Long-term Experience and Outcomes of Programmatic Antiretroviral Therapy for Human Immunodeficiency Virus Type 2 Infection in Senegal, West Africa.

BACKGROUND: Programmatic treatment outcome data for people living with human immunodeficiency virus type 2 (HIV-2) in West Africa, where the virus is most prevalent, are scarce. METHODS: Adults with HIV-2 initiating or receiving antiretroviral therapy (ART) through the Senegalese national AIDS program were invited to participate in this prospective, longitudinal observational cohort study. We analyzed HIV-2 viral loads, CD4 cell counts, antiretroviral drug resistance, loss to follow-up, and mortality. We also examined changes in treatment guidelines over time and assessed progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets for HIV-2. RESULTS: We enrolled 291 participants at 2 sites for 926.0 person-years of follow-up over 13 years. Median follow-up time was 2.2 years per participant. There were 21 deaths reported (7.2%), and 117 individuals (40.2%) were lost to follow-up, including 43 (14.7%) who had an initial visit but never returned for follow-up. CD4 counts and HIV-2 viral suppression (< 50 copies/mL) at enrollment increased over calendar time. Over the study period, 76.7% of plasma viral loads for participants receiving ART were suppressed, and median CD4 gain was 84 cells/µL in participants' first 2 years on study. Since the UNAIDS 90-90-90 strategy was published, 88.1% of viral loads were suppressed. Fifteen percent of patients experienced virologic failure with no known resistance mutations, while 56% had evidence of multiclass drug resistance. CONCLUSIONS: Participants in the Senegalese national AIDS program are initiating ART earlier in the course of disease, and more modern therapeutic regimens have improved outcomes among those receiving therapy. Despite these achievements, HIV-2 treatment remains suboptimal, and significant challenges to improving care remain.

African voices and leadership is imperative for the global AIDS response.

This position paper is written in reference to the recent extensive media coverage of the report of the Independent Panel describing Harassment, Including Sexual Harassment, Bullying and Abuse of Power at UNAIDS Secretariat by several newspapers and authoritative journals such as Science and The Lancet. Unfortunately, none of these publications provide any clear evidence to support the accusations and merely repeat what are, in our view, unsubstantiated statements made in the report. Given the critical role that Africans have played in dealing with one of the most severe epidemics that the world has seen and the gravity of these charges, we believe it is essential to reaffirm that African voices and leadership is imperative for the global AIDS response.

Nonlinear multiple imputation for continuous covariate within semiparametric Cox model: application to HIV data in Senegal.

Multiple imputation is commonly used to impute missing covariate in Cox semiparametric regression setting. It is to fill each missing data with more plausible values, via a Gibbs sampling procedure, specifying an imputation model for each missing variable. This imputation method is implemented in several softwares that offer imputation models steered by the shape of the variable to be imputed, but all these imputation models make an assumption of linearity on covariates effect. However, this assumption is not often verified in practice as the covariates can have a nonlinear effect. Such a linear assumption can lead to a misleading conclusion because imputation model should be constructed to reflect the true distributional relationship between the missing values and the observed values. To estimate nonlinear effects of continuous time invariant covariates in imputation model, we propose a method based on B-splines function. To assess the performance of this method, we conducted a simulation study, where we compared the multiple imputation method using Bayesian splines imputation model with multiple imputation using Bayesian linear imputation model in survival analysis setting. We evaluated the proposed method on the motivated data set collected in HIV-infected patients enrolled in an observational cohort study in Senegal, which contains several incomplete variables. We found that our method performs well to estimate hazard ratio compared with the linear imputation methods, when data are missing completely at random, or missing at random.

Mortality, AIDS-morbidity, and loss to follow-up by current CD4 cell count among HIV-1-infected adults receiving antiretroviral therapy in Africa and Asia: data from the ANRS 12222 collaboration.

BACKGROUND: In resource-limited countries, estimating CD4-specific incidence rates of mortality and morbidity among patients receiving antiretroviral therapy (ART) may help assess the effectiveness of care and treatment programmes, identify program weaknesses, and inform decisions. METHODS: We pooled data from 13 research cohorts in 5 sub-Saharan African (Benin, Burkina Faso, Cameroon, Cote d'Ivoire, and Senegal) and 2 Asian (Cambodia and Laos) countries. HIV-infected adults (18 years and older) who received ART in 1998-2008 and had at least one CD4 count available were eligible. Changes in CD4 counts over time were estimated by a linear mixed regression. CD4-specific incidence rates were estimated as the number of first events occurring in a given CD4 stratum divided by the time spent within the stratum. RESULTS: Overall 3917 adults (62% women) on ART were followed up during 10,154 person-years. In the ≤ 50, 51-100, 101-200, 201-350, 351-500, 501-650, and >650 cells/mm CD4 cells strata, death rates were 20.6, 11.8, 6.7, 3.3, 1.8, 0.9, and 0.3 per 100 person-years; AIDS rates were 50.5, 32.9, 11.5, 4.8, 2.8, 2.2, and 2.2 per 100 person-years; and loss-to-follow-up rates were 4.9, 6.1, 3.5, 3.1, 2.9, 1.7, and 1.2 per 100 person-years, respectively. Mortality and morbidity were higher during the first year after ART initiation. CONCLUSIONS: In these resource-limited settings, death and AIDS rates remained substantial after ART initiation, even in individuals with high CD4 cell counts. Ensuring earlier ART initiation and optimizing case finding and treatment for AIDS-defining diseases should be seen as priorities.

Long-term effectiveness and safety of didanosine combined with lamivudine and efavirenz or nevirapine in antiretroviral-naive patients: a 9-year cohort study in Senegal.

OBJECTIVE: The use of didanosine (ddI) in first-line antiretroviral therapy has been recently promoted for resource-limited settings. We therefore compared the long-term effectiveness and safety of the regimen combining ddI, lamivudine, and efavirenz or nevirapine with that of the WHO-recommended regimen of zidovudine (ZDV), lamivudine, and efavirenz or nevirapine in antiretroviral-naïve patients in Senegal. METHODS: Observational cohort study of patients enrolled between January 2000 and April 2002 in the Senegalese antiretroviral drug access initiative. Multivariate analyses were performed to compare, between the ddI and ZDV groups, the proportion of patients with a viral load <500 copies/ml during follow-up; the increase in the CD4 cell count; survival; treatment changes and severe adverse events. RESULTS: Of 151 patients, 71 received the ddI-based treatment and 80 received the ZDV-based treatment. Throughout follow-up, 80-95% of patients had a viral load below 500 copies/ml in both the ddI and ZDV groups (P = 0.5). The CD4 cell count increased after treatment initiation from 176 to 497 cells/mm(3) in the ddI group and from 176 to 567 cells/mm(3) in the ZDV group (P > 0.3). The rate of death tended to be higher in the ddI group (P = 0.06). ddI was less commonly discontinued than ZDV (P = 0.03). CONCLUSION: The combination of ddI, lamivudine, and efavirenz or nevirapine resulted in sustained viral suppression and immunological recovery.

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.

Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case-control study.

OBJECTIVE: To assess adverse effects of long-term highly active antiretroviral therapy (HAART), that is, lipodystrophy and metabolic disorders, in a cohort of African patients. METHODS: One hundred eighty HIV-1-infected patients treated with HAART for 4-9 years in Dakar and 180 age-matched and sex-matched controls were enrolled. Regional subcutaneous fat changes were assessed by physicians, and fasting blood samples were drawn. Centralization of body fat was estimated using skinfold ratio, waist circumference, and waist to hip ratio (WHR). RESULTS: Mean duration of HAART was 5.4 years. Main drugs received were zidovudine, stavudine, and protease inhibitors. The prevalence of moderate-severe lipodystrophy was 31.1% (95% confidence interval: 24.3 to 37.9), with 13.3%, 14.5%, and 3.3% for lipoatrophy, lipohypertrophy, and mixed forms, respectively. Mild-severe lipodystrophy affected 65.0% (58.0; 72.0) of patients. Stavudine was the only independent risk factor (any vs. none: odds ratio = 2.8; 1.4 to 5.5). Patients had lower body mass index and skinfolds but greater centralization of body fat (WHR, P < 0.0001 and skinfold ratio, P < 0.001), fasting glucose (P < 0.0001), homeostasis model assessment insulin resistance, and triglyceride levels (P < 0.01 for both) than controls. Moderately-severely lipodystrophic patients had higher triglyceride and low-density lipoprotein cholesterol than other patients (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Moderate-severe lipodystrophy affected one third of West African patients on long-term HAART and was associated with a less favorable metabolic profile.

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.

A 84-month follow up of adherence to HAART in a cohort of adult Senegalese patients.

OBJECTIVES: To assess long-term adherence of the first HIV-1 patients receiving highly active antiretroviral therapy (HAART) in Senegal, and to identify the main determinants of adherence. METHODS: The first 180 patients enrolled in the Senegalese HAART initiative between August 1998 and April 2001 followed up for at least 30 days were eligible. Adherence was assessed monthly at each drug dispensation between November 1999 and November 2006 by a pharmacist using a pill count completed by a questionnaire. Adherence was expressed as the proportion of tablets taken to prescribed tablets. An adherence of 95% was considered to be good. A random-intercept logit model was fitted to identify the main determinants of adherence. RESULTS: Adherence data were available for 158 of 167 eligible patients. Twenty-nine patients died during the study period and 10 were lost to follow-up. Median treatment duration was 78 months, accruing to 6657 person-months of observation. Overall, mean adherence reached 91% [median: 100%, interquartile range (IQR) 96-100%] and adherence exceeded 95% in 78% [95% CI 77-79%] of observations. After 4 years of treatment mean adherence stabilized around 90% and adherence > or =95% stabilized around 70%. Treatment duration and protease inhibitor (PI)-based regimen (indinavir) had a negative effect on adherence, but adherence tended to improve with time for patients receiving a PI. Patient-level variance was highly significant and accounted for a third of total variance. CONCLUSIONS: This work demonstrates that good long-term adherence can be achieved in the sub-Saharan context given close monitoring and adherence support measures, confirms the worse adherence for indinavir and underlines the importance of patient heterogeneity.

No evidence for recombination between HIV type 1 and HIV type 2 within the envelope region in dually seropositive individuals from Senegal.

To investigate the frequency of recombination between HIV-1 and HIV-2 in vivo during dual infection, we performed a retrospective analysis of blood samples from 46 dual HIV-1/HIV-2-seropositive adults for evidence of recombination. HIV viral DNA from peripheral blood mononuclear cells (PBMC) was subjected to two separate nested polymerase chain reaction (PCR) assays using opposing HIV-1 and HIV-2 primer pairs selected to flank a approximately 650-base pair region including the V3 loop of the envelope gene. In the first assay, primers were chosen to amplify recombinants with HIV-1 on the 5' end and HIV-2 on the 3' end, and in the second assay, primers were chosen to amplify recombinants with the opposite orientation. All PCR experiments were run in parallel with positive controls consisting of partial-length env fragments bearing a single central HIV-1/2 recombination site, and appropriate primer-binding sites on each end. The limit of detection for both assays was <10 copies of recombinant product per 150,000 cell equivalents of input PBMC DNA. In all 46 dually seropositive patients in this study, PCR screening of PBMC failed to detect evidence of HIV-1/HIV-2 recombinants in the C2-V5 env region. Although genetic recombination between HIV-1 and HIV-2 may occur, we conclude that any such events within env are exceedingly rare, and do not result in the outgrowth of recombinant strains.

Molecular epidemiology of dual HIV-1/HIV-2 seropositive adults from Senegal, West Africa.

Dual infection with HIV-1 and HIV-2 can occur in locales where these viruses co-circulate, most commonly in West Africa. Although dual seropositivity is common in this region, the true rate of dual infection remains unclear. In addition, whether unique HIV-1 subtypes are circulating in dually infected individuals is unknown. A cohort of 47 HIV-1 and HIV-2 dually seropositive individuals from Senegal, West Africa was screened for the presence of HIV-1 and HIV-2 gag and env PBMC viral DNA sequences using PCR. Of the 47 dual HIV-1/HIV-2 seropositive individuals tested, 19 (40.4%) had infection with both HIV-1 and HIV-2 confirmed by genetic sequence analysis, whereas only HIV-1 or HIV-2 was confirmed in 17 (36.2%) or 9 (19.1%), respectively. The majority of HIV-1 subtypes found were CRF-02 and A, although subtypes D, C, G, J and B were also found, reflecting the subtypes known to be circulating in Senegal. There was no significant difference in HIV-1 subtype distribution between individuals with confirmed dual infection and patients in this study with dual seropositivity but lacking HIV-2, or with HIV-1 infected patients within the general population in Senegal, although the study was underpowered to detect anything but large differences. The prevalence of HIV-1/HIV-2 dual infection appears to be significantly less than that of dually seropositive individuals and this likely reflects cross-reactive serology. The common HIV-1 subtypes prevalent in West Africa (CRF-02 and subtype A) have a similar distribution to those found in our cohort of dually infected and dually seropositive subjects.

Equal plasma viral loads predict a similar rate of CD4+ T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa.

Human immunodeficiency virus (HIV) type 2 infection is characterized by slower disease progression to acquired immunodeficiency syndrome than results from HIV-1 infection. To better understand the biological factors underlying the different natural histories of infection with these 2 retroviruses, we examined the relationship between HIV RNA and DNA levels and the rate of CD4(+) T cell decline among 472 HIV-1- and 114 HIV-2-infected individuals from Senegal. The annual rate of CD4(+) T cell decline in the HIV-2 cohort was approximately one-fourth that seen in the HIV-1 cohort. However, when the analysis was adjusted for baseline plasma HIV RNA level, the rates of CD4(+) T cell decline per year for the HIV-1 and HIV-2 cohorts were similar (a rate increase of approximately 4% per year for each increase in viral load of 1 log(10) copies/mL). Therefore, plasma HIV load is predictive of the rate of CD4(+) T cell decline over time, and the correlation between viral load and the rate of decline appears to be similar among all HIV-infected individuals, regardless of whether they harbor HIV-1 or HIV-2.