Ralf Weigel

Bio: Ralf Weigel is an academic researcher from Witten/Herdecke University. The author has contributed to research in topics: Population & Medicine. The author has an hindex of 25, co-authored 51 publications receiving 2217 citations. Previous affiliations of Ralf Weigel include Liverpool School of Tropical Medicine & Kamuzu Central Hospital.

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

Abstract: BACKGROUND: Over 150000 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/microl (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/microl (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

Abstract: 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. Taki...

Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality.

Abstract: BACKGROUND: Mortality in HIV-infected patients who have access to highly active antiretroviral therapy (ART) has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV-infected population. We compared mortality rates observed in HIV-1-infected patients starting ART with non-HIV-related background mortality in four countries in sub-Saharan Africa. METHODS AND FINDINGS: Patients enrolled in antiretroviral treatment programmes in Cote d'Ivoire, Malawi, South Africa, and Zimbabwe were included. We calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 y, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting ART. The excess mortality rate was 17.5 (95% CI 14.5-21.1) per 100 person-years SMR in patients who started ART with a CD4 cell count of less than 25 cells/microl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55-1.81) per 100 person-years in patients who started with 200 cells/microl or above with WHO stage I/II. The corresponding SMRs were 47.1 (39.1-56.6) and 3.44 (1.91-6.17). Among patients who started ART with 200 cells/microl or above in WHO stage I/II and survived the first year of ART, the excess mortality rate was 0.27 (0.08-0.94) per 100 person-years and the SMR was 1.14 (0.47-2.77). CONCLUSIONS: Mortality of HIV-infected patients treated with combination ART in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of ART. Much of the excess mortality might be prevented by timely initiation of ART.

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

Abstract: Background: The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. Methods and Findings: We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to followup. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in subSaharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. Conclusions: The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up. Please see later in the article for the Editors’ Summary.

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

Abstract: Summary 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. Methods Clinicians in two urban ART clinics in Malawi used clinical and immunological monitoring to identify adult patients for switching to second-line ART. If patients met clinical and/or immunological failure criteria of WHO guidelines and had a viral load <400 copies/ml there was misclassification of virological ART failure. Results Between January 2006 and July 2007, we identified 155 patients with WHO criteria for immunological and/or clinical failure. Virological ART failure had been misclassified in 66 (43%) patients. Misclassification was significantly higher in patients meeting clinical failure criteria (57%) than in those with immunological criteria (30%). On multivariate analysis, misclassification was associated with being on ART 200 cells/μl [OR = 5.03 (2.05, 12.34)]. Active tuberculosis and Kaposi’s sarcoma were the most common conditions causing misclassification of virological ART failure. Conclusion Misclassification of virological ART failure occurs frequently using WHO clinical and immunological criteria of ART failure for poor settings. A viral load test confirming virological ART failure is therefore advised to avoid unnecessary switching to second-line regimens. Diagnostic de l’echec de l’ART au Malawi: mauvais performance des criteres cliniques et immunologiques de l’OMS Objectifs: Dans la therapie antiretrovirale (ART) le deploiement de programmes de suivi de la charge virale en Afrique sub-saharienne n’est pas recommande. Nous avons voulu etudier l’impact de la seule utilisation du suivi clinique et immunologique sur le diagnostic de l’echec virologique ART dans les circonstances de routine. Methodes: Les cliniciens dans deux cliniques ART urbains au Malawi ont utilise le suivi clinique et immunologique afin d’identifier les patients adultes necessitant le passage a un traitement ART de seconde ligne. Lorsque les patients repondaient aux criteres d’echec clinique et/ou immunologique des directives de l’OMS et avaient une charge virale < 400 copies/ml, il en resultait une mauvaise classification de l’echec virologique ART. Resultats: Entre janvier 2006 et juillet 2007, nous avons identifie 155 patients avec des criteres d’echec clinique et/ou immunologique de l’OMS. L’echec virologique ART a ete mal classifie chez 66 (43%) patients. L’erreur de classification a ete significativement plus elevee chez les patients repondant aux criteres d’echec clinique (57%) que chez ceux avec des criteres immunologiques (30%). En analyse multivariee, l’erreur de classification etait associee au fait d’etre sous ART depuis 200 cellules/μl (OR = 5,03 (2,05 - 12,34)). La tuberculose active et le sarcome de Kaposi etaient les conditions les plus courantes entrainant une mauvaise classification de l’echec virologique ART. Conclusion: une mauvaise classification de l’echec virologique ART se produit frequemment avec l’utilisant les criteres cliniques et immunologiques d’echec de l’ART de l’OMS dans les regions pauvres. Une mesure de la charge virale confirmant l’echec virologique ART est donc conseillee afin d’eviter des passages non necessaires vers des traitements de seconde ligne. Diagnostico de fallo del TAR en Malawi: desempeno pobre de los criterios de la OMS clinicos e inmunologicos Objetivos: En los programas de aumento a escala de la terapia antirretroviral (TAR) en Africa sub-Sahariana, la monitorizacion de la carga viral no esta recomendada. Queriamos estudiar el impacto de utilizar solamente la monitorizacion clinica e inmunologica en el diagnostico del fallo virologico del TAR bajo circunstancias rutinarias. Metodos: Los clinicos de dos clinicas urbanas de TAR en Malawi utilizaron monitorizacion clinica e inmunologica para identificar pacientes adultos para cambiar a segunda linea de tratamiento. Si los pacientes cumplian con los criterios clinicos o inmunologicos de fallo segun las guias de la OMS y tenian una carga viral de <400 copias/ml habia una clasificacion erronea del fallo virologico del TAR. Resultados: Entre enero 2006 julio 2007, identificamos 155 pacientes con criterios de la OMS para fallo inmunologico o clinico. El fallo virologico del TAR ha sido mal clasificado en 66 (43%) pacientes. La clasificacion erronea era significativamente mayor en pacientes que cumplian con los criterios clinicos de fallo (57%) que en aquellos con criterios inmunologicos (30%). En un analisis multivariado, el error en la classificacon estaba asociado con estar en TAR 200 cel/¼l (OR=5.03 (2.05, 12.34)). Una tuberculosis active y el sarcoma de Kaposi eran las condiciones mas comunes responsables de la clasificacion erronea de fallo virologico del TAR. Conclusion: La clasificacion erronea de fallo virologico del TAR ocurre frecuentemente utilizando los criterios de fallo de TAR de la OMS, tanto clinicos como inmunologicos, para entornos pobres. Una prueba de carga viral que confirme es, por lo tanto recomendable, para evitar posibles cambios a tratamientos de segunda linea.

Patient Retention in Antiretroviral Therapy Programs in Sub-Saharan Africa: A Systematic Review

Abstract: Background Long-term retention of patients in Africa’s rapidly expanding antiretroviral therapy (ART) programs for HIV/AIDS is essential for these programs’ success but has received relatively little attention. In this paper we present a systematic review of patient retention in ART programs in sub-Saharan Africa. Methods and Findings We searched Medline, other literature databases, conference abstracts, publications archives, and the ‘‘gray literature’’ (project reports available online) between 2000 and 2007 for reports on the proportion of adult patients retained (i.e., remaining in care and on ART) after 6 mo or longer in sub-Saharan African, non-research ART programs, with and without donor support. Estimated retention rates at 6, 12, and 24 mo were calculated and plotted for each program. Retention was also estimated using Kaplan-Meier curves. In sensitivity analyses we considered best-case, worst-case, and midpoint scenarios for retention at 2 y; the best-case scenario assumed no further attrition beyond that reported, while the worst-case scenario assumed that attrition would continue in a linear fashion. We reviewed 32 publications reporting on 33 patient cohorts (74,192 patients, 13 countries). For all studies, the weighted average follow-up period reported was 9.9 mo, after which 77.5% of patients were retained. Loss to follow-up and death accounted for 56% and 40% of attrition, respectively. Weighted mean retention rates as reported were 79.1%, 75.0% and 61.6 % at 6, 12, and 24 mo, respectively. Of those reporting 24 mo of follow-up, the best program retained 85% of patients and the worst retained 46%. Attrition was higher in studies with shorter reporting periods, leading to monthly weighted mean attrition rates of 3.3%/mo, 1.9%/mo, and 1.6%/month for studies reporting to 6, 12, and 24 months, respectively, and suggesting that overall patient retention may be overestimated in the published reports. In sensitivity analyses, estimated retention rates ranged from 24% in the worse case to 77% in the best case at the end of 2 y, with a plausible midpoint scenario of 50%.

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

Abstract: Two-thirds of the world's 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/mul 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 enrollment 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.

Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission

Abstract: Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. Conclusions The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials .gov number, NCT00164736.)

Life Expectancy of Persons Receiving Combination Antiretroviral Therapy in Low-Income Countries: A Cohort Analysis From Uganda

Abstract: BACKGROUND: Little is known about the effect of combination antiretroviral therapy (cART) on life expectancy in sub-Saharan Africa. OBJECTIVE: To estimate life expectancy of patients once they initiate cART in Uganda. DESIGN: Prospective cohort study. SETTING: Public sector HIV and AIDS disease-management program in Uganda. PATIENTS: 22 315 eligible patients initiated cART during the study period of whom 1943 were considered to have died. MEASUREMENTS: All-cause mortality rates were calculated and abridged life tables were constructed and stratified by sex and baseline CD4 cell count status to estimate life expectancies for patients receiving cART. The average number of years remaining to be lived by patients who received cART at varying age categories was estimated. RESULTS: After adjustment for loss to follow-up crude mortality rates (deaths per 1000 person-years) ranged from 26.9 (95% CI 25.4 to 28.5) in women to 43.9 (CI 40.7 to 47.0) in men. For patients with a baseline CD4 cell count less than 0.050 x 10(9) cells/L the mortality rate was 67.3 (CI 62.1 to 72.9) deaths per 1000 person-years whereas among persons with a baseline CD4 cell count of 0.250 x 10(9) cells/L or more the mortality rate was 19.1 (CI 16.0 to 22.7) deaths per 1000 person-years. Life expectancy at age 20 years for the overall cohort was 26.7 (CI 25.0 to 28.4) additional years and at age 35 years was 27.9 (CI 26.7 to 29.1) additional years. Life expectancy increased substantially with increasing baseline CD4 cell count. Similar trends are observed for older age groups. LIMITATIONS: A small (6.4%) proportion of patients were lost to follow-up and it was imputed that 30% of these patients had died. Few patients with a CD4 cell count greater than 0.250 x 10(9) cells/L initiated cART. CONCLUSION: Ugandan patients receiving cART can expect an almost normal life expectancy although there is considerable variability among subgroups of patients. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.