Antiretroviral Therapy for Prevention of HIV Infection: New Clues From an Animal Model

The introduction of antiretroviral therapy (ART) in the early 1990s profoundly changed the face of HIV infection by improving survival rates. But ART has equal potential for prevention, since it reduces the probability of HIV transmission from an infected person to their sexual partner(s). Although there have been no randomized controlled clinical trials on the subject, antiretroviral drugs are currently used in clinical practice for post-exposure prophylaxis after inadvertent occupational exposure (based on the results of a case control study) or after sexual exposure to the virus. Pre- and postexposure prophylaxis (PrEP and PEP, respectively) have been used successfully to interrupt transmission of HIV from infected mothers to their babie

Pre-exposure prophylaxis for HIV prevention: how to predict success

Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052, showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 004 and VOICE), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX, TDF2, Partners in Prevention [PIP], and Fem-PrEP), and two used oral TDF alone (VOICE and PIP). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004, iPrEx, TDF2, and PIP) and of futility (VOICE and Fem-PrEP)

Non-initiation of hepatitis C virus antiviral therapy in patients with human immunodeficiency virus/hepatitis C virus co-infection

AIM: To assess whether reasons for hepatitis C virus (HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus (HIV)/HCV co-infection. METHODS: Analysis included co-infected HCV treatment- naïve patients in the University of North Carolina CFAR HIV Clinical Cohort (January 1, 2004 and December 31, 2011). Medical records were abstracted to document non-modifiable medical (e.g. , hepatic decompensation, advanced immunosuppression), potentially modifiable medical (e.g. , substance abuse, severe depression, psychiatric illness), and non-medical (e.g. , personal, social, and economic factors) reasons for non-initiation. Statistical differences in the prevalence of reasons for non-treatment between racial/ethnic groups were assessed using the two-tailed Fisher's exact test. Three separate regression models were fit for each reason category. Odds ratios and their 95%CIs (Wald's) were computed. RESULTS: One hundred and seventy-one patients with HIV/HCV co-infection within the cohort met study inclusion. The study sample was racially and ethnically diverse; most patients were African-American (74%), followed by Caucasian (19%), and Hispanic/other (7%). The median age was 46 years (interquartile range = 39-50) and most patients were male (74%). Among the 171 patients, reasons for non-treatment were common among all patients, regardless of race/ethnicity (50% with ≥ 1 non-modifiable medical reason, 66% with ≥ 1 potentially modifiable medical reason, and 66% with ≥ 1 non-medical reason). There were no significant differences by race/ethnicity. Compared to Caucasians, African-Americans did not have increased odds of nonmodifiable [adjusted odds ratio (aOR) = 1.47, 95%CI: 0.57-3.80], potentially modifiable (aOR = 0.72, 95%CI: 0.25-2.09) or non-medical (aOR = 0.90, 95%CI: 0.32-2.52) reasons for non-initiation. CONCLUSION: Race/ethnicity alone is not predictive of reasons for HCV therapy non-initiation. Targeted interventions are needed to improve access to therapy for all co-infected patients, including minorities

Randomized Pharmacokinetic Crossover Study Comparing 2 Curcumin Preparations in Plasma and Rectal Tissue of Healthy Human Volunteers

Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues

Predicting Efavirenz Concentrations in the Brain Tissue of HIV-Infected Individuals and Exploring their Relationship to Neurocognitive Impairment

Sparse data exist on the penetration of antiretrovirals into brain tissue. In this work, we present a framework to use efavirenz (EFV) pharmacokinetic (PK) data in plasma, cerebrospinal fluid (CSF), and brain tissue of eight rhesus macaques to predict brain tissue concentrations in HIV-infected individuals. We then perform exposure-response analysis with the model-predicted EFV area under the concentration-time curve (AUC) and neurocognitive scores collected from a group of 24 HIV-infected participants. Adult rhesus macaques were dosed daily with 200 mg EFV (as part of a four-drug regimen) for 10 days. Plasma was collected at 8 time points over 10 days and at necropsy, whereas CSF and brain tissue were collected at necropsy. In the clinical study, data were obtained from one paired plasma and CSF sample of participants prescribed EFV, and neuropsychological test evaluations were administered across 15 domains. PK modeling was performed using ADAPT version 5.0 Biomedical Simulation Resource, Los Angeles, CA) with the iterative two-stage estimation method. An eight-compartment model best described EFV distribution across the plasma, CSF, and brain tissue of rhesus macaques and humans. Model-predicted median brain tissue concentrations in humans were 31 and 8,000 ng/mL, respectively. Model-predicted brain tissue AUC was highly correlated with plasma AUC (γ = 0.99, P 0.05). This analysis provides an approach to estimate PK the brain tissue in order to perform PK/pharmacodynamic analyses at the target site. © 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics

Differential Extracellular, but Similar Intracellular, Disposition of two Tenofovir Formulations in the Male Genital Tract

Background: The male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinet-ics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to eradication and cure. Tenofovir alafenamide (TAF) is a tenofovir (TFV) formulation designed to maximize efficacy/minimize toxicity with unknown MGT PK. Methods: HIV-positive and HIV-negative men receiving TFV-based regimens provided six paired blood plasma (BP) and semen samples. Extracellular (TFV, TAF, emtricitabine [FTC]) drug concentrations in BP and seminal plasma (SP), and intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations were measured in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs). Exposure ratios for SP:BP, SMC:PBMC and IM:EN were calculated from PK parameters generated by noncompartmental analysis. HIV viral load was measured in BP and SP. Results: Sixteen HIV-positive (n=8, TDF/FTC; n=8, TAF/FTC) and eight HIV-negative (TDF/FTC) men provided samples. Median TFV SP:BP ratios differed between TDF and TAF (1.5 versus 7.4), due to lower TFV BP concentrations with TAF coupled with TFV SP concentrations similar to TDF. FTC SP:BP ratios were approximately 3. SMC concentrations of IMs and ENs were a fraction of PBMC concentrations (1–22%), though IM:EN ratios exceed a suggested protective threshold. Conclusions: TAF SP PK was unexpected. IM SMC concentrations were low relative to PBMC, as were EN concentrations, suggesting differences in cell phenotype and lineage in the MGT; these differences in phenotype and pharmacology may have an impact on selecting and dosing ARVs used in cure strategies

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART

Food insecurity is associated with lower levels of antiretroviral drug concentrations in hair among a cohort of women living with human immunodeficiency virus in the United States

Background. Food insecurity is a well-established determinant of suboptimal, self-reported antiretroviral therapy (ART) adherence, but few studies have investigated this association using objective adherence measures. We examined the association of food insecurity with levels of ART concentrations in hair among women living with human immunodeficiency virus (WLHIV) in the United States. Methods. We analyzed longitudinal data collected semiannually from 2013 through 2015 from the Women's Interagency HIV Study, a multisite, prospective, cohort study of WLHIV and controls not living with HIV. Our sample comprised 1944 person-visits from 677 WLHIV. Food insecurity was measured using the US Household Food Security Survey Module. ART concentrations in hair, an objective and validated measure of drug adherence and exposure, were measured using high-performance liquid chromatography with mass spectrometry detection for regimens that included darunavir, atazanavir, raltegravir, or dolutegravir. We conducted multiple 3-level linear regressions that accounted for repeated measures and the ART medication(s) taken at each visit, adjusting for sociodemographic and clinical characteristics. Results. At baseline, 67% of participants were virally suppressed and 35% reported food insecurity. In the base multivariable model, each 3-point increase in food insecurity was associated with 0.94-fold lower ART concentration in hair (95% confidence interval, 0.89 to 0.99). This effect remained unchanged after adjusting for self-reported adherence. Conclusions. Food insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with suboptimal ART adherence and/or drug absorption. Interventions seeking to improve ART adherence among WLHIV should consider and address the role of food insecurity

Brief Report: Blood and Genital Fluid Viral Load Trajectories Among Treated and Untreated Persons With Acute HIV Infection in Malawi

Background: Persons with acute HIV infection (AHI) are highly infectious and responsible for a disproportionate share of incident infections. Immediate antiretroviral therapy (ART) rapidly reduces blood viral loads (VLs), but genital VLs after ART initiation during AHI are less well described. Setting: Lilongwe, Malawi, 2012-2014.Methods:HIV-seronegative and HIV-serodiscordant persons aged ≥18 years were screened for AHI (RNA positive) and randomized to standard of care, behavioral intervention, or behavioral intervention plus short-term ART (raltegravir/emtricitabine/tenofovir) (1:2:2). Persons who were ART eligible under Malawi guidelines could receive first-line therapy. Blood and genital VLs were assessed at weeks 1, 4, 8, and 12. Fisher's Exact test was used to compare viral suppression by ART status. Results: Overall, 46 persons with AHI were enrolled; of whom, 17 started ART within 12 weeks. Median blood VL at AHI diagnosis was 836,115 copies/mL. At week 12, 7% (1/14) of those who initiated ART had a blood VL of ≥400 copies/mL, compared with 100% (23/23; P < 0.0001) of those who did not initiate ART (median VL: 61,605 copies/mL). Median genital VL at week 1 was 772 copies/mL, with 13 of 22 (59%) having VL of ≥400 copies/mL. At week 12, 0 of 10 (0%) of those who initiated ART had genital VL of ≥400 copies/mL, compared with 7 of 15 (47%) of those who did not initiate ART (P = 0.02). Conclusion: Although highly correlated, VLs in blood and genital fluids occupy discrete biological compartments with distinct virologic dynamics. Our results corroborate the dramatic reduction in both compartments after ART initiation. Increasing AHI screening and rapidly initiating treatment is key to interrupting transmission

Updated guideline to perform therapeutic drug monitoring for antiretroviral agents.

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