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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities.

ABSTRACT: To summarize current knowledge and provide perspective on relationships between human genetic variants, antiretroviral medications, and aging-related complications of HIV-1 infection.Human genetic variants have been convincingly associated with interindividual variability in antiretroviral toxicities, drug disposition, and aging-associated complications in HIV-1 infection. Screening for HLA-B5701 to avoid abacavir hypersensitivity reactions has become a routine part of clinical care, and has markedly improved drug safety. There are well established pharmacogenetic associations with other agents (efavirenz, nevirapine, atazanavir, dolutegravir, and others), but this knowledge has yet to have substantial impact on HIV-1 clinical care. As metabolic complications including diabetes mellitus, dyslipidemia, osteoporosis, and cardiovascular disease are becoming an increasing concern among individuals who are aging with well controlled HIV-1 infection, human genetic variants that predispose to these complications also become more relevant in this population.Pharmacogenetic knowledge has already had considerable impact on antiretroviral prescribing. With continued advances in the field of human genomics, the impact of pharmacogenomics on HIV-1 clinical care and research is likely to continue to grow in importance and scope.

SUBMITTER: Haas DW

PROVIDER: S-EPMC4428758 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities.

Haas David W DW Tarr Philip E PE

Current opinion in HIV and AIDS 20150301 2

<h4>Purpose of review</h4>To summarize current knowledge and provide perspective on relationships between human genetic variants, antiretroviral medications, and aging-related complications of HIV-1 infection.<h4>Recent findings</h4>Human genetic variants have been convincingly associated with interindividual variability in antiretroviral toxicities, drug disposition, and aging-associated complications in HIV-1 infection. Screening for HLA-B5701 to avoid abacavir hypersensitivity reactions has b ...[more]

PMID: 25565175

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Project description:OBJECTIVE:The aging HIV population has increased comorbidity burden and consequently non-antiretroviral medication utilization. Many non-antiretroviral medications have known neurocognitive-adverse effects ("NC-AE medications"). We assessed the cognitive effects of NC-AE medications in HIV+ and HIV- women. METHODS:One thousand five hundred fifty-eight participants (1037 HIV+; mean age 46) from the Women's Interagency HIV Study completed a neuropsychological test battery between 2009 and 2011. The total number of NC-AE medications and subgroups (eg, anticholinergics) were calculated based on self-report. Generalized linear models for non-normal data were used to examine the cognitive burden of medications and factors that exacerbate these effects. RESULTS:HIV+ women reported taking more NC-AE medications vs. HIV- women (P < 0.05). NC-AE medication use altogether was not associated with cognitive performance. However, among NC-AE medication subgroups, anticholinergic-acting medications, but not opioids or anxiolytics/anticonvulsants, were negatively associated with performance. HIV status moderated the association between these NC-AE medication subgroups and performance (P's < 0.05). HIV-serostatus differences (HIV- < HIV+) in global, learning, fluency, and motor function were greatest among women taking >1 anticholinergic medications. HIV-serostatus differences in performance on learning and psychomotor speed were also greatest among women taking 1 or more anxiolytics/anticonvulsants and 1 or more opioids, respectively. CONCLUSIONS:HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.

Project description:IntroductionMultiple comorbidities among HIV-positive individuals may increase the potential for polypharmacy causing drug-to-drug interactions and older individuals with comorbidities, particularly those with cognitive impairment, may have difficulty in adhering to complex medications. However, the effects of age-associated comorbidities on the treatment outcomes of combination antiretroviral therapy (cART) are not well known. In this study, we investigated the effects of age-associated comorbidities on therapeutic outcomes of cART in HIV-positive adults in Asian countries.MethodsPatients enrolled in the TREAT Asia HIV Observational Database cohort and on cART for more than six months were analysed. Comorbidities included hypertension, diabetes, dyslipidaemia and impaired renal function. Treatment outcomes of patients ?50 years of age with comorbidities were compared with those <50 years and those ?50 years without comorbidities. We analysed 5411 patients with virological failure and 5621 with immunologic failure. Our failure outcomes were defined to be in-line with the World Health Organization 2016 guidelines. Cox regression analysis was used to analyse time to first virological and immunological failure.ResultsThe incidence of virologic failure was 7.72/100 person-years. Virological failure was less likely in patients with better adherence and higher CD4 count at cART initiation. Those acquiring HIV through intravenous drug use were more likely to have virological failure compared to those infected through heterosexual contact. On univariate analysis, patients aged <50 years without comorbidities were more likely to experience virological failure than those aged ?50 years with comorbidities (hazard ratio 1.75, 95% confidence interval (CI) 1.31 to 2.33, p < 0.001). However, the multivariate model showed that age-related comorbidities were not significant factors for virological failure (hazard ratio 1.31, 95% CI 0.98 to 1.74, p = 0.07). There were 391 immunological failures, with an incidence of 2.75/100 person-years. On multivariate analysis, those aged <50 years without comorbidities (p = 0.025) and age <50 years with comorbidities (p = 0.001) were less likely to develop immunological failure compared to those aged ?50 years with comorbidities.ConclusionsIn our Asia regional cohort, age-associated comorbidities did not affect virologic outcomes of cART. Among those with comorbidities, patients <50 years old showed a better CD4 response.

Project description:BackgroundManagement of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial.MethodsThe BREATHE trial recruited 6-19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weight-based dose of 1-5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112.ResultsThe 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites.ConclusionThe majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care.

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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities.

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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities.

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