-Acting Injectable Cabotegravir and Rilpivirine: An Analysis of Subtypes, Drug Levels, Resistance, and Therapeutic Implications · Clinical Infectious Diseases · 2026
• New catalyst for synthesis of cyclic nucleosides: Insights into silyl-Hilbert-Johnson reaction, ADME survey, dynamic simulation and molecular docking studies targeting HCV · Inorganic Chemistry Communications · 2026
• HIV persistence in tissues on dolutegravir-based therapy is not associated with resistance mutations to dolutegravir · Communications Medicine · 2026
• P-344. Modeling Confirms Islatravir 0.25 mg Administered Daily Has No Adverse Effect on Total Lymphocyte or CD4+ T-cell Counts in People Living with HIV · Open Forum Infectious Diseases · 2026

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