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Experience of Indinavir/Ritonavir 400/100 mg Twice-Daily Highly Active Antiretroviral Therapy-Containing Regimen in HIV-1-Infected Patients in Bamako, Mali

2007; Lippincott Williams & Wilkins; Volume: 45; Issue: 4 Linguagem: Inglês

10.1097/qai.0b013e318061b5c3

1944-7884

Ana Canestri, Mamadou Cissé, Anne‐Geneviève Marcelin, Gilles Peytavin, Emmanuel Traore, Lambert Assoumou, Ousmane Traoré, Victoria Koita, Fodié Diallo, Awa Thiero Sangare, M. Sidibé, Vincent Cálvez, Aliou Sylla, Christine Katlama, Roland Tubiana,

HIV Research and Treatment

To the Editor: The combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) is the first-line antiretroviral treatment of choice in developing countries.1 NNRTIs are not effective against HIV-2 or on HIV-1 group O,2 and present a low genetic barrier resulting in failure rates of 16% to 38% in different African studies.3-5 In these situations, access to protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) regimens is essential. In Mali, unboosted indinavir (IDV) was the only PI available to treat adults. This regimen necessitates 3 daily intakes and dietary restrictions leading to poor adherence, and therefore to a risk of resistance. Twice-daily low-dose ritonavir-boosted IDV (IDV/r) regimens (400/100 mg) had shown satisfactory efficacy, pharmacokinetics, adherence, and tolerability in HIV-infected patients,6-13 but no study had been conducted in Africa mainly because of ritonavir (RTV) storage conditions. This open, single-arm, single-center pilot study was designed to evaluate the efficacy and tolerability of IDV/r (400/100 mg) during 48 weeks in patients with a plasma viral load (pVL) <400 copies/mL while on an antiretroviral regimen containing 800 mg of IDV administered 3 times daily in CESAC (Care and Counselling Centre) HIV/AIDS Unit in Bamako. The protocol was approved by the Mali National Ethics Committee, and all the patients gave their written consent. Patients were eligible if they had documented HIV-1 infection, were on a stable antiretroviral regimen containing 800 mg of IDV administered 3 times daily plus 2 NRTIs and had a pVL less than 400 copies/mL and creatinemia <200 μmol/L. Physical examinations were performed monthly, and biologic parameters, including an HIV-RNA assay (Amplicor 1.5 HIV Monitor kit; Roche, Branchburg, NJ), CD4 cell counts (FacsCount Immunocytochemistry Systems; Becton-Dickinson, Miami, FL), and IDV trough concentration (Ctrough) determinations, were performed at baseline, week 4, week 24, and week 48. Steady-state IDV plasma concentrations were determined by means of high-performance liquid chromatography with ultraviolet (UV) detection.14 Ctrough was determined just before dosing, and the exact time of the last IDV intake was recorded for each assay. The IDV Ctrough was considered adequate if it was greater than 150 ng/mL.6,7,15 The primary endpoint was the percentage of patients with a pVL <400 copies/mL at week 24. Data were analyzed with the Wilcoxon matched pairs signed rank test in intent-to-treat and on-treatment analyses. Among 48 consecutive patients receiving IDV, 30 were eligible. Table 1 shows their baseline characteristics. None of the patients was lost to follow-up.TABLE 1: Baseline Characteristics of the 30 PatientsIn the intent-to-treat analysis, the proportion of patients in whom the pVL remained less than 400 copies/mL was 97% at week 24 (95% inhibitory concentration [IC95%]: 83%-99%) and 93% at week 48 (IC95%: 79%-98%; Table 2).TABLE 2: Virologic Responses: Proportion of Patients With Plasma HIV RNA (pVL) 400 copies/mL, attributable to 1 antacid self-treatment and 1 treatment interruption for a malaria episode. Both pVLs returned less than 400 copies/mL at week 52, and no major resistance mutations were found in the reverse transcriptase or protease gene. Table 3 shows IDV and RTV plasma Ctrough values during the study period. At baseline, on 800 mg of IDV administered 3 times daily, the median Ctrough was 191 ng/mL (range: 12-425 ng/mL), and it rose to 458 ng/mL (range: 5-1414 ng/mL) at week 48 (P < 0.001). At baseline, only 64% of the patients had an IDV Ctrough >150 ng/mL compared with 96% at week 48 (P < 0.001). The inter- and intraindividual coefficients of variation were 69% and 41%, respectively.TABLE 3: Plasma IDV Ctrough Values in Patients Switched to 400/100 mg of IDV/r (Weeks 4, 24, and 48) From 800 mg of IDV Administered 3 Times DailyEighteen patients (62%) stored RTV in a refrigerator, 6 (21%) in a thermos flask, and 5 (17%) in the traditional jar-a plate containing sand located in a shady part of the house, where food is also kept. Virologic responses were similar in patients using a refrigerator or not, with 100% and 91%, respectively, with a plasma HIV RNA level <400 copies/mL at week 24 and 91% with a plasma HIV RNA level <400 copies/mL at week 48 in both groups. The proportion of patients with adequate Ctrough values was also similar whether RTV was stored in a refrigerator or elsewhere (94% and 100% at week 24 and 94% and 100% at week 48, respectively). Tolerability was satisfactory, with only 1 interruption of the studied regimen for digestive intolerance and no reported nephrolithiasis. This open pilot study shows the efficacy of IDV/r, with the viral load remaining less than 400 copies/mL at week 48 after switching from an IDV thrice-daily regimen in 93% of patients from a clinical center in Bamako. The approximate IDV Ctrough in our study (median of 458 ng/mL at week 48) is comparable to those of other published pharmacokinetic studies,6-8,12,16 even if the patients have different ethnicities and body weight differs. The antiviral response, the pharmacokinetic parameters, and the lack of severe side effects in our study are in line with data from Europe6,7,9,11,12 and Thailand8,10,13 and confirm that the combination of IDV/r (400/100 mg) is a satisfactory balance between toxicity and efficacy in different populations. Because many people do not have access to a refrigerator in Mali, where the new lopinavir/r formulation is not available, our study addresses the issue of RTV storage. Although the number of patients included is small, neither IDV Ctrough values nor virologic efficacy differed according to whether the patients stored RTV in a refrigerator or in a traditional jar or thermos. Moreover twice-daily IDV/r at a dose of 400/100 mg costs at least one third less than the standard IDV regimen, with a reduction in pill burden. This regimen allows Muslims to observe Ramadan without interrupting their treatment. Finally, most HIV-infected patients in Africa are women of child-bearing potential (60% of patients in our study), and IDV/r (400/100 mg) showed good efficacy and tolerability in pregnant women and newborns.17 These findings deserve confirmation, and larger studies are needed to examine the feasibility of extending RTV boosting to other PIs in developing countries. ACKNOWLEDGMENTS A. Canestri and M. Cisse contributed equally to this work. This study was supported by SIDACTION and was presented, in part, at the 2005 International AIDS Society Conference, July 25-27, 2005, Rio de Janeiro, Brazil (abstract MoPe11.7C08). Ana Canestri* Mamadou Cisse† Anne-Geneviève Marcelin‡ Gilles Peytavin§ Emmanuel Traore† Lambert Assoumou∥ Ousmane Traore† Victoria Koita† Fodie Diallo† Awa Thiero Sangare¶ Mayrama Koita Sidibé# Vincent Calvez‡ Aliou Sylla† Christine Katlama* Roland Tubiana* *Département des Maladies Infectieuses Hôpital Pitié-Salpêtrière, INSERM U762 Paris, France †Centre de soins d'Animation et de Conseil pour les personnes vivant avec le VIH/SIDA Bamako, Mali ‡Département de Virologie Hôpital Pitié-Salpétriêre Paris, France §Laboratoire de Toxicologie et de Dosage de Médicaments Hôpital Bichat Claude Bernard Paris, France ∥INSERM U720 Hôpital Pitié-Salpétriêre Paris, France ¶Institut National de Recherche en Santé Publique Bamako, Mali #Laboratoire de biologe, Hôpital du point G Bamako, Mali