Sex-dependent interactions between leptin, wasting and humoral immunity in two ethnic communities of school-aged children differentially exposed to Schistosoma haematobium.

Background: Leptin is a nutritional hormone whose production is generally higher in females. We investigated how leptin is associated with sex dimorphism during urinary schistosomiasis in relation with wasting. Methods: A cross-sectional study was carried out in three villages in northern Senegal. Ninety-eight school-aged children belonging to the Fulani or Wolof villages were enrolled. We performed parasitic diagnosis and anthropometric measurement to evaluate nutritional status. We collected peripheral blood to determine the amount of circulating leptin and immunoglobulin G (IgG), IgG4 and IgE directed to soluble worm antigen preparation (SWAP). Results: The prevalence of Schistosoma haematobium infection was higher among boys regardless of ethnic group, but exposure to parasites did not exacerbate malnutrition. The greater ability of girls to produce leptin was not altered by schistosomiasis and was recovered in both ethnic groups. However, while the usual correlation between leptin and fat storage was preserved in Fulani girls, it was disrupted in Fulani boys, who displayed a remarkable susceptibility for wasting. Finally, we observed that leptin was negatively associated with the level of antibodies in Wolof boys. Conclusions: Leptin can be disconnected from body fat and may exert a sex-dependent influence on host immune response to S. haematobium infection in Senegalese children.

Disease patterns and causes of death of hospitalized HIV-positive adults in West Africa: a multicountry survey in the antiretroviral treatment era.

OBJECTIVE: We aimed to describe the morbidity and mortality patterns in HIV-positive adults hospitalized in West Africa. METHOD: We conducted a six-month prospective multicentre survey within the IeDEA West Africa collaboration in six adult medical wards of teaching hospitals in Abidjan, Ouagadougou, Cotonou, Dakar and Bamako. From April to October 2010, all newly hospitalized HIV-positive patients were eligible. Baseline and follow-up information until hospital discharge was recorded using standardized forms. Diagnoses were reviewed by a local event validation committee using reference definitions. Factors associated with in-hospital mortality were studied with a logistic regression model. RESULTS: Among 823 hospitalized HIV-positive adults (median age 40 years, 58% women), 24% discovered their HIV infection during the hospitalization, median CD4 count was 75/mm(3) (IQR: 25-177) and 48% had previously received antiretroviral treatment (ART). The underlying causes of hospitalization were AIDS-defining conditions (54%), other infections (32%), other diseases (8%) and non-specific illness (6%). The most frequent diseases diagnosed were: tuberculosis (29%), pneumonia (15%), malaria (10%) and cerebral toxoplasmosis (10%). Overall, 315 (38%) patients died during hospitalization and the underlying cause of death was AIDS (63%), non-AIDS-defining infections (26%), other diseases (7%) and non-specific illness or unknown cause (4%). Among them, the most frequent fatal diseases were: tuberculosis (36%), cerebral toxoplasmosis (10%), cryptococcosis (9%) and sepsis (7%). Older age, clinical WHO stage 3 and 4, low CD4 count, and AIDS-defining infectious diagnoses were associated with hospital fatality. CONCLUSIONS: AIDS-defining conditions, primarily tuberculosis, and bacterial infections were the most frequent causes of hospitalization in HIV-positive adults in West Africa and resulted in high in-hospital fatality. Sustained efforts are needed to integrate care of these disease conditions and optimize earlier diagnosis of HIV infection and initiation of ART.

Two doses of candidate TB vaccine MVA85A in antiretroviral therapy (ART) naïve subjects gives comparable immunogenicity to one dose in ART+ subjects.

Tuberculosis (TB) is a global public health problem exacerbated by the HIV epidemic. Here we evaluate a candidate TB vaccine, MVA85A, in a Phase I study in HIV-infected adults in Senegal. 24 patients were enrolled: Group 1∶12, antiretroviral therapy (ART) naïve, adults, with CD4 counts >300 and HIV RNA load <100,000 copies/ml. Group 2∶12 adults, stable on ART, with CD4 counts >300, and an undetectable HIV RNA load. Safety was evaluated by occurrence of local and systemic adverse events (AEs) and by monitoring of CD4 count, HIV RNA load, haematology and biochemistry. Immunogenicity was evaluated by ex-vivo interferon-gamma ELISpot assay. 87.7% of AEs were mild; 11.6% were moderate; and 0.7% were severe. 29.2% of AEs were systemic; 70.8% were expected local AEs. There were no vaccine-related Serious Adverse Events (SAEs) or clinically significant effects on HIV RNA load or CD4 count. In ART naive subjects, the first MVA85A immunisation induced a significant immune response at 1 and 4 weeks post-immunisation, which contracted to baseline by 12 weeks. Durability of immunogenicity in subjects on ART persisted out to 24 weeks post-vaccination. A second dose of MVA85A at 12 months enhanced immunogenicity in ART naïve subjects. Subjects on ART had higher responses after the first vaccination compared with ART naïve subjects; responses were comparable after 2 immunisations. In conclusion, MVA85A is well-tolerated and immunogenic in HIV-infected subjects in Senegal. A two dose regimen in ART naïve subjects is comparable in immunogenicity to a single dose in subjects on ART. Clinicaltrials.gov trial identifier NCT00731471.

HIV-1 outcompetes HIV-2 in dually infected Senegalese individuals with low CD4⁺ cell counts.

OBJECTIVE: Dual infection with HIV-1 and HIV-2, which is not uncommon in West Africa, has implications for transmission, progression, and antiretroviral therapy (ART). Few studies have examined viral dynamics in this setting. Our objective was to directly compare HIV-1 and HIV-2 viral loads and to examine whether this relationship is associated with CD4⁺ cell count. STUDY DESIGN: This is a retrospective analysis of data from observational cohort studies. METHODS: We compared HIV-1 and HIV-2 viral loads from 65 dually infected, ART-naive Senegalese individuals. Participants provided blood, oral fluid, and cervicovaginal lavage (CVL) or semen samples for virologic and immunologic testing. We assessed relationships between HIV-1 and HIV-2 levels using linear regression with generalized estimating equations to account for multiple study visits. RESULTS: After adjusting for CD4⁺ cell count, age, sex, and commercial sex work, HIV-1 RNA levels were significantly higher than HIV-2 levels in semen, CVL, and oral fluids. Despite similar peripheral blood mononuclear cell DNA levels among individuals with CD4⁺ cell counts above 500 cells/µl, individuals with CD4⁺ cell counts below 500 cells/µl had higher HIV-1 and lower HIV-2 DNA levels. Individuals with high CD4⁺ cell counts had higher mean HIV-1 plasma RNA viral loads than HIV-2, with HIV-1 levels significantly higher and HIV-2 levels trending toward lower mean viral loads among individuals with low CD4⁺ cell counts. CONCLUSION: Our data are consistent with the hypothesis that with disease progression, HIV-1 outcompetes HIV-2 in dually infected individuals. This finding helps explain differences in prevalence and outcomes between HIV-1, HIV-2, and HIV-dual infection.

Risk of virological failure and drug resistance during first and second-line antiretroviral therapy in a 10-year cohort in Senegal: results from the ANRS 1215 cohort.

BACKGROUND: In 1998, Senegal launched one of Africa's first antiretroviral therapy (ART) programs. Since then, the number of treated patients in Africa has substantially increased thanks to simplification in treatment management. Although good outcomes over the first years of ART have been observed in sub-Saharan Africa, little is known about the long-term (>5 years) risks of virological failure and drug resistance and about second-line treatment response. METHODS: Patients from the ANRS-1215 cohort in Senegal, started with either one nonnucleoside reverse transcriptase inhibitor or indinavir, a first-generation nonboosted protease inhibitor, followed for >6 months and having >1 viral load (VL) measurement were included. Virological failure was defined as 2 consecutive VL measurements >1000 copies/mL. RESULTS: Of the 366 patients included, 89% achieved a VL <500 copies/mL. The risk of virological failure at 12, 24, and 60 months was 5%, 16%, and 25%, being higher in younger patients (P = 0.05), those receiving a protease inhibitor-containing regimen (P = 0.05), and those with lower adherence (P = 0.03). The risk of resistance to any drug at 12, 24, and 60 months was 3%, 11%, and 18%. After virological failure, 60% of the patients were switched to second-line treatments. Although 81% of the patients achieved virological success, the risk of virological failure was 27% at 24 months, mostly in patients with multiple resistances. CONCLUSIONS: In this cohort, virological outcomes for first-line treatments were good compared with those from high-resource settings. However, the rate of virological failure for second-line treatment was high, probably because of accumulation of resistances.

Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance.

OBJECTIVES: Raltegravir is the first integrase strand transfer inhibitor approved for treating HIV-1 infection. Although emerging data suggest that raltegravir may also be useful for HIV-2 treatment, studies addressing the in-vitro susceptibility of HIV-2 to raltegravir are scarce, and the genetic pathways leading to raltegravir resistance in HIV-2 have not been adequately characterized. Our objectives were to directly compare the susceptibilities of HIV-1 and HIV-2 to raltegravir and to examine the role of mutations in HIV-2 integrase in emergent raltegravir resistance. MATERIALS AND METHODS: Single-cycle and spreading infection assays were used to quantify the sensitivities of wild-type HIV-1 and HIV-2 strains to raltegravir. HIV-2 integrase mutants were constructed by site-directed mutagenesis, and the replication capacities and raltegravir susceptibilities of the resultant variants were analyzed in single-cycle assays. RESULTS: Raltegravir showed comparable activity against wild-type HIV-1 and HIV-2 in both single-cycle and spreading infections, with EC(50) values in the low nanomolar range. Amino acid changes Q148R and N155H individually conferred resistance to raltegravir (14-fold and seven-fold, respectively), whereas the Y143C replacement had no statistically significant effect on raltegravir sensitivity. The combination of Q148R with N155H resulted in high-level raltegravir resistance (>1000-fold). In addition, all HIV-2 integrase variants tested showed impairments in replication capacity. CONCLUSION: Our data support clinical studies of raltegravir for treating HIV-2 infection and show that the Q148R and N155H changes alone are sufficient for raltegravir resistance in HIV-2. Further efforts are needed to improve access to HIV-2-active antiretrovirals, including raltegravir, in resource-limited areas where HIV-2 is endemic.

Incidence and determinants of new AIDS-defining illnesses after HAART initiation in a Senegalese cohort.

BACKGROUND: Although a dramatic decrease in AIDS progression has been observed after Highly Active Anti Retroviral Therapy (HAART) in both low- and high-resource settings, few data support that fact in low-resource settings.This study describes the incidence of AIDS-defining illnesses (ADI) after HAART initiation and analyzes their risk factors in a low-resource setting. A focus was put on CD4 cell counts and viral load measurements. METHODS: 404 HIV-1-infected Senegalese adult patients were enrolled in a prospective observational cohort and data censored as of April 2008. A Poisson regression was used to model the incidence of ADIs over two periods and to assess its association with baseline variables, current CD4, current viral load, CD4 response, and virological response. RESULTS: ADI incidence declined from 20.5 ADIs per 100 person-years, 95% CI = [16.3;25.8] during the first year to 4.3, 95% CI = [2.3;8.1] during the fourth year but increased afterwards. Before 42 months, the decrease was greater in patients with clinical stage CDC-C at baseline and with a viral load remaining below 1000 cp/mL but was uniform across CD4 strata (p = 0.1). After 42 months, 293 patients were still at risk. The current CD4 and viral load were associated with ADI incidence (decrease of 21% per 50 CD4/mm3 and of 61% for patients with a viral load < 1000 cp/mL). CONCLUSIONS: During the first four years, a uniform decline of ADI incidence was observed even in patients with low CD4-cell counts at HAART initiation as long as the viral load remained undetectable. An increase was noted later in patients with immunologic and virological failures but also in patients with only virological failure.

Sensitivity of IFN-gamma release assay to detect latent tuberculosis infection is retained in HIV-infected patients but dependent on HIV/AIDS progression.

BACKGROUND: Detection and treatment of latent TB infection (LTBI) in HIV infected individuals is strongly recommended to decrease morbidity and mortality in countries with high levels of HIV. OBJECTIVE: To assess the validity of a newly developed in-house ELISPOT interferon-gamma release assay (IGRA) for the detection of LTBI amongst HIV infected individuals, in comparison with the Tuberculin Skin Test (TST). METHODOLOGY/PRINCIPAL FINDINGS: ESAT6/CFP10 (EC) ELISPOT assays were performed, together with a TST, in 285 HIV infected individuals recruited in HIV clinics in Dakar, Senegal, who had no signs of active TB at time of enrolment. Thirty eight of the subjects (13.3%) failed to respond to PHA stimulation and were excluded from the analysis. In the 247 remaining patients, response to PHA did not vary according to CD4 cell count categories (p = 0.51). EC ELISPOT was positive in 125 (50.6%) subjects, while 53 (21.5%) had a positive TST. Concordance between EC ELISPOT and TST was observed in 151 patients (61.1%) (kappa = 0.23). The proportion of subjects with a positive response to the EC ELISPOT assay decreased with declining CD4 counts (p trend = 0.001), but were consistently higher than the proportion of TST responders. In multivariate analysis, the risk of being EC-ELISPOT positive in HIV infected individuals was associated with age, CD4 count and HIV-1 strain. CONCLUSION: Our study indicates that IGRAs using M. tuberculosis specific antigens are likely to retain their validity for the diagnosis of LTBI among HIV positive individuals, but may be impaired by T-cell anergy in severely immuno-suppressed individuals.

Implementation of an antiretroviral access program for HIV-1-infected individuals in resource-limited settings: clinical results from 4 African countries.

BACKGROUND: We assessed the effectiveness and safety of highly active antiretroviral therapy (HAART) in HIV-1-infected patients in resource-limited African countries. HIV-1 screening, therapy, counseling, monitoring, training, and education were provided free of charge. METHODS: In an open-label cohort program, 206 antiretroviral-naive HIV-1-infected patients who could not afford HAART were recruited in 4 urban clinics in Senegal, Côte d'Ivoire, Uganda, and Kenya and were treated with saquinavir boosted with ritonavir (1600/100 mg once daily), lamivudine (150 mg twice daily), and zidovudine (300 mg twice daily). The primary outcome was a plasma viral load (pVL) of <400 copies/mL after 96 weeks of treatment. Secondary analyses included CD4 cell count changes and the occurrence of treatment-emergent adverse events. RESULTS: The median age of the patient group was 36 years, 38% were male, 35% of the patients had AIDS, the median CD4 count was 119 cells/microL, and the median pVL was 304,210 copies/mL. Overall, 65%/52% (on treatment [OT]/intent to treat [ITT]) of the patients had a pVL <400 copies/mL after 96 weeks of follow-up. This proportion varied significantly between sites, however; although in Nairobi and Dakar, 51%/40% and 56%/46% (OT/ITT) were found, respectively, Abidjan and Kampala showed proportions of 69%/54% and 83%/69% (OT/ITT), respectively. The median increase in the CD4 count was 198 cells/microL (interquartile range: 86-319 cells/microL), ranging from 191 to 292 cells/microL between the sites. Fourteen patients (6.8%) died between 8 and 96 weeks of follow-up, whereas 18 (9%) developed an AIDS-defining event between 8 and 96 weeks of follow-up. Non-HIV-related serious adverse events occurred in 55 patients (26.7%), of whom 13 were diagnosed with severe anemia. Thirty-five patients (17%) changed treatment for toxicity reasons. CONCLUSIONS: Although a statistically significant difference was observed between sites with respect to virologic success, overall virologic and immunologic responses to HAART in resource-limited African settings can be as good as in Western settings. There were some difficulties (eg, laboratory, logistics, proper training) during the early phase of the program. Therefore, provision of adequate medical care, counseling, proper instruction, and education of patients and medical staff during the entire study is warranted in such programs, with special care in the early phase.

Characterization of pathogenic Escherichia coli in human immunodeficiency virus-related diarrhea in Senegal.

Stool samples obtained from 594 Senegalese patients were examined for characterization of pathogenic Escherichia coli in human immunodeficiency virus (HIV)-related diarrhea. Multiple virulence genes were observed in stool samples obtained from HIV-infected patients with diarrhea. Enteroaggregative E. coli and enteroinvasive E. coli were present in stool samples obtained from patients with diarrhea significantly more often than in stool samples obtained from patients without diarrhea (P=.000001). Quinolones may be an effective alternative treatment for E. coli-related diarrhea in HIV-infected adults in Senegal.

Access to antiretroviral drugs and AIDS management in Senegal.

OBJECTIVES: Description and analysis of the Senegalese Antiretroviral Drug Access Initiative (ISAARV), the first governmental highly active antiretroviral therapy (HAART) treatment programme in Africa, launched in 1998. METHODS AND RESULTS: ISAARV was initially an experimental project designed to evaluate the feasibility, efficacy and acceptability of HAART in an African context. It was based on four principles: collective definition of the strategy, with involvement of the health professionals who would be called on to execute the programme; matching the objectives to available means (gradual enrollment according to drug availability); monitoring by several research programmes; and ongoing adaptation of treatment and follow-up according to the latest international recommendations. Persons qualifying for antiretroviral (ARV) therapy are selected on the basis of immunological and clinical criteria, regardless of economic and social considerations. A system of subsidies was created to favor access to ARV. Following the ARV price reductions that occurred in November 2000, 100% subsidies were created for the poorest participants. Optimal adherence was ensured by monthly follow-up by pharmacists and support groups held by social workers and patient associations. The chosen supply and distribution system allowed drug dispensing to be strictly controlled. CONCLUSION: The ISAARV programme demonstrates that HAART can be successfully prescribed in Africa. This experience has served as the basis for the creation of a national treatment programme in Senegal planned to treat 7000 patients by 2006.