Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz

Background. A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Methods. Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration > 10 ng/mL for > 95% of the chemoprevention period. Results. PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), lt 1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and > 96% of women, respectively. All regimens were safe, with lt = 2% of women predicted to have >= 30 msec QTc increase. Conclusions. For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing

Individual level data meta-analysis from HIV pre-exposure prophylaxis (PrEP) clinical trials

Introduction: Daily tenofovir has proven efficacy in preventing HIV infection in high-risk populations, when patients are compliant. However, effective preventive concentration has not been determined using HIV infection as outcome, due to lack of power in a single clinical trial and large cofounding with non-adherence. Furthermore, infection risk in target populations is poorly defined, making it difficult to properly identify key patients who would benefit the most from PrEP therapy. To address those pertinent questions, we have constructed the largest individual data base up to date from the 5 latest Phase 3 HIV prevention clinical trials. Our aims were (i) to identify patient subgroups at the highest risk of HIV infection in target populations, (ii) to estimate preventive tenofovir concentrations in target populations based on pharmacokinetic (PK)-HIV outcome modeling and (iii) to evaluate the target site tenofovir diphosphate PK in peripheral blood mononuclear cells (PBMC) vs plasma tenofovir as a marker of HIV prevention. Methods:(i) Longitudinal PK data of tenofovir in plasma and tenofovir metabolite in PBMC, (ii) HIV outcome and (iii) individual’s demographics and risk factors data from 13,727 individuals obtained from 5 phase 3 randomized controlled trials were integrated and analyzed with NONMEM 7.4 using population approaches. Those trials evaluated tenofovir-based PrEP therapy efficacy in different HIV risk groups: injection drug users (Bangkok1), men or transgender women who have sex with men (iPrEX2), women at high risk of infection (VOICE3), HIV serodiscordant heterosexual couples (Partners4), and high risk heterosexual men and women (TDF25). The analyses were done sequentially: The probability of HIV infection over time was analyzed through parametric survival analysis using data from the placebo arms of the 5 PrEP trials (n=5313). Studies were analyzed separately due to availability of baseline covariates specific for target populations. Baseline survival models were evaluated and covariate analysis was performed by stepwise covariate modelling. Patient-specific risk stratification algorithm was developed. The PK analysis of tenofovir (2 compartment model) and its metabolite (effect compartment model) was done sequentially pooling the available data from iPrEX, VOICE and Partners (n=2360). Longitudinal adherence to the treatment was assessed by applying mixture modeling approaches on the relative bioavailability fraction. Data below limit of quantification were handled with the M3 method. PK exposure metrics for tenofovir in plasma were linked to the probability of HIV infection in parametric survival analysis. The effect of tenofovir diphosphate in PBMC as predictor of HIV prevention was explored. Results: Exponential hazard distribution best fitted the time to HIV infection data from the control arms of the PrEP studies. The analysis identified set of risk factors which are common (e.g. female sex, age) or unique to each population (e.g non-condom receptive anal intercourse, and syphilis seroreactivity in iPrEX study). Most surprisingly, women appear to be at greater risk of HIV infection compared to men. In population PK model, 2 patient subpopulations were identified, adherent F=100% and non-adherent F=<1%) through the application of a mixture model on relative bioavailability, with an estimated probability of being in adherent group of 55%. Longitudinal adherence and PK profiles were reconstructed for each patient based on the established mixture model and PK data. These were then linked to HIV infection (characterized by a survival model with Surge hazard distribution) using a sigmoidal Emax model. Underlying individuals risk hazard was found to be important factor in determining accurate PKPD. The EC50 identified in high risk group was found to be 10.21 ng/mL. Tenofovir diphosphate, appeared to be a better marker of HIV prevention compared to the plasma tenofovir, with an estimated EC50 of 6.91 fmol/106cells. Conclusions: We have quantified tenofovir preventive concentration based on the largest database up to date which includes HIV outcome. We have established patient-specific risk stratification algorithm for HIV infection. These models and tools will further be used for: (i) optimization of novel PrEP clinical trial designs, enrollment and follow up strategies, (ii) the development of novel tenofovir formulations and (iii) implementation of patient management strategies in the clinic. References: [1]Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083–90. [2]Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99. [3]Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2015;372:509–18. [4]Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367:399–410. [5]Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med. 2012;367:423–34.PAGE 28 (2019)Oral: Drug/Disease modellin

Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials

Background. Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. Methods. Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. Results. Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (≏90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (≏7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. Conclusions. Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved