Modeling CD4+ cell count increase over a six-year period in HIV-1-infected patients on highly active antiretroviral therapy in Senegal.

To assess the extents and determinants of long-term CD4 cell increases after initiation of antiretroviral therapy (ART), changes in CD4 cell counts were analyzed in a cohort of HIV-1-infected Senegalese using a mixed-effects model. After a median follow-up of 54 months, an average of 483 CD4 cells/mm3 (95% confidence interval [CI] = 331; 680) was reached. The average asymptote level was approximately 421 cells/mm3 (95% CI = 390; 454) in patients with < 200 cells/mm3 at baseline and approximately 500 cells/mm3 in patients with > 200 cells/mm3. The independent predictors of long-term CD4 cell reconstitution were the baseline CD4 cell count and the monthly average viral load over the entire follow-up. This good long-term immune reconstitution, optimal in subjects with low average viral loads and > 200 CD4 cells/mm3 at baseline, argues in favor of the earliest possible access to ART and underlines the importance of strict compliance with the treatment.

Change over time of mortality predictors after HAART initiation in a Senegalese cohort.

BACKGROUND: In 1998, Senegal was among the first sub-Saharan African countries to launch a Highly active anti-retroviral therapy (HAART) access program. Initial studies have demonstrated the feasibility and efficacy of this initiative. Analyses showed a peak of mortality short after starting HAART warranting an investigation of early and late mortality predictors. METHODS: 404 HIV-1-infected Senegalese adult patients were enrolled and data censored as of September 2005. Predictor effects on mortality were first examined over the whole follow-up period (median 46 months) using a Cox model and Shoenfeld residuals. Then, changes of these effects were examined separately over the early and late treatment periods; i.e., less and more than 6-month follow-up. RESULTS: During the early period, baseline body mass index and baseline total lymphocyte count were significant predictors of mortality (Hazard Ratios 0.82 [0.72-0.93] and 0.80 [0.69-0.92] per 200 cell/mm3, respectively) while baseline viral load was not significantly associated with mortality. During the late period, viro-immunological markers (baseline CD4-cell count and 6-month viral load) had the highest impact. In addition, the viral load at 6-month was a significant predictor (HR = 1.42 [1.20-1.66]). CONCLUSION: In this cohort, impaired clinical status could explain the high early mortality rate while viro-immunological markers were rather predictors of late mortality.

Urban malaria in Dakar, Senegal: chemosusceptibility and genetic diversity of Plasmodium falciparum isolates.

The chemosusceptibility and genetic polymorphism of Plasmodium falciparum populations from 48 patients hospitalized for malaria at the Hospital Principal in Dakar, Senegal were investigated during the 2002 malaria transmission season. Sixty-two percent of the isolates collected were from patients with severe malaria and 38% were from patients with mild malaria. In vitro activities of chloroquine, quinine, cycloguanil, atovaquone, mefloquine, halofantrine, and artesunate were evaluated. The prevalence of mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and dihyropteroate synthetase (dhps) genes and the P. falciparum chloroquine resistance transporter (Pfcrt) gene associated with cycloguanil, pyrimethamine, sulfadoxine, and chloroquine resistance were estimated. The genetic polymorphism of the parasite populations was evaluated by analysis of the highly polymorphic regions of merozoite surface protein 1 (msp1) block 2 and msp2. Seventy percent of the isolates were assessed by an in vitro assay. Fifty-two percent of the isolates were chloroquine resistant, 45% were cycloguanil resistant, and 24% were atovaquone resistant. Four percent had low susceptibility to quinine. The Pfcrt and dhfr mutations were associated with in vitro chloroquine- and antimetabolic drug-resistant isolates, respectively. Approximately 70% of the isolates contained two or more clones. Genetic diversity of P. falciparum was high. The prevalence of allelic family K1 of msp1 was 68%. Isolates of P. falciparum were highly resistant to chloroquine, cycloguanil and atovaquone. The transmission rate of malaria in Dakar is low but a high degree of genetic polymorphism can increase severe malaria, as shown by persons coming to Dakar from areas highly endemic for malaria. Areas with urban malaria should use vector control measures and efficient chemoprophylaxis for non-immune populations.

Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study.

OBJECTIVES: To evaluate survival and investigate causes of death among HIV-1 infected adults receiving HAART in Senegal. DESIGN: An observational prospective cohort. METHODS: Mortality was assessed in the first patients enrolled between August 1998 and April 2002 in the Senegalese antiretroviral drug access initiative. First-line regimen combined two nucleoside reverse transcriptase inhibitors and either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. The most likely causes of death were ascertained through medical records or post-mortem interviews (verbal autopsy). RESULTS: Four hundred and four patients (54.7% women) were enrolled in the study and were followed for a median of 46 months (interquartile range: 32-57 months) after HAART initiation. At baseline, 5% were antiretroviral therapy (ART) non-naive, 39 and 55% were respectively at CDC stage B and C, median age, CD4 cell count and viral load were 37 years, 128 cells/microl and 5.2 log cp/ml, respectively. Ninety-three patients died during follow-up and the overall incidence rate of death was 6.3/100 person-years [95% confidence interval (CI), 5.2-7.7]. During the first year after HAART initiation, 47 patients died and seven were lost to follow-up, yielding to a probability of dying of 11.7% (95% CI, 8.9-15.3%). The death rate, which was highest during the first year after HAART initiation, decreased with time yielding a cumulative probability of dying of 17.4% (95% CI, 13.9-21.5%) and 24.6% (95% CI, 20.4-29.4%) at 2 and 5 years. Causes of death were ascertained in 76 deaths. Mycobacterial infections, neurotropic infections and septicaemia were the most frequent likely causes of death. CONCLUSIONS: This study underlines the early mortality pattern after HAART initiation and highlights the leading role of mycobacterial infections in the causes of death.

Long-term benefits of highly active antiretroviral therapy in Senegalese HIV-1-infected adults.

OBJECTIVES: To assess the long-term survival, as well as the immunologic and virologic effectiveness, adherence, and drug resistance, in HIV-infected patients receiving highly active antiretroviral therapy (HAART) in one of the oldest and best-documented African cohorts. METHODS: A prospective observational cohort study included the first 176 HIV-1-infected adults followed in the Senegalese government-sponsored antiretroviral therapy initiative launched in August 1998. Patients were followed for a median of 30 months (interquartile range, 21-36 months). HAART comprised 2 nucleoside reverse transcriptase inhibitors and either 1 protease inhibitor or 1 nonnucleoside reverse transcriptase inhibitor. RESULTS: At baseline, 92% of patients were antiretroviral naive and 82% had AIDS; the median CD4 count was 144 cells/mm, and median viral load was 202,368 copies/mL. The survival probability was high (0.81 at 3 years; 95% CI, 0.74-0.86) and was independently related to a baseline hemoglobin level <10 g/dL and a Karnofsky score <90%. Antiviral efficacy was consistently observed during the 3 years of treatment (-2.5 to -3.0 log10 copies/mL; 60-80% of patients with viral load <500 copies/mL) and the CD4 count increase reached a median of 225 cells/mm. Most patients reported good adherence (80-90%). The emergence of drug resistance was relatively rare (12.5%). CONCLUSION: This study shows that clinical and biologic results similar to those seen in Western countries can be achieved and sustained during the long term in Africa.

Low rate of genotypic HIV-1 drug-resistant strains in the Senegalese government initiative of access to antiretroviral therapy.

OBJECTIVE: To monitor the prevalence of antiretroviral (ARV)-resistant HIV-1 viruses, and the genotypic mutations in patients enrolled in the Senegalese initiative for access to antiretroviral treatment (ART). METHODS: A total of 80 patients with a virological follow-up of at least 6 months were selected, 68 were ART-naive and 12 ART-experienced. Genotypic resistance to ARV was studied at baseline for a random subset of patients and at each rebound in plasma viral load during ART, by sequencing the protease and reverse transcriptase genes. RESULTS: At baseline, 66 patients received highly active antiretroviral therapy (HAART) [2 nucleoside reverse transcriptase inhibitors (NRTIs) +1 protease inhibitor (PI) (n = 64) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (n = 2)] and 14 patients (17.5%) started with a dual therapy because of ongoing antitubercular therapy or efficient previous bitherapy for the ART-experienced patients. The emergence of drug-resistant viruses (n = 13) during follow-up was more frequent in ART-experienced patients than in ART-naive patients, 41.7 versus 11.8%, resistant viruses emerged at comparable follow-up periods, a median of 17.8 and 18.3 months, respectively. In patients receiving zidovudine and lamivudine in their drug regimen, resistance to lamivudine was more frequent than to zidovudine. Two of the three patients, with viruses resistant to PIs, acquired mutations associated with cross-resistance. Strikingly, five (39%) of the 13 patients developed resistances to drugs that they had never received (n = 3) or that they received 18 or 36 months ago (n = 2). Didanosine/stavudine pressure had selected zidovudine-resistant viruses in four patients, and indinavir had selected a nelfinavir-resistant virus in one patient. CONCLUSION: In contrast to other reports from developing countries where patients had received ARVs in an uncontrolled manner, our study showed that implementation of HAART together with good clinical, biological and logistical monitoring can reduce the emergence of resistant strains in Africa.