HIV-1 infection in South Kivu (Democratic Republic of Congo): high genotypic resistance to antiretrovirals.

BACKGROUND: Panzi General Reference Hospital (HGR Panzi) in the Democratic Republic of Congo follows a large number of patients living with HIV-1 (PLWHIV). Although antiretrovirals (ARVs) are available, HIV-1 viral load (HIV-VL) measurement has only been implemented in the hospital since 2018. No data on ARV resistance levels and ARV dosage in plasma have yet been published for this region. We determined the prevalence of virological failure due to ARV resistance amongst patients and assessed the degree of genotypic resistance of the viral strains. METHODS: We performed an HIV-VL test and determined dosage of ARVs on samples collected from 205 PLWHIV at HGR Panzi between 2017 and 2018, including 13 ARV-naive patients. Genotypic resistance testing was performed on all samples with detectable HIV-VLs, and interpreted with the Agence Nationale de Recherches sur le Sida (ANRS) 2018 algorithm. RESULTS: Baseline resistance to NNRTIs was found in 2 of the 13 treatment-naive individuals (15%). ARV dosage was non-optimal for 44/192 of treated patients (22.9%), with an HIV-VL ≥1000 IU/mL for 40/192 (20.8%) of them. In particular, treatment-experienced viruses presented resistance to at least one NRTI (52.5%), to at least one NNRTIs (70%) or to at least one PIs (15%). Finally, two samples contained viruses with resistance polymorphism in the integrase gene. CONCLUSIONS: The high level of resistance to ARVs observed during this study, mainly due to treatment compliance default, fully justifies the implementation of means for closer patient monitoring. The provision of VL tests and therapeutic education management tools in a PLWHIV follow-up remains an absolute necessity to best adapt the current treatment lines in this region.

Placental transfer of doravirine, a recent HIV-1 NNRTI in the ex vivo human cotyledon perfusion model.

BACKGROUND: The recent HIV-1 NNRTI doravirine is likely to be used in pregnant women despite the complete lack of data on safety and exposure in the fetus. The objective of this study was to determine its placental transfer. METHODS: Maternal-to-fetal transfer was investigated using the open-circuit ex vivo dually perfused human cotyledon model. Doravirine was added to a maternal perfusate (theoretical doravirine concentration of 250 ng/mL) containing 2 g/L human albumin and 20 g/L antipyrine, a marker to validate the cotyledon's viability, and cotyledons were dually perfused for up to 90 min. RESULTS: In five experiments, the median (IQR) doravirine concentrations in the maternal and fetal compartments were, respectively, 303 (178-420) and 40 (30-54) ng/mL, the fetal-to-maternal ratio was 16% (12%-18%) and the clearance index (in comparison with antipyrine transfer) was 48% (35%-64%). The median accumulation index in cotyledon tissue was 39% (range 10%-66%). CONCLUSIONS: Doravirine both crosses and accumulates in the placenta. This may be useful as pre/post-exposure prophylaxis to reduce the risk of vertical HIV transmission but carries the potential for fetal toxicities. Further investigation is required to determine the safety and efficacy of this new antiretroviral agent in pregnancy.

Intermittent two-drug antiretroviral therapies maintain long-term viral suppression in real life in highly experienced HIV-infected patients.

OBJECTIVES: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks. METHODS: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia. RESULTS: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period. CONCLUSIONS: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies.

Once-daily etravirine/raltegravir (400/800 mg q24h) dual therapy maintains viral suppression over 48 weeks in HIV-infected patients switching from a twice-daily etravirine/raltegravir (200/400 mg q12h) regimen.

BACKGROUND: Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study. OBJECTIVES: As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h. METHODS: Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF. RESULTS: A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52-62), CD4 count of 710 cells/mm3 (501-919) and viral suppression for 7.9 years (5.9-10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5-7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5-93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280-603) for etravirine and 62 ng/mL (31-140) for raltegravir. CONCLUSIONS: Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19.

Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and sulfobutylether ß-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).

Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial.

Around the world, several dose regimens of hydroxychloroquine have been used for COVID-19 infection treatment, with the objective of identifying a short-term course. Hydroxychloroquine was found to decrease the viral replication in a concentration-dependent manner in vitro and to be more active when added prior to the viral challenge. A loading dose is used to rapidly attain a target drug concentration, which is usually considered as approximately the steady-state concentration. With a loading dose, the minimum effective concentration is reached much more rapidly than when using only the maintenance dose from the start. Thus, we propose a hydroxychloroquine sulphate dose regimen of 400 mg twice daily at Day 1 then 400 mg once daily from Day 2 to Day 10. We aim to evaluate this in the C-20-15 DisCoVeRy trial.

Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

BACKGROUND: The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000-8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir. OBJECTIVES: To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir. PATIENTS AND METHODS: Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored. RESULTS: Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928-32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394-32 735). CONCLUSIONS: In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.

Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients.

AIMS: The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. METHODS: A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. RESULTS: Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). CONCLUSIONS: This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.

Concentration-response model of rilpivirine in a cohort of HIV-1-infected naive and pre-treated patients.

BACKGROUND: Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. OBJECTIVES: To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration-response relationship for future treatment optimization. METHODS: A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. RESULTS: Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. CONCLUSIONS: The concentration-response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

PURPOSE: Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. METHODS: We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. RESULTS: We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. CONCLUSIONS: Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Outbreak of Pneumocystis jirovecii Infection Among Heart Transplant Recipients: Molecular Investigation and Management of an Interhuman Transmission.

Background: An outbreak of Pneumocystis jirovecii pneumonia (PCP) occurred among heart transplant recipients (HTR) at the outpatient clinic of a university hospital, from March to September 2015. Clinical, therapeutic, biological, and molecular data were analyzed to determine its origin and control the outbreak. Methods: Clinical and biological data regarding all HTR followed in the outpatient clinic were collected. PCP diagnosis was based on microscopy and real-time polymerase chain reaction (PCR). Investigations were performed by building a transmission map, completed by genotyping Pneumocystis isolates and by a control of chemoprophylaxis observance. Asymptomatic exposed patients were screened for colonization using real-time PCR. Results: Among 124 HTR, 7 PCP cases were confirmed. Screening identified 3 additional patients colonized by P. jirovecii. All patients were cured, and no further cases were identified after trimethoprim-sulfamethoxazole prophylaxis was introduced in the entire cohort. Genotyping demonstrated the same strain in all PCP cases and colonized patients. All cases were linked with possible transmission chains from 2 possible index patients. Interhuman transmission was significantly associated with more frequent visits in the outpatient clinic. Six cases were receiving atovaquone as a prophylaxis. The occurrence of PCP was significantly associated with atovaquone prophylaxis. Conclusions: This is the first outbreak with detailed molecular analysis in HTR so far. Genotyping and transmission chain confirmed interhuman transmission in all colonized/infected PCP cases. Outpatient clinic layout and high encounters probably caused this PCP cluster, which was controlled after systematic trimethoprim-sulfamethoxazole prophylaxis in exposed patients.

Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii.

Objectives: Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Methods: Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). Results: A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 µg/mL (6.2-27.8) and the median Cmax was 13.4 µg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin <15 µg/mL, a threshold associated with a low rate of clinical response in PCP treatment. Conclusions: Atovaquone is poorly absorbed in more than half of immunocompromised patients and its bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic drug monitoring, in order to identify patients with low concentrations and those who could benefit from regimen adaptation or from alternatives.

Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. METHODS: Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. RESULTS: Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. CONCLUSIONS: A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. LAY SUMMARY: Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV-containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective.

High efficacy of first-line ART in a West African cohort, assessed by dried blood spot virological and pharmacological measurements.

OBJECTIVES: The objectives of this study were to determine the rate of viral success in HIV-infected patients on first-line ART by the assessment of dried blood spot (DBS) viral load (VL) and to assess the performance of DBS sampling for VL measurement, genotypic resistance and antiretroviral concentration determinations. METHODS: HIV-infected patients treated for >1 year with first-line ART in Niamey, Niger were included. VL based on nucleic acid sequence-based amplification (NASBA) assay (limit of quantification <800 copies/mL) was measured on DBS capillary samples. Resistance genotype was assessed for all detectable VLs (limit of detection >100 copies/mL); antiretroviral concentrations were interpreted using standard plasma cut-offs after extrapolation of blood to plasma results. Median (IQR) results are presented. RESULTS: Two hundred and eighteen patients (61% women), aged 41 (34-46) years, with 138 (56-235) CD4 cells/mm3 at baseline were included. After 4 (2-6) years of follow-up under therapy, CD4 gain was +197 (98-372) cells/mm3; 81% had VL <800 copies/mL. Antiretroviral concentrations were adequate in 87% of patients and nevirapine/efavirenz concentrations were related to viral success (P < 0.001). DBS genotypic resistance amplification succeeded in 71% of failing patients: NRTI drug resistance mutations were identified in 73% including resistance to lamivudine/emtricitabine (67%), abacavir (30%) and tenofovir (21%); and NNRTI drug resistance mutations were identified in 82% including resistance to rilpivirine (39%) and etravirine (15%). CONCLUSIONS: This study demonstrated a good response after 4 years of first-line ART in Niger. Adherence was high, according to antiretroviral concentrations, and the majority of failures were explained by selection of drug resistance mutations detected in the DBS genotype. Using DBS might improve the assessment of ART failure in HIV-infected patients in low-income countries.

Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models.

AIMS: Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. METHODS: Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. RESULTS: Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. CONCLUSION: The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

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.