Presence Of Antiretrovirals Research Articles

HIV incidence and prevalence among adults aged 15-64 years in Rwanda: Results from the Rwanda Population-based HIV Impact Assessment (RPHIA) and District-level Modeling, 2019

ObjectivesThe 2018–2019 Rwanda Population–based HIV Impact Assessment (RPHIA) was conducted to measure national HIV incidence and prevalence. District-level estimates were modeled to inform resources allocation. MethodsRPHIA was a nationally representative cross-sectional household survey. Consenting adults were interviewed and tested for HIV using the national diagnostic algorithm followed by laboratory-based confirmation of HIV status and testing for viral load (VL), limiting antigen (LAg) avidity, and presence of antiretrovirals. Incidence was calculated using normalized optical density ≤ 1·5, VL ≥ 1,000 copies/mL, and undetectable antiretrovirals. Survey and programmatic data were used to model district-level HIV incidence and prevalence. ResultsOf 31,028 eligible adults, 98·7% participated in RPHIA and 934 tested HIV positive. HIV prevalence among adults in Rwanda was 3·0% (95% CI:2·7–3·3). National HIV incidence was 0·08% (95% CI:0·02–0·14) and 0·11% (95% CI:0·00–0·26) in the City of Kigali (CoK). Based on district-level modeling, HIV incidence was greatest in the 3 CoK districts (0·11% to 0·15%) and varied across other districts (0·03% to 0·10%). ConclusionsHIV prevalence among adults in Rwanda is 3.0%; HIV incidence is low at 0.08%. District-level modeling has identified disproportionately affected urban hotspots: areas to focus resources.

Undisclosed exposure to antiretrovirals prior to treatment initiation: An exploratory analysis.

BackgroundThe proportion of individuals with a history of exposure (‘pre-exposure’) to antiretrovirals (ARVs) prior to formal initiation into antiretroviral treatment (ART) is unknown.ObjectivesThis study describes the detection of ARVs in plasma and/or hair, of persons who self-reported no pre-exposure to ART at their first-time initiation onto ART in three clinics in the province of Limpopo, South Africa (SA).MethodConcentrations of tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV) in the plasma and hair of individuals initiating ART were analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Next generation sequences of HIV polymerase gene were analysed with Geneious software 11.15, and drug resistance (DR) mutations were determined according to the Stanford HIV Drug-Resistance database. Participants’ demographic data were collected on a structured questionnaire. Data that describe prior exposure to ARV were also collected by this self-reporting method.ResultsPaired blood and hair samples were collected from 77 individuals newly initiated onto ART from 2017 to 2019. We detected at least one of the drugs in the plasma or hair of 41/77 (53.2%) patients who responded with a ‘no’ to the question ‘have you received ARVs before initiation onto ART?’ Thirty-one participants (n = 31/77, 40.3%) had TDF in either plasma or hair. Emtricitabine and EFV were found in the plasma or hair of 12/77 (15.6%) and 25/77 (32.4%) of participants respectively. Six (n = 6/77, 7.792%) had all three ARVs in plasma or hair. Prevalence of DR mutations at the > 5% significance threshold level in those known to have had ARV-exposure determined by LC-MS/MS prior to ART-initiation was not significant (χ2 = 0.798; p = 0.372), when compared to those who had no prior exposure but still showed DR.ConclusionAntiretroviral levels in the hair of individuals initiating treatment imply prolonged prior-exposure to that ARV. The presence of ARV in plasma and hair of persons living with HIV (PLWH) who deny ARV-use, requires an explanation. A larger study at multiple sites and regular DR surveillance of ART-naïve PLWH will be necessary to confirm the generalisability of these findings to the wider South African population.

Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents.

While latently HIV-infected cells have been described in the blood, it is unclear whether a similar inducible reservoir exists in the gut, where most HIV-infected cells reside. Tissue-specific environments may contribute to differences in the mechanisms that govern latent HIV infection and amenability to reactivation. We sought to determine whether HIV-infected cells from the blood and gut differ in their responses to T-cell activation and mechanistically distinct latency reversing agents (LRAs). Cross sectional study using samples from HIV-infected individuals (n = 11). Matched peripheral blood mononuclear cells (PBMC) and dissociated total cells from rectum ± ileum were treated ex vivo for 24 h with anti-CD3/CD28 or LRAs in the presence of antiretrovirals. HIV DNA and 'read-through', initiated, 5' elongated, completed, and multiply-spliced HIV transcripts were quantified using droplet digital PCR. T-cell activation increased levels of all HIV transcripts in PBMC and gut cells, and was the only treatment that increased multiply-spliced HIV RNA. Disulfiram increased initiated HIV transcripts in PBMC but not gut cells, while ingenol mebutate increased HIV transcription more in gut cells. Romidepsin increased HIV transcription in PBMC and gut cells, but the increase in transcription initiation was greater in PBMC. The gut harbors HIV-infected cells in a latent-like state that can be reversed by T-cell activation involving CD3/CD28 signaling. Histone deacetylation and protein kinase B may contribute less to HIV transcriptional initiation in the gut, whereas protein kinase C may contribute more. New LRAs or combinations are needed to induce multiply-spliced HIV and should be tested on both blood and gut.

Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.

BackgroundPeople living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively.ObjectiveThis study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug–drug interactions (DDIs) with antiretrovirals (ARVs).MethodsThe atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM®. Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs.ResultsFull pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively.ConclusionThis study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00876-0) contains supplementary material, which is available to authorized users.

Perspectives on the Barrier to Resistance for Dolutegravir + Lamivudine, a Two-Drug Antiretroviral Therapy for HIV-1 Infection.

In HIV-1-infected patients, virological failure can occur as a consequence of the mutations that accumulate in the viral genome that allow replication to continue in the presence of antiretrovirals (ARVs). The development of treatment-emergent resistance to an ARV can limit a patient's options for future therapy, prompting the need for ARV regimens that are resilient to the emergence of resistance. The genetic barrier to resistance refers to the number of mutations in an ARV's therapeutic target that are required to confer a clinically meaningful loss of susceptibility to the drug. The emergence of resistance can be affected by pharmacological aspects of the ARV, including its structure, inhibitory quotient, therapeutic index, and pharmacokinetic characteristics. Dolutegravir (DTG) has demonstrated a high barrier to resistance, including when used in a two-drug regimen (2DR) with lamivudine (3TC). In the GEMINI-1 and GEMINI-2 studies, DTG +3TC was noninferior to DTG + emtricitabine/tenofovir disoproxil fumarate in treatment-naive participants, with similar proportions achieving HIV-1 RNA <50 copies/mL through 96 weeks. Furthermore, in the TANGO study, virological suppression was maintained at 48 weeks after switching to DTG +3TC from a tenofovir alafenamide (TAF)-based regimen compared with continuing a TAF-based regimen. Most other 2DRs with successful outcomes compared with three-drug regimens have been based on protease inhibitors (PIs); however, this class is associated with adverse metabolic effects and drug–drug interactions. In this review, we discuss the barrier to resistance in the context of a 2DR in which a boosted PI is replaced with DTG +3TC.

Antiretroviral Therapy and Alcohol Interactions: X-raying Testicular and Seminal Parameters Under the HAART Era.

The prevalence of alcohol use among HIV-infected patients undergoing antiretroviral (ARV) treatments has raised several concerns related to key therapeutic indices. These include drug interactions, compliance, efficacy and toxicity with the possibility of accelerated disease progression. Interaction of ARVs with alcohol can result in therapeutic failures or place patients at significant risk for toxicities. Research findings in this particular area are, however, limited and sometimes conflicting. This review focuses on alcohol and ARV interactions affecting testicular and spermatogenic indices. Antiretroviral drugs are known to negatively impact testicular functions via altered mitochondrial DNA and oxidative stress mechanisms. Interaction with alcohol can significantly affect seminal fluid concentration of ARVs. Habitual consumption of alcohol causes testicular hypofunction with potential for lowered fertility. Concomitant use of ARVs appears to act synergistically to exacerbate this toxicity. Alcohol also induces cytochrome P450 (CYPs) microsomal enzymes, which in turn affect ARVs metabolized by these enzymes. In the presence of ARVs with strong inhibitory activity, increased bioavailability with toxicities predominates. In addition, alcohol and ARVs have pronounced effects on membrane-associated drug transporters. Alcohol alters the properties of the lipid bilayer by changing membrane permeability and protein distribution. Since drug transporters critical to pharmacokinetics are integral membrane proteins, alcohol tends to diminish the activity of both the efflux and influx transporters. While excessive alcohol precipitates accelerated hypogonadism, future research needs to be directed to quantifying these effectsof alcohol and ARVs in human testicular tissue.

Evaluation of hidden HIV infections in an urban ED with a rapid HIV screening program

BackgroundTo investigate the prevalence of undiagnosed HIV infections in an emergency department (ED) with an established screening program. MethodsEvaluation of the prevalence and risk factors for HIV from an 8-week (June 24, 2007–August 18, 2007) identity-unlinked HIV serosurvey, conducted at the same time as an ongoing opt-in rapid oral-fluid HIV screening program. Testing facilitators offering 24/7 bedside rapid testing to patients aged 18 to 64 years, with concordant collection of excess sera collected as part of routine clinical procedures. Known HIV positivity was determined by (1) medical record review or self-report from the screening program and/or (2) presence of antiretrovirals in serum specimens. ResultsAmong 3207 patients, 1165 (36.3%) patients were offered an HIV test. Among those offered, 567 (48.7%) consented to testing. Concordance identity-unlinked study revealed that the prevalence of undiagnosed infections was as follows: 2.3% in all patients, 1.0% in those offered testing vs 3.0% in those not offered testing (P < .001); and 1.3% in those who declined testing compared with 0.4% in those who were tested (P = .077). Higher median viral loads were observed in those not offered testing (14255 copies/mL; interquartile range, 1147-64354) vs those offered testing (1865 copies/mL; interquartile range, undetectable-21786), but the difference was not statistically significant. ConclusionsHigh undiagnosed HIV prevalence was observed in ED patients who were not offered HIV testing and those who declined testing, compared with those who were tested. This indicates that even with an intensive facilitator-based rapid HIV screening model, significant missed opportunities remain with regard to identifying undiagnosed infections in the ED.

HIV Care Continuum for HIV-Infected Emergency Department Patients in an Inner-City Academic Emergency Department

The recently released HIV Care Continuum Initiative is a cornerstone of the National AIDS Strategy and a model for improving care for those living with HIV. To our knowledge, there are no studies exploring the entirety of the HIV Care Continuum for patients in the emergency department (ED). We determine gaps in the HIV Care Continuum to identify potential opportunities for improved care for HIV-infected ED patients. A mixed-methods approach was used in 1 inner-city ED in 2007. Data elements were derived from an identity-unlinked HIV seroprevalence study, an ongoing nontargeted HIV screening program, and a structured survey of known HIV-positive ED patients. Identity-unlinked testing of 3,417 unique ED patients found that 265 (7.8%) were HIV positive. Of patients testing HIV positive, 73% had received a previous diagnosis (based on self-report, chart review, or presence of antiretrovirals in serum), but only 61% were recognized by the clinician as being HIV infected (based on self-report or chart review). Of patients testing positive, 43% were linked to care, 39% were retained in care, 27% were receiving antiretrovirals, 26% were aware of their receiving antiretroviral treatment, 22% were virally suppressed, and only 9% were self-aware of their viral suppression. To our knowledge, this study is the first to quantify gaps in HIV care for an ED patient population, with the HIV Care Continuum as a framework. Our findings identified distinct phases (ie, testing, provider awareness of HIV diagnosis, and linkage to care) in which the greatest opportunities for intervention exist, if appropriate resources were allocated. This schema could serve as a model for other indolent treatable diseases frequently observed in EDs, where continuity of care is critical.

Emergence of Resistance Mutations Preceding Virologic Failure in Patients Receiving Antiretroviral Therapy

Emergence of Resistance Mutations Preceding Virologic Failure in Patients Receiving Antiretroviral Therapy