Daniel Fekade

High prevalence of Cryptococcal antigenemia among HIV-infected patients receiving antiretroviral therapy in Ethiopia.

Background Cryptococcal disease is estimated to be responsible for significant mortality in Sub-Saharan Africa; however, only scarce epidemiology data exists. We sought to evaluate the prevalence of and risk factors for cryptococcal antigenemia in Ethiopia. Methods Consecutive adult HIV-infected patients from two public HIV clinics in Addis Ababa, Ethiopia were enrolled into the study. A CD4 count ≤200 cells/μl was required for study participation. Patients receiving anti-retroviral therapy (ART) were not excluded. A cryptococcal antigen test was performed for all patients along with an interview, physical exam, and medical chart abstraction. Logistic regression analysis was used to assess risk factors for cryptococcal antigenemia. Results 369 HIV-infected patients were enrolled; mean CD4 123 cells/μl and 74% receiving ART. The overall prevalence of cryptococcal antigenemia was 8.4%; 11% in patients with a CD4 count <100 cells/μl, 8.9% with CD4 100 to 150 cells/μl and 5.7% with CD4150-200 cell/μl. 84% of patients with cryptococcal antigenemia were receiving ART. In multivariable analysis, increasing age, self reported fever, CD4 count <100 cells/μl, and site of screening were associated with an increased risk of cryptococcal antigenemia. No individual or combination of clinical symptoms had optimal sensitivity or specificity for cryptococcal antigenemia. Conclusion Cryptococcal antigenemia is high in Ethiopia and rapid scale up of screening programs is needed. Screening should be implemented for HIV-infected patients with low CD4 counts regardless of symptoms or receipt of ART. Further study into the effect of location and environment on cryptococcal disease is warranted.

Recombinant Human Interleukin-10 Fails to Alter Proinflammatory Cytokine Production or Physiologic Changes Associated with the Jarisch-Herxheimer Reaction

Interleukin (IL)-10 may have a role in the treatment of cytokine-associated inflammatory syndromes. The Jarisch-Herxheimer reaction (J-HR), which follows antibiotic treatment of Borrelia recurrentis infection, is a useful model of acute systemic inflammation associated with a cytokine surge and characteristic pathophysiologic changes. In a double-blind, placebo-controlled study, 49 Ethiopian men with B. recurrentis infection were randomized to receive a single intravenous bolus of either 25 microg/kg of recombinant human (rh) IL-10 or vehicle control shortly before receiving intramuscular penicillin. Patients were monitored for physiologic changes, and plasma samples were taken repeatedly for 24 h after treatment. rhIL-10 had no impact on changes in any of the physiologic parameters of J-HR, plasma cytokine levels, or the rate of spirochete clearance. A single intravenous bolus of 25 microgram/kg of rhIL-10 does not seem to have a useful role in the treatment of the J-HR associated with B. recurrentis infection.

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

BackgroundCCR5 coreceptor using HIV-1 subtype C (HIV-1C) has been reported to dominate the Ethiopian epidemic. However, almost all data have been obtained from two large cities in the central and north-west regions and recent data is lacking.MethodsPlasma were obtained from 420 treatment-naïve patients recruited 2009–2011 to a large country-wide Ethiopian cohort. The V3 region was sequenced and the co-receptor tropism was predicted by the clinical and clonal models of the geno2pheno tool at different false positive rates (fpr) and for subtype. In an intention to treat analysis the impact of baseline tropism on outcome of antiretroviral therapy was evaluated.ResultsV3 loop sequencing was successful in 352 (84%) patients. HIV-1C was found in 350 (99.4%) and HIV-1A in two (0.6%) patients. When comparing the geno2pheno fpr10% clonal and clinical models, 24.4% predictions were discordant. X4-virus was predicted in 17.0 and 19.0%, respectively, but the predictions were concordant in only 6%. At fpr5%, concordant X4-virus predictions were obtained in 3.1%. The proportion of X4-tropic virus (clonal fpr10%) increased from 5.6 to 17.3% (p < 0.001) when 387 Ethiopian V3 loop sequences dated from 1984 to 2003 were compared with ours. In an intention to treat analysis, 67.9% reached treatment success at month 6 and only 50% at month 12. Only age and not tropism predicted therapy outcome and no difference was found in CD4+ cell gain between R5-tropic and X4-tropic infected patients. At viral failure, R5 to X4 switch was rare while X4 to R5 switch occurred more frequently (month 6: p = 0.006; month 12: p = 0.078).ConclusionThe HIV-1C epidemic is monophylogenetic in all regions of Ethiopia and R5-tropic virus dominates, even in patients with advanced immunodeficiency, although the proportion of X4-tropic virus seems to have increased over the last two decades. Geno2pheno clinical and clonal prediction models show a large discrepancy at fpr10%, but not at fpr5%. Hence further studies are needed to assess the utility of genotypic tropism testing in HIV-1C. In ITT analysis only age and not tropism influenced the outcome.

No Association of Cryptococcal Antigenemia with Poor Outcomes among Antiretroviral Therapy-Experienced HIV-Infected Patients in Addis Ababa, Ethiopia

Introduction There are limited data on clinical outcomes of ART-experienced patients with cryptococcal antigenemia. We assessed clinical outcomes of a predominantly asymptomatic, ART-experienced cohort of HIV+ patients previously found to have a high (8.4%) prevalence of cryptococcal antigenemia. Methods The study took place at All Africa Leprosy, Tuberculosis and Rehabilitative Training Centre and Black Lion Hospital HIV Clinics in Addis Ababa, Ethiopia. A retrospective study design was used to perform 12-month follow-up of 367 mostly asymptomatic HIV-infected patients (CD4<200 cells/µl) with high levels of antiretroviral therapy use (74%) who were previously screened for cryptococcal antigenemia. Medical chart abstraction was performed approximately one year after initial screening to obtain data on clinic visit history, ART use, CD4 count, opportunistic infections, and patient outcome. We evaluated the association of cryptococcal antigenemia and a composite poor outcome of death and loss to follow-up using logistic regression. Results Overall, 323 (88%) patients were alive, 8 (2%) dead, and 36 (10%) lost to follow-up. Among the 31 patients with a positive cryptococcal antigen test (titers ≥1∶8) at baseline, 28 were alive (all titers ≤1∶512), 1 dead and 2 lost to follow-up (titers ≥1∶1024). In multivariate analysis, cryptococcal antigenemia was not predictive of a poor outcome (aOR = 1.3, 95% CI 0.3–4.8). A baseline CD4 count <100 cells/µl was associated with an increased risk of a poor outcome (aOR 3.0, 95% CI 1.4–6.7) while an increasing CD4 count (aOR 0.1, 95% CI 0.1–0.3) and receiving antiretroviral therapy at last follow-up visit (aOR 0.1, 95% CI 0.02–0.2) were associated with a reduced risk of a poor outcome. Conclusions Unlike prior ART-naïve cohorts, we found that among persons receiving ART and with CD4 counts <200 cells/µl, asymptomatic cryptococcal antigenemia was not predictive of a poor outcome.

Prediction of coreceptor usage by five bioinformatics tools in a large Ethiopian HIV-1 subtype C cohort

Background Genotypic tropism testing (GTT) has been developed largely on HIV-1 subtype B. Although a few reports have analysed the utility of GTT in other subtypes, more studies using HIV-1 subtype C (HIV-1C) are needed, considering the huge contribution of HIV-1C to the global epidemic. Methods Plasma was obtained from 420 treatment-naïve HIV-1C infected Ethiopians recruited 2009–2011. The V3 region was sequenced and the coreceptor usage was predicted by five tools: Geno2Pheno clinical–and clonal–models, PhenoSeq-C, C-PSSM and Raymond’s algorithm. The impact of baseline tropism on antiretroviral treatment (ART) outcome was evaluated. Results Of 352 patients with successful baseline V3 sequences, the proportion of predicted R5 virus varied between the methods by 12.5% (78.1%-90.6%). However, only 58.2% of the predictions were concordant and only 1.7% were predicted to be X4-tropic across the five methods. Compared pairwise, the highest concordance was between C-PSSM and Geno2Pheno clonal (86.4%). In bivariate intention to treat (ITT) analysis, R5 infected patients achieved treatment success more frequently than X4 infected at month six as predicted by Geno2Pheno clinical (77.8% vs 58.7%, P = 0.004) and at month 12 by C-PSSM (61.9% vs 46.6%, P = 0.038). However, in the multivariable analysis adjusted for age, gender, baseline CD4 and viral load, only tropism as predicted by C-PSSM showed an impact on month 12 (P = 0.04, OR 2.47, 95% CI 1.06–5.79). Conclusion Each of the bioinformatics models predicted R5 tropism with comparable frequency but there was a large discordance between the methods. Baseline tropism had an impact on outcome of first line ART at month 12 in multivariable ITT analysis but only based on prediction by C-PSSM which thus possibly could be used for predicting outcome of ART in HIV-1C infected Ethiopians.

Baseline predictors of antiretroviral treatment failure and lost to follow up in a multicenter countrywide HIV-1 cohort study in Ethiopia

Background Antiretroviral therapy (ART) has been rapidly scaled up in Ethiopia since 2005, but factors influencing the outcome are poorly studied. We therefore analysed baseline predictors of first-line ART outcome after 6 and 12 months. Material and methods 874 HIV-infected patients, who started first-line ART, were enrolled in a countrywide prospective cohort. Two outcomes were defined: i) treatment failure: detectable viremia or lost-to-follow-up (LTFU) (confirmed death, moved from study sites or similar reasons); ii) LTFU only. Using stepwise logistic regression, four multivariable models identified baseline predictors for odds of treatment failure and LTFU. Results The treatment failure rates were 23.3% and 33.9% at 6 and 12 months, respectively. Opportunistic infections (OI), tuberculosis (TB), CD4 cells <50/μl, and viral load >5 log10 copies/ml increased the odds of treatment failure both at 6 and 12 months. The odds of LTFU at month 6 increased with baseline functional disabilities, WHO stage III/IV, and CD4 cells <50/μl. TB also increased the odds at month 12. Importantly, ART outcome differed across hospitals. Compared to the national hospital in Addis Ababa, patients from most regional sites had higher odds of treatment failure and/or LTFU at month 6 and/or 12, with the exception of one clinic (Jimma), which had lower odds of failure at month 6. Conclusions In this first countrywide Ethiopian HIV cohort, a high ART failure rate was identified, to the largest extent due to LTFU, including death. The geographical region where the patients were treated was a strong baseline predictor of ART failure. The difference in ART outcome across hospitals calls the need for provision of more national support at regional level.