Ralf Weigel

The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy

Background:Over 150 000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi. Methods:Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed. Results:Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/μl (23–174), 4.72 copies/ml (4.26–5.16), and 36.5 months (26.6–49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/μl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine. Conclusion:When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.

Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration.

AIMS To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. METHODS The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. RESULTS Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. CONCLUSIONS Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.

Mortality of HIV-Infected Patients Starting Antiretroviral Therapy in Sub-Saharan Africa: Comparison with HIV- Unrelated Mortality

Comparing mortality rates between patients starting HIV treatment and the general population in four African countries, Matthias Egger and colleagues find the gap decreases over time, especially with early treatment.

Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs.

Diagnosis of antiretroviral therapy failure in Malawi: poor performance of clinical and immunological WHO criteria.

Objectives  In antiretroviral therapy (ART) scale‐up programmes in sub‐Saharan Africa viral load monitoring is not recommended. We wanted to study the impact of only using clinical and immunological monitoring on the diagnosis of virological ART failure under routine circumstances.

Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa

Background:Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. Patients and Methods:Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. Results:Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing ≥120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing ≥20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). Conclusions:In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.

Second‐line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline*

The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second‐line ART. We report outcomes for patients evaluated and initiated on second‐line treatment in Malawi.

Early active follow-up of patients on antiretroviral therapy (ART) who are lost to follow-up: the ‘Back-to-Care’ project in Lilongwe, Malawi

Objectives  To determine the proportion of patients returning to antiretroviral treatment (ART) and factors associated with their return in a resource‐limited setting.

Mortality and loss to follow-up in the first year of ART: Malawi National ART Programme

Objectives:To analyse mortality, loss to follow-up (LTFU) and retention on antiretroviral treatment (ART) in the first year of ART across all age groups in the Malawi national ART programme. Design:Cohort study including all patients who started ART in Malawis public sector clinics between 2004 and 2007. Methods:ART registers were photographed, information entered into a database and merged with data from clinics with electronic records. Rates per 100 patient-years and cumulative incidence of retention were calculated. Subhazard ratios (sHRs) of outcomes adjusted for patient and clinic-level characteristics were calculated in multivariable analysis, applying competing risk models. Results:A total of 117 945 patients contributed 85 246 person-years: 1.0% were infants below 2 years, 7.4% children 2–14, 7.5% young people 15–24, and 84.2% adults 25 years and above. Sixty percent of patients were female: women outnumbered men from age 14 to 35 years. Mortality and LTFU were higher in men from age 20 years. Infants and young people had the highest rates per 100 person-years for mortality (23.0 and 19.4) and LTFU (24.7 and 19.3), and the highest adjusted relative risks compared to age group 25–34 years: sHRs were 1.37 [95% confidence interval (CI) 1.17–1.60] and 1.17 (95% CI 1.10–1.25) for death and 1.37 (95% CI 1.18–1.59) and 1.27 (95% CI 1.19–1.35) for LTFU, respectively. Conclusion:In this country-wide study patients aged 0–1 and 15–24 years had the highest risk of death and LTFU, and from age 20 men were at higher risk than women. Interventions to improve outcomes in these patient groups are required.

Outcomes and associated risk factors of patients traced after being lost to follow-up from antiretroviral treatment in Lilongwe, Malawi

BackgroundLoss to follow-up is a major challenge of antiretroviral treatment (ART) programs in sub-Saharan Africa. Our objective was to a) determine true outcomes of patients lost to follow-up (LTFU) and b) identify risk factors associated with successful tracing and deaths of patients LTFU from ART in a large public sector clinic in Lilongwe, Malawi.MethodsPatients who were more than 2 weeks late according to their last ART supply and who provided a phone number or address in Lilongwe were eligible for tracing. Their outcomes were updated and risk factors for successful tracing and death were examined.ResultsOf 1800 patients LTFU with consent for tracing, 724 (40%) were eligible and tracing was successful in 534 (74%): 285 (53%) were found to be alive and on ART; 32 (6%) had stopped ART; and 217 (41%) had died. Having a phone contact doubled tracing success (adjusted odds ratio, aOR = 2.1, 95% CI 1.4-3.0) and odds of identifying deaths [aOR = 1.8 (1.2-2.7)] in patients successfully traced. Mortality was higher when ART was fee-based at initiation (aOR = 2.3, 95% CI 1.1-4.7) and declined with follow-up time on ART. Limiting the analysis to patients living in Lilongwe did not change the main findings.ConclusionAscertainment of contact information is a prerequisite for tracing, which can reveal outcomes of a large proportion of patients LTFU. Having a phone contact number is critical for successful tracing, but further research should focus on understanding whether phone tracing is associated with any differential reporting of mortality or LTFU.