Tenofovir plasma concentrations related to estimated glomerular filtration rate changes in first-line regimens in African HIV-infected patients: ANRS 12115 DAYANA substudy.

OBJECTIVES: An open-label randomized trial (DAYANA) was conducted in sub-Saharan settings to evaluate four different regimens containing tenofovir disoproxil fumarate as first-line treatment for HIV infection. The objectives of the present substudy were to assess the relationship between trough concentrations of tenofovir in plasma collected after 24 h (C24) and estimated glomerular filtration rates (eGFR) calculated by the different formulae that are available. METHODS: The criteria for eligibility were those of the DAYANA trial, recruiting naive patients. The four tenofovir regimens were: Group 1, tenofovir/emtricitabine/nevirapine; Group 2, tenofovir/lopinavir/ritonavir; Group 3, tenofovir/emtricitabine/zidovudine; and Group 4, tenofovir/emtricitabine/efavirenz. The C24 of tenofovir was determined using LC-MS/MS. The eGFR was calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae. RESULTS: The median C24 of tenofovir was 42 ng/mL. The C24 of tenofovir was higher with lopinavir/ritonavir than with the other three regimens: at Week 4, 84 ng/mL versus 25 ng/mL; and at Week 48, 81 ng/mL versus 52 ng/mL. The baseline merged eGFR was 98.2 mL/min/1.73 m(2) with the CKD-EPI equation. Only the mean changes in eGFR in Group 2 differed from the absolute value of zero (-8.2 mL/min/1.73 m(2)) with the CKD-EPI equation between baseline and Week 48. The Cockcroft-Gault formula is inappropriate for these African patients because it underestimated the baseline eGFR and overestimated the changes in eGFR between baseline and Week 48. CONCLUSIONS: In this population of mostly female HIV-1-infected African patients, tenofovir plasma overexposure was associated with PI/ritonavir and a time-dependent decrease in eGFR, probably via an inhibition of MRP2/MRP4 efflux transporters. The close monitoring over time of the eGFR using MDRD or CKD-EPI calculations and by using other biomarkers of renal disorder should be proposed as an alternative to therapeutic drug monitoring in resource-limited countries.

Evaluation of four tenofovir-containing regimens as first-line treatments in Cameroon and Senegal: the ANRS 12115 DAYANA Trial.

BACKGROUND: The aim of the present study was to determine appropriate tenofovir-based regimens meriting evaluation in large-scale randomized trials among sub-Saharan African patients. METHODS: This was a randomized open-label 96-week prospective pilot study evaluating four first-line regimens: tenofovir/emtricitabine/nevirapine (group 1), tenofovir/lopinavir/ritonavir (group 2), tenofovir/emtricitabine/zidovudine (group 3) and tenofovir/emtricitabine/efavirenz (group 4) in antiretroviral-naive, HIV-1-infected patients in Senegal and Cameroon. The primary end point was defined as an HIV-1 RNA viral load <50 copies/ml (study detection limit) at week 16 in ≥50% of patients using intention-to-treat analysis. RESULTS: At baseline, 119 patients included were 34% male, had a median plasma viral load of 5.4 log10 copies/ml and median CD4(+) T-cell count of 200 cells/mm(3) (range 53-358). The primary end point was achieved for groups 1, 3 and 4 (58% [n=31], 62% [n=29] and 53% [n=30], respectively), but not for group 2 (38% [n=29]). At week 96, undetectable HIV-1 RNA had been achieved in 74% of patients in group 1, 38% in group 2, 72% in group 3 and 73% in group 4. Patients with detectable HIV-1 RNA at week 16 were more likely to have baseline HIV-1 RNA≥100,000 copies/ml (adjusted OR 5.56, 95% CI 1.72, 16.67). HIV mutations associated with protease inhibitor resistance emerged in three patients, all of whom were in group 2. Anaemia occurred in two group 3 patients and was the only serious treatment-related adverse event. CONCLUSIONS: Three efficient and safe tenofovir-based triple regimens were identified; the two-drug regimen (tenofovir/lopinavir/ritonavir) did not achieve the protocol-defined virological threshold of efficacy.

Adherence to antiretroviral therapy assessed by drug level monitoring and self-report in cameroon.

OBJECTIVES: To compare adherence to antiretroviral therapy using drug level monitoring and self-report and to explore the relation between these 2 methods and viral load measurements. METHODS: Sixty patients received a fixed-dose combination of nevirapine, stavudine, and lamivudine in a clinical study in Cameroon. Adherence was assessed every 6 months until month 36 by nevirapine minimal plasma concentration and self-report. Plasma HIV-1 viral load was determined at the same time. Analyses included 159 complete observations. RESULTS: The proportion of patients labeled as "adherent" was significantly lower using nevirapine monitoring (88.7%, 95% confidence interval [CI]: 82.7 to 93.2) than self-report (97.5%, CI: 93.7 to 99.3; P = 0.002). Virologic failure was associated with the nevirapine concentration (adjusted odds ratio [aOR] = 4.43; P = 0.018) but not with the self-reported adherence (aOR = 0.84; P = 0.9). As compared with the virologic outcome, the sensitivity of nevirapine level monitoring for predicting inadequate adherence was 20.5%, the specificity was 91.7%, the positive predictive value was 44.4%, and the negative predictive value was 78.0%. For self-report, the respective values were 2.6%, 97.5%, 25.0%, and 75.5%. CONCLUSIONS: Drug level monitoring provided a more reliable estimate of adherence than self-report. This method could be used in research settings. Operational research is required to define how to improve the accuracy of the self-report method because it is the most feasible method in clinical practice.