Xavier Anglaret

Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa

Two-thirds of the worlds HIV-infected people live in sub-Saharan Africa, and more than 1.5 million of them die annually. As access to antiretroviral treatment has expanded within the region; early pessimism concerning the delivery of antiretroviral treatment using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months. Patients typically access antiretroviral treatment with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count less than 50 cells/μl and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but more fundamentally on how advanced disease is at programme enrolment and the quality of preceding healthcare. In addition to improving delivery of antiretroviral treatment and providing it free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment. Health systems delays in antiretroviral treatment initiation must be minimized, especially in patients who present with advanced immunodeficiency.

A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa.

BACKGROUND In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.).

Early loss of HIV-infected patients on potent antiretroviral therapy programmes in lower-income countries

OBJECTIVE To analyse the early loss of patients to antiretroviral therapy (ART) programmes in resource-limited settings. METHODS Using data on 5491 adult patients starting ART (median age 35 years, 46% female) in 15 treatment programmes in Africa, Asia and South America with (3) 12 months of follow-up, we investigated risk factors for no follow-up after treatment initiation, and loss to follow-up or death in the first 6 months. FINDINGS Overall, 211 patients (3.8%) had no follow-up, 880 (16.0%) were lost to follow-up and 141 (2.6%) were known to have died in the first 6 months. The probability of no follow-up was higher in 2003-2004 than in 2000 or earlier (odds ratio, OR: 5.06; 95% confidence interval, CI: 1.28-20.0), as was loss to follow-up (hazard ratio, HR: 7.62; 95% CI: 4.55-12.8) but not recorded death (HR: 1.02; 95% CI: 0.44-2.36). Compared with a baseline CD4-cell count (3) 50 cells/microl, a count < 25 cells/microl was associated with a higher probability of no follow-up (OR: 2.49; 95% CI: 1.43-4.33), loss to follow-up (HR: 1.48; 95% CI: 1.23-1.77) and death (HR: 3.34; 95% CI: 2.10-5.30). Compared to free treatment, fee-for-service programmes were associated with a higher probability of no follow-up (OR: 3.71; 95% CI: 0.97-16.05) and higher mortality (HR: 4.64; 95% CI: 1.11-19.41). CONCLUSION Early patient losses were increasingly common when programmes were scaled up and were associated with a fee for service and advanced immunodeficiency at baseline. Measures to maximize ART programme retention are required in resource-poor countries.

When to Start Antiretroviral Therapy in Resource-Limited Settings

BACKGROUND The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years. OBJECTIVE To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa while awaiting the results of these trials. DESIGN Cost-effectiveness analysis by using a computer simulation model of HIV disease. DATA SOURCES Published data from randomized trials and observational cohorts in South Africa. TARGET POPULATION HIV-infected patients in South Africa. TIME HORIZON 5-year and lifetime. PERSPECTIVE Modified societal. INTERVENTION No treatment, ART initiated at a CD4 count less than 0.250 x 10(9) cells/L, and ART initiated at a CD4 count less than 0.350 x 10(9) cells/L. OUTCOME MEASURES Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 10(9) cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 10(9) cells/L; cost increases would range from

Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in West Africa.

142 million (10%) to

Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Cote d'Ivoire: a trial-based analysis

1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 10(9) cells/L. Compared with an initiation threshold of 0.250 x 10(9) cells/L, a threshold of 0.350 x 10(9) cells/L has an incremental cost-effectiveness ratio of

Resurgence of Ebola virus disease in Guinea linked to a survivor with virus persistence in seminal fluid for more than 500 days

1200 per year of life saved. RESULTS OF SENSITIVITY ANALYSIS Initiating ART at a CD4 count less than 0.350 x 10(9) cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%. LIMITATION This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 x 10(9) cells/L or of reduced HIV transmission. CONCLUSION Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 10(9) cells/L, earlier than is currently recommended. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.

Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis.

Objective:To estimate the incidence and risk factors of mortality and severe morbidity during the first months following antiretroviral therapy (ART) initiation in West African adults. Methods:A cohort study in Abidjan in which 792 adults started ART with a median CD4 cell count of 252 cells/μl and were followed for a median of 8 months. Severe morbidity was defined as all World Health Organization stage 3 or 4-defining morbidity events other than oral candidiasis. Results:In patients with pre-ART CD4 cell count < 200, at 200–350 and > 350 cells/μl, incidence of mortality was 5.0 [95% confidence interval (CI), 2.6–8.7], 1.7 (95% CI, 0.6–3.8) and 0.0 (95% CI, 0.0–3.4]/100 person-years, and incidence of severe morbidity was 13.3 (95% CI, 9.0–19.1), 9.5 (95% CI, 6.2–12.9) and 7.9 (95% CI, 3.4–15.5)/100 person-years, respectively. The most frequent diseases were invasive bacterial diseases (32/65 episodes, 49%) and tuberculosis (25/65 episodes, 38%). Both diseases followed the same curve of decreasing incidence over time. Patients who experienced severe morbidity had higher risks of mortality, virological failure and immunological failure. Other independent risk factors for mortality and/or severe morbidity were: at baseline, high viral load, advanced clinical stage, past history of tuberculosis, low BMI, low haemoglobin and low CD4 cell count; during follow-up: low CD4 cell count and persistently detectable viral load. Conclusion:These data give new arguments to reinforce the hypothesis that, in this region, ART should be started before the CD4 cell count drops below 350 cells/μl. Further studies should assess whether patients with low BMI, low haemoglobin, high viral load or past history of tuberculosis should start ART earlier.

Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A Côte d'Ivoire Appraisal

Background:In 2000, WHO/UNAIDS recommended co-trimoxazole prophylaxis for persons at early stages of HIV infection (WHO stage ≥ 2) in sub-Saharan Africa. Objective:To assess the cost-effectiveness of alternative strategies for initiation of co-trimoxazole in Côte d’Ivoire. Design:Cost-effectiveness analysis with an HIV simulation model using clinical and cost data from a randomized trial of co-trimoxazole in HIV-infected adults. Methods:The study included HIV-infected patients in Côte d’Ivoire, with median age 33 years. Thirty-four percent were classified as WHO stage 2, 59% as stage 3, and 7% as stage 4. The mean CD4 cell count was 331 × 106 cells/l. The interventions were no prophylaxis, clinical criteria-based co-trimoxazole initiation (early: WHO stage ≥ 2; late: WHO stage ≥ 3), CD4-based co-trimoxazole initiation (< 500, < 200, < 50 × 106 CD4 cells/l). The outcome measures were life expectancy, lifetime costs, and incremental cost-effectiveness. Results:The most effective strategy, initiation of co-trimoxazole prophylaxis at WHO stage ≥ 2, increased undiscounted life expectancy by 5.2 months, discounted life expectancy by 4.4 months, and lifetime costs by US

Tolerance and Acceptability of an Efavirenz-based Regimen in 740 Adults (predominantly Women) in West Africa

60, compared with no prophylaxis. Delaying prophylaxis initiation until WHO stage ≥ 3 was less costly and less effective. All CD4-based strategies were dominated. The incremental cost-effectiveness of early versus late co-trimoxazole prophylaxis initiation was US