Kara Bennett

Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398

ABSTRACT The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression

BackgroundVirologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DesignMulticenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. MethodsSubjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 × 106 cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. ResultsTreatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. ConclusionsSwitching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey

BACKGROUND HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswanas progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90-90-90). METHODS A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. FINDINGS 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83·3%, 95% CI 81·4-85·2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87·4%, 95% CI 85·8-89·0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96·5%, 95% CI 96·0-97·0) had viral load of 400 copies per mL or less. Overall, 70·2% (95% CI 67·5-73·0) of HIV-infected people had virological suppression, close to the UNAIDS target of 73%. INTERPRETATION UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden. FUNDING US Presidents Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV.

BACKGROUND Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. METHODS Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment. RESULTS Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (β=0.003, P=0.02), CD4(+) T-cell nadir (β=0.001, P<0.01) and gender (β=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5-433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01). CONCLUSIONS ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.

Pretreatment factors associated with 3-year (144-week) virologic and immunologic responses to potent antiretroviral therapy.

Objective:To examine pretreatment factors associated with longer term (144 weeks) responses to antiretroviral therapy (ART). Methods:Of 1498 ART-naive subjects randomized to ART regimens, including ≥3 agents, 1083 patients who had plasma HIV RNA (vRNA) levels and CD4 cell counts at baseline and week 144 were analyzed. Primary baseline factors evaluated were CD4 cell count, vRNA level, gender, race, and age, using multivariable Cox, log-binomial, and linear regression models. Results:Shorter time to achieving a vRNA level <50 copies/mL was associated with lower baseline vRNA level (P < 0.001), older age (P = 0.007), and lower baseline CD4 cell count (P = 0.055). After adjusting for race, gender, and baseline CD4 cell count, older age was associated with a vRNA level <50 copies/mL at week 144 (P = 0.018). Greater CD4 count increases from baseline to week 144 (mean = 284 cells/μL) were seen in younger men, blacks, and subjects with higher pretreatment vRNA levels; the effect of pretreatment vRNA level was most apparent in women. Conclusions:Older age was the most important baseline predictor of a vRNA level <50 copies/mL at week 144; lower pretreatment vRNA level and older age were the most important predictors of time to a vRNA level <50 copies/mL. The influence of pretreatment factors on increases in CD4 cell counts differed between men and women.

Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir

Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates forand inhibitors of CYP3A4. The goal of this model‐based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms toaccount for them.

Measurement of Naive CD4 Cells Reliably Predicts Potential for Immune Reconstitution in HIV

Background:Pathogenesis studies show that naive CD4 cells are preferentially depleted in lymphoid tissues during HIV infection, and studies of advanced patients suggest levels of naive CD4 cells in blood correlate to total CD4 cells after starting antiretroviral therapy (ARV). We hypothesized that measuring naive CD4 cells in blood in people at earlier stages of disease would identify those at highest risk for poor CD4 reconstitution who may benefit from earlier initiation of ARV. Methods and Findings:We identified 348 patients from multiple AIDS Clinical Trials Group studies who were ARV naive, had a CD4 count between 200 and 500 cells per microliter, a measure of pretreatment-naive CD4 percent, and serial follow-up measures of CD4 count and plasma HIV RNA after starting ARV. We used logistic regression to model the ability of naive CD4 percent to predict 100 and 200 CD4 cell increases after 24 months of therapy. After controlling for baseline viral load and demographic variables, baseline naive but not total CD4 cell count strongly predicted CD4 cell increases. Lower baseline naive CD4 percent was associated with greater time spent at lower CD4 T-cell counts after initiating ARV. Conclusions:Measurement of naive CD4 percent in patients can identify those least likely to reconstitute immunity, who may benefit from earlier ARV treatment.

Baseline predictors of CD4 T-lymphocyte recovery with combination antiretroviral therapy.

&NA; CD4 T‐cell recovery with potent antiretroviral therapy varies considerably among HIV‐1‐infected patients. Data from two studies that enrolled subjects at different stages of disease progression were retrospectively combined. This analysis assessed the association between patient‐specific factors and three measures of CD4 T‐cell recovery after the initiation of triple‐drug therapy: overall changes in CD4 cell counts; changes in CD4 cell counts during the first 8 weeks (phase I); and changes in CD4 cell counts during weeks 8‐24 (phase II). Higher initial HIV‐1 RNA values corresponded to greater increases in overall and phase I changes in mean CD4 cell counts, particularly among subjects with less advanced disease. In the overall and phase II cases, those subjects with suppressed HIV RNA levels had consistently higher increases in mean CD4 cell counts across both baseline HIV‐1 RNA levels and CD4 cell counts than did the respective unsuppressed group. Based on a multivariate model, increases in mean phase I CD4 cell counts corresponded to higher log10 baseline HIV‐1 RNA levels (p = .0001) and log10 changes in HIV‐1 RNA levels at week 4 (p= .03). Patients with earlier stages of disease (p =.0001) and females (p = .01) had higher increases in phase I changes. Phase II CD4 cell counts did not depend solely on baseline HIV‐1 RNA levels and CD4 cell counts but on their interaction (p = .0001) as well as on achieving virologic suppression (p = .0009).

HIV-Infected Ugandan Women on Antiretroviral Therapy Maintain HIV-1 RNA Suppression Across Periconception, Pregnancy, and Postpartum Periods.

Background:HIV-infected women risk sexual and perinatal HIV transmission during conception, pregnancy, childbirth, and breastfeeding. We compared HIV-1 RNA suppression and medication adherence across periconception, pregnancy, and postpartum periods, among women on antiretroviral therapy (ART) in Uganda. Methods:We analyzed data from women in a prospective cohort study, aged 18–49 years, enrolled at ART initiation and with ≥1 pregnancy between 2005 and 2011. Participants were seen quarterly. The primary exposure of interest was pregnancy period, including periconception (3 quarters before pregnancy), pregnancy, postpartum (6 months after pregnancy outcome), or nonpregnancy related. Regression models using generalized estimating equations compared the likelihood of HIV-1 RNA ⩽400 copies per milliliter, <80% average adherence based on electronic pill caps (medication event monitoring system), and likelihood of 72-hour medication gaps across each period. Results:One hundred eleven women contributed 486 person-years of follow-up. Viral suppression was present at 89% of nonpregnancy, 97% of periconception, 93% of pregnancy, and 89% of postpartum visits, and was more likely during periconception (adjusted odds ratio, 2.15) compared with nonpregnant periods. Average ART adherence was 90% [interquartile range (IQR), 70%–98%], 93% (IQR, 82%–98%), 92% (IQR, 72%–98%), and 88% (IQR, 63%–97%) during nonpregnant, periconception, pregnant, and postpartum periods, respectively. Average adherence <80% was less likely during periconception (adjusted odds ratio, 0.68), and 72-hour gaps per 90 days were less frequent during periconception (adjusted relative risk, 0.72) and more frequent during postpartum (adjusted relative risk, 1.40). Conclusions:Women with pregnancy were virologically suppressed at most visits, with an increased likelihood of suppression and high adherence during periconception follow-up. Increased frequency of 72-hour gaps suggests a need for increased adherence support during postpartum periods.

Body Mass Index and CD4+ T-Lymphocyte Recovery in HIV-Infected Men with Viral Suppression on Antiretroviral Therapy

Abstract Purpose: To better characterize the relationship between body mass index (BMI) and CD4+ T-lymphocyte recovery in HIV disease.Methods: We analyzed the association between baseline BMI and CD4+ T-lymphocyte increases, as well as the association between BMI and immune activation (CD38 and HLA-DR co-expression on CD4+ and CD8+ T-lymphocytes), in male HIV-infected patients who achieved viral suppression on antiretroviral therapy (ART).Results: Baseline BMI predicted change in CD4+ T-lymphocyte count at weeks 96 ( P = .03, n = 461) and 144 ( P = .005, n = 357) but not at week 48 ( P = .38, n = 558). Relative to men with a normal BMI, overweight and obese men had increases at week 144 that were 35 and 113 cells/ mm3 higher, respectively, while underweight men had CD4+ T-lymphocyte increases that were 94 cells/mm3 lower. No significant correlations between baseline BMI and cellular immune activation were seen.Conclusions: BMI predicts CD4+ T-lymphocyte gains in men started on ART.