Advances in antiretroviral drug development have led to safer drugs with improved tolerability, enhanced activity against drug-resistant HIV, higher genetic barrier to resistance, and fewer drug-drug interactions. Genetic polymorphisms in drug-metabolizing enzymes, transporters, and immune pathways contribute to interindividual variability in antiretroviral pharmacokinetics and toxicity. HLA-B *57:01 screening prior to abacavir initiation is an example of clinically implemented pharmacogenetics in high-income settings. Conversely, despite robust evidence linking UGT1A1 variants to atazanavir-associated hyperbilirubinaemia, routine UGT1A1 testing has not been widely adopted. We conducted a narrative review of genetic polymorphisms associated with the toxicity and pharmacokinetics of current antiretroviral therapy. We searched Pharmacogenomics Knowledgebase (PharmGKB®) for abacavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, emtricitabine, dolutegravir, elvitegravir, raltegravir, bictegravir, cabotegravir, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, lenacapavir, rilpivirine and doravirine. We supplemented our review with targeted searches in PubMed®. We found that most pharmacogenetic associations for current antiretroviral drugs come from single studies and lack replication. Although UGT1A1 loss-of-function alleles increase dolutegravir and cabotegravir exposure, no association with toxicity has been shown. No relevant studies were identified for doravirine, lenacapavir or bictegravir. Actionable pharmacogenetic associations with antiretroviral drugs remain limited to abacavir. Future research should prioritize replicating pharmacogenetic associations across diverse populations and establishing clinical relevance.

Patient is an HLA-B*57:01 positive, 43-year-old male with a history of diabetes type II and admission 10 weeks ago at another institution for pubic symphysis osteomyelitis and associated pseudomonas. Cefepime IV was started and the patient presented with fevers, aches, agranulocytosis, thrombocytopenia and rash as a suspected side effect of cefepime after 3 weeks of treatment. Cefepime was replaced with piperacillin-tazobactam and symptoms resolved. Question to be resolved is whether an HLA-B*57:01 positive, abacavir sensitive patient could have an agranulocytosis cross reaction to cefepime.

Data from the REPRIEVE trial have been used to study the association between treatment with abacavir and cardiovascular disease in people with HIV. Past exposure to abacavir before the trial was found to be just as risky as exposure during the trial. This calls into doubt the widely accepted hypothesis that recent exposure to abacavir increases the risk of cardiovascular disease but that risk rapidly attenuates after exposure ends. The evidence for this hypothesis is weak while evidence for an alternative hypothesis has been neglected. An alternative hypothesis is that risk from exposure to abacavir is not immediate but increases as exposure cumulates, plateauing after about three years. Confusion over the likely effect of abacavir has arisen partly because overly simplistic methods have been used to model the exposure outcome relationship in observational cohort data. Better methods are available and should be used in future to avoid misdirected research effort.

Aim: There are limited studies of antiretroviral therapy persistence among people with HIV (PWH) who have a mental health disorder and/or substance use disorder (MHD/SUD). This real-world study analyzed persistence among treatment-experienced PWH who had an MHD/SUD or suboptimal adherence (proportion of days covered [PDC] < 85%). Materials & methods: In this retrospective cohort study of claims from the Optum Research Database, nonpersistence (i.e., discontinuation, switch, add-on or death) was assessed in treatment-experienced PWH who switched to or restarted an antiretroviral therapy regimen of interest (i.e., bictegravir [B]/emtricitabine [F]/tenofovir alafenamide [TAF], dolutegravir [DTG]/lamivudine [3TC], DTG/abacavir [ABC]/3TC, DTG + F/TAF, DTG + F/tenofovir disoproxil fumarate [TDF] or cabotegravir + rilpivirine) from 1 July 2017 to 30 November 2023. Baseline characteristics across regimens were balanced by inverse probability treatment weighting. Kaplan-Meier analysis was conducted on weighted data to examine regimen persistence at 12 months. Adjusted Cox proportional hazards models assessed nonpersistence throughout follow-up. Results: Overall, 14,826 PWH were eligible and treatment experienced; 5310 had an MHD/SUD and 4090 had PDC < 85% during follow-up. Among treatment-experienced PWH who received B/F/TAF, persistence at 12 months was 80.3% for those with an MHD/SUD and 78.6% for those with PDC < 85%; this was greater compared with PWH who received DTG/3TC (76.7% and 70.8%), DTG/ABC/3TC (68.9% and 66.3%), DTG + F/TAF (62.4% and 58.9%) and DTG + F/TDF (36.7% and 41.9%; all p < 0.05). Compared with B/F/TAF, nonpersistence risk was greater with DTG/3TC, DTG/ABC/3TC, DTG + F/TAF and DTG + F/TDF in the MHD/SUD (all p < 0.05) and PDC < 85% (all p < 0.05 except DTG/3TC) groups. Conclusion: These results indicate that B/F/TAF may offer greater likelihood of persistence and emphasize the importance of regimen selection to optimize outcomes in treatment-experienced PWH with an MHD/SUD or suboptimal adherence.

Abacavir (brand name Ziagen) is used in the treatment of human immunodeficiency virus (HIV) infection. Abacavir is a nucleoside (and nucleotide) reverse transcriptase inhibitor (NRTI), and is used in combination with other medications as part of highly active antiretroviral therapy (HAART) (1). Hypersensitivity reactions associated with abacavir can be severe and potentially fatal. Symptoms include fever, rash, vomiting, and shortness of breath. They typically appear within the first 42 days of treatment (11 days median onset). HLA-B*57:01 significantly increases the risk of hypersensitivity reactions when abacavir is administered. Approximately 6% of Caucasians and 2-3% of African Americans carry this allele in the human leukocyte antigen B (HLA-B) gene. The HLA-B gene plays an important role in how the immune system recognizes and responds to pathogens, and mediates hypersensitivity reactions. HLA-B*57:01 has been found to be associated with abacavir hypersensitivity across different ethnicities, including Caucasians, Hispanics, and individuals of African origin (2, 3). Screening for the HLA-B*57:01 allele before starting abacavir therapy is recommended for all patients according to the FDA drug label for abacavir (Table 1). Even if previously tolerated, screening should happen before restarting abacavir therapy if HLA-B*57:01 status is unknown. Abacavir is contraindicated in HLA-B*5701-positive patients, and in patients with a prior hypersensitivity reaction to abacavir. Dosing guidelines from the professional societies, Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), also recommend that HLA-B*57:01 screening should be performed prior to initiation of abacavir therapy and an alternate drug be administered for patients with the allele (Table 2, Table 3)(1, 3-5).

The use of antiretroviral (ART) treatment during pregnancy has dramatically reduced rates of perinatally-acquired human immunodeficiency virus 1 (HIV-1) infection to <1% in the United States. Despite this success, we have limited knowledge of how ART drugs that cross the placental barrier affect fetal development, particularly in the central nervous system (CNS). During gestation, large populations of oligodendroglia are produced that are responsible for critical postnatal CNS myelination enabling appropriate neurological function. Previous studies have shown that antiretrovirals impair oligodendrocyte (OL) differentiation leading us to hypothesize that OL maturation might be inhibited by exposure to a frontline ART drug cocktail (Triumeq®) prescribed during pregnancy containing dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC). In this study, we demonstrated that exposing primary rat oligodendrocyte precursor cells (OPCs) and OLs to the Triumeq drug combination decreased OL maturation and myelin protein production in a concentration-dependent manner, and that DTG was solely responsible. Regardless of the timing of exposure during OL development, a high concentration of DTG inhibited OL maturation. Bulk RNA sequencing revealed transcriptional changes after DTG exposure related to a variety of cellular mechanisms, including cellular responses to stress pathways, amino acid starvation, and mitochondrial dysfunction. Although we found that DTG robustly activated the integrated stress response (ISR), attempted rescue experiments showed that DTG primarily inhibits OL maturation independently of the ISR. Collectively, our novel data on DTG underscore the necessity of investigating how ART drugs that are administered during pregnancy and cross the placental barrier can affect fetal CNS development.

Gestational antiretroviral therapy (ART) has significantly reduced the risk of vertical transmission of HIV, but concerns linger about its long-term effects on the fetal immune system and intestinal health. Our previous work has demonstrated dose-dependent changes in the fecal and mucosa-associated microbiome of adult rat offspring perinatally exposed to TC-ART (tri-combination ART: dolutegravir, abacavir, and lamivudine). These changes may either be driven by alterations in immune system and intestinal barrier integrity or potentially impact them.

Optimizing nucleoside reverse transcriptase inhibitor (NRTI) backbones is vital for pediatric and adolescent HIV treatment, yet real-world comparative evidence is limited. This study assessed backbone regimen effectiveness and factors influencing viral suppression (VLS) in Uganda.

Dissolved black carbon (DBC) plays a critical role in the photochemical transformation of emerging contaminants in aquatic systems. However, the source-dependent molecular composition of DBC and its mechanistic influence on contaminant photodegradation remain poorly understood. Here, we characterize the optical properties and molecular structure of DBC derived from five crop straws and evaluate their effects on the photodegradation of antiviral drug abacavir. Results demonstrate that light absorption capacity of five DBC follows the order: DBCrice>DBCpeanut>DBCsorghum>DBCwheat>DBCbamboo (DBCX, where X = crop straw). DBCrice is characterized by low molecular weight, high nitrogen content, and lignin-like components, with unsaturation provided by the carbon backbone. In contrast, DBCbamboo exhibits strong reducibility, high sulfur content, and protein-like constituents, where unsaturation is attributed to oxygen-containing functional groups. The distinct molecular composition and structure of DBCrice lead to a higher steady-state concentration of reactive intermediates than DBCbamboo, which accounts for the enhanced photodegradation rates of abacavir. The abacavir is easily transformed via photolysis in waters due to the presence of cyclopropyl and amino functional groups, and reaction pathways mainly involves with hydroxylation, oxidation, hydrogen abstraction, and C-N bond cleavage. This study highlights the critical role of source-specific molecular composition in dictating the photochemical activity of DBC, which is essential for accurately predicting the environmental fate of antiviral drugs in sunlit waters.