Ersilia Buonomo

Incidence and Predictors of Death, Retention, and Switch to Second-Line Regimens in Antiretroviral-Treated Patients in Sub-Saharan African Sites with Comprehensive Monitoring Availability

BACKGROUND Antiretroviral treatment programs in sub-Saharan Africa have high rates of early mortality and loss to follow-up. Switching to second-line regimens is often delayed because of limited access to laboratory monitoring. METHODS Retrospective analysis was performed of a cohort of adults who initiated a standard first-line antiretroviral treatment at 5 public sector sites in 3 African countries. Monitoring included routine CD4 cell counts, human immunodeficiency virus RNA measures, and records of whether appointments were kept. Incidence and predictors of death, loss to follow-up, and switch to second-line regimens were analyzed by time-to-event approaches. RESULTS A total of 3749 patients were analyzed; at baseline, 37.1% were classified as having World Health Organization disease stage 3 or 4, and the median CD4 cell count was 192 cells/mL. First-line regimens were nevirapine based in 96.5% of patients; 17.7% of patients attended <95% of their drug pickup appointments. During 4545 person-years of follow-up, mortality was 8.6 deaths per 100 person-years and was predicted by lower baseline CD4 cell count, lower hemoglobin level, and lower body mass index (calculated as weight in kilograms divided by the square of height in meters); more-advanced clinical stage of infection; male sex; and more missed drug pickup appointments. Dropouts (which accrued at a rate of 2.1 dropouts per 100 person-years) were predicted by a lower body mass index, more missed visits and missed drug pickup appointments, and later calendar year. Incidence of switches to second-line regimens was 4.9 per 100 person-years; increased hazards were observed with lower CD4 cell count and earlier calendar year at baseline. In patients who switched, virological failure was predicted by combined clinical and CD4 criteria with 74% sensitivity and 30% specificity. CONCLUSIONS In an antiretroviral treatment program employing comprehensive monitoring, the probability of switching to second-line therapy was limited. Regular pickup of medication was a predictor of survival and was also strongly predictive of patient retention.

Increased infant human immunodeficiency virus-type one free survival at one year of age in Sub-Saharan Africa with maternal use of highly active antiretroviral therapy during breast-feeding.

Background: Reduction of HIV-1 breast-feeding transmission remains a challenge for prevention of pediatric infections in Sub-Saharan Africa. Provision of formula decreases transmission but often increases child mortality in this setting. Methods: A prospective observational cohort study of HIV-1 exposed infants of mothers receiving pre and postnatal medical care at Drug Resource Enhancement Against AIDS and Malnutrition centers in Mozambique was conducted. Live-born infants of HIV-1-infected women receiving medical care were enrolled. HIV-1 testing was performed at 1, 6, and 12 months of age using branched DNA. Mothers were counseled to breast-feed exclusively for 6 months and were provided HAART antenatally and postnatally for the first 6 months. Women with CD4 cell counts less than 350/cmm at baseline continued HAART indefinitely. Results: Of 341 infants followed from birth, 313 mother-infant pairs (92%) completed 6 months and 283 (83%) completed 12 months of follow-up. HIV-1 diagnosis was ascertained in 287 infants (84%) including 4 who died. There were 8 cases of HIV-1 transmission: 4 of 341 (1.2%) at 1 month, 2 of 313 (0.6%) at 6 months, and 2 of 276 (0.7%) at 12 months (cumulative rate: 2.8%). Two mothers (0.6%) and 11 infants (3.2%) died. Maternal and infant mortality rates were 587 of 100,000 and 33 of 1000, while country rates are 1000 of 100,000 and 101 of 1000. HIV risk reduction was 93% and HIV-free survival at 12 months was 94%. Conclusions: Late postnatal transmission of HIV-1 is significantly decreased by maternal use of HAART with high infant survival rates up to 12 months of age.

Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes

Objective:To evaluate pregnancy outcomes in a cohort of HIV-infected women receiving triple antiretroviral therapy (ART) for prevention of mother-to-child-transmission. Methods:A retrospective cohort study with review of records of 3273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009 was conducted in Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) centers. Patients were offered nevirapine-based triple ART initiated in pregnancy until 6 months postpartum. Main outcome measures were maternal mortality, abortion/stillbirth, prematurity, and low birth weight. Results:Maternal mortality was 1.2% (42/3273): 7.4% in 68 women with no antenatal ART and 0.7% in 1370 with at least 90 days of antenatal ART [P < 0.001; odds ratio (OR) 0.29 (95% confidence interval [CI] 0.14–0.96]. Abortion/stillbirth was 5.2% (169/3273): 26.5% in 68 women with no ART and 5.0% in 1370 women with at least 90 days of antenatal ART [P < 0.001; OR 0.39 (95% CI 0.27–0.57)]. Prematurity was 19.1%: 70% in 10 women with no antenatal ART and 8.5% in 1330 women with at least 90 days of antenatal ART [P < 0.001; OR 0.15 (95% CI 0.14–0.19)]. Low birth weight was 11.5% (57/496) and not associated with ART duration. The protective effect of antenatal ART against mortality, fetal demise, and prematurity was independent of CD4 strata. Multivariate analysis for BMI, CD4 cell count, virus load, days in care, predelivery length of ART, and hemoglobin demonstrated an independent association between predelivery length of ART and CD4 with maternal mortality, abortion/stillbirth, and prematurity. ART toxicities were infrequent (5.2%). Conclusion:Antenatal triple ART reduces adverse pregnancy outcomes in HIV-infected women.

Maternal antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Malawi: maternal and infant outcomes two years after delivery.

Background Optimized preventive strategies are needed to reach the objective of eliminating pediatric AIDS. This study aimed to define the determinants of residual HIV transmission in the context of maternal antiretroviral therapy (ART) administration to pregnant women, to assess infant safety of this strategy, and to evaluate its impact on maternal disease. Methodology/Principal Findings A total of 311 HIV-infected pregnant women were enrolled in Malawi in an observational study and received a nevirapine-based regimen from week 25 of gestation until 6 months after delivery (end of breastfeeding period) if their CD4+ count was > 350/mm3 at baseline (n = 147), or indefinitely if they met the criteria for treatment (n. 164). Mother/child pairs were followed until 2 years after delivery. The Kaplan-Meier method was used to estimate HIV transmission, maternal disease progression, and survival at 24 months. The rate of HIV infant infection was 3.2% [95% confidence intervals (CI) 1.0-5.4]. Six of the 8 transmissions occurred among mothers with baseline CD4+ count > 350/mm3. HIV-free survival of children was 85.8% (95% CI 81.4-90.1). Children born to mothers with baseline CD4+ count < 350/mm3 were at increased risk of death (hazard ratio 2.6, 95% CI 1.1-6.1). Among women who had stopped treatment the risk of progression to CD4+ count < 350/mm3 was 20.6% (95% CI 9.2-31.9) by 18 months of drug discontinuation. Conclusions HIV transmission in this cohort was rare however, it occurred in a significative proportion among women with high CD4+ counts. Strategies to improve treatment adherence should be implemented to further reduce HIV transmission. Mortality in the uninfected exposed children was the major determinant of HIV-free survival and was associated to maternal disease stage. Given the considerable proportion of women reaching the criteria for treatment within 18 months of drug discontinuation, life-long ART administration to HIV-infected women should be considered.

Reduction of Maternal Mortality with Highly Active Antiretroviral Therapy in a Large Cohort of HIV-Infected Pregnant Women in Malawi and Mozambique

Background HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002. Methods Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2). Results 10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23–30), CD4 count 392 cells/mm3 (IQR:258–563), Viral Load log10 3.9 (IQR:3.2–4.4), BMI 23.4 (IQR:21.5–25.7), Hemoglobin 10.0 (IQR: 9.0–11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with <than 350 CD4 cells/mm3 and 0.7% in women with greater than 350 CD4s cells/mm3 [OR = 1.9 (CL 1.3–2.9) p = 0.001]. Mortality was higher in patients with shorter antenatal HAART: 22/991 (2.2%) if less than 30 days and 79/9159 (0.9%) if 31 days or greater [OR = 2.6 (CL 1.6–4.2) p<0.001]. By multivariate analysis, shorter antenatal HAART (p<0.001), baseline values for CD4 cell count (p = 0.012), hemoglobin (p = 0.02), and BMI (p<0.001) were associated with mortality. Four years later, survival was 92% for women with shorter antenatal HAART and 98% for women on established therapy prior to pregnancy, p = 0.001. Conclusions Antiretrovirals for PMTCT purposes have significant impact on maternal mortality as do CD4 counts and nutritional status. In resource-limited settings, PMTCT programs should provide universal HAART to all HIV+ pregnant women given its impact in prevention of maternal death.

Extended antenatal antiretroviral use correlates with improved infant outcomes throughout the first year of life

Objectives:To evaluate the effect of extended antenatal triple antiretroviral therapy (ART) on infant outcomes. Design:Retrospective cohort study using pooled data from health clinics in Malawi and Mozambique from July 2005 to December 2009. Methods:Computerized records of 3273 HIV-infected pregnant women accessing Drug Resource Enhancement Against AIDS and Malnutrition centers were reviewed. ART regimens consisted of nevirapine-based HAART as of 14–25 weeks gestation until 6 months postpartum. Infant infection was determined at 1, 6 and 12 months of age by branched DNA. Results:A total of 3071 pregnancies resulted in 3148 live births. Lost to follow-up, infant deaths and HIV-1 infection rates at 1 and 12 months were 1.3 and 11.5, 0.8 and 6.7 and 0.8 and 2.0, respectively. Infant HIV-1-free survival at 12 months was 92.5%. Mother-to-child transmission and/or infant deaths correlated with length of maternal antenatal ART by multivariate analysis at 1, 6 and 12 months: 14% in women with more than 30 days of triple antenatal ART and 6.9% in mothers receiving at least 90 days of antenatal ART, P = 0.001. Fifty percent of 54 episodes of transmission occurred in women with higher CD4 cell counts (>350 cells/μl). Infant mortality was 67/1000, lower than background rates (78–100/1000). Growth failure (weight-for-age Z score <−2) was present in 8% of infants around birth, 6% at 6 months, 23% at 12 months (lower than country-specific rates). Conclusion:Extended antenatal ART is protective against adverse infant outcomes up to 12 months of age even in children born to mothers with higher CD4 cell counts.

Predicting Trends in HIV-1 Sexual Transmission in Sub-Saharan Africa Through the Drug Resource Enhancement Against AIDS and Malnutrition Model: Antiretrovirals for 5 Reduction of Population Infectivity, Incidence and Prevalence at the District Level

BACKGROUND The use of antiretrovirals to reduce the incidence of human immunodeficiency virus (HIV) infection has been evaluated in mathematical models as potential strategies for curtailing the epidemic. Cohort data from the Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) Program was used to generate a realistic model for the HIV epidemic in sub-Saharan Africa. METHODS Two combined stochastic models were developed: patient and epidemic models. Models were combined using virus load as a parameter of infectivity. DREAM data that assessed patient care in Mozambique and Malawi were used to generate measures of infectivity, survival, and adherence. The Markov chain prediction model was used for the analysis of disease progression in treated and untreated patients. A partnership model was used to assess the probability that an infected individual would transmit HIV. RESULTS Data from 26565 patients followed up from January 2002 through July 2009 were analyzed with the model; 63% of patients were female, the median age was 35 years, and the median observation time was 25 months. In the model, a 5-fold reduction in infectivity (from 1.6% to 0.3%) occurred within 3 years when triple ART was used. The annual incidence of HIV infection declined from 7% to 2% in 2 years, and the prevalence was halved, from 12% to 6%, in 11 years. Mortality in HIV-infected individuals declined by 50% in 5 years. A cost analysis demonstrated economic efficiency after 4 years. CONCLUSIONS Our model, based on patient data, supports the hypothesis that treatment of all infected individuals translates into a drastic reduction in incident HIV infections. A targeted implementation strategy with massive population coverage is feasible in sub-Saharan Africa.

Immunologic Response to Highly Active Antiretroviral Therapy and Mortality Reduction in a Cohort of Human Immunodeficiency Virus–Positive Persons in Mozambique

Since February 2002, the Drug Resources Enhancement against AIDS and Malnutrition Program has provided highly active antiretroviral therapy (HAART) and immunologic and virologic monitoring free of charge. We conducted a cohort study of persons infected with human immunodeficiency virus in Mozambique. Only persons treated with HAART with available CD4 cell counts at baseline and ≥ 1 CD4 cell count after HAART were included. Survival analysis was applied to evaluate the prognostic value of CD4 cell counts measured at three months. Possible confounders were considered. A total of 753 persons who started HAART included; 59% were females. Median age was 34 years (range = 16-67 years), and the median CD4 cell count at baseline was 172 cells/mm3 (interquartile range = 87-261 cells/mm3, range = 0-1,322 cells/mm3). Overall, 105 persons (14%) died. Of these persons 54 (51%) developed AIDS before they died; 25 (3%) died during the first three months. After three months of therapy, the individual median CD4 cell count change from the baseline value was +101 cells/mm3 (interquartile range = +27 to +187 cells/mm3, range = -723 to +310 cells/mm3). A median CD4 increment of 100 cells/mm3 in three months was associated with a mortality reduction of 50% compared with an increase of < 50 cells (relative hazard of death adjusted for baseline CD4 cell count = 0.54, 95% confidence interval = 0.30-0.95). A good initial response to HAART was associated with a significant reduction of mortality. This finding supports the effectiveness of HAART in resource-poor settings.

Elimination of Mother-To-Child Transmission of HIV Infection: The Drug Resource Enhancement against AIDS and Malnutrition Model

The Drug Resource Enhancement against AIDS and Malnutrition Program (DREAM) gathered professionals in the field of Elimination of HIV-Mother-To-Child Transmission (EMTCT) in Maputo in 2013 to discuss obstacles and solutions for the elimination of HIV vertical transmission in sub-Saharan Africa. During this workshop, the benefits of administrating combined antiretroviral therapy (cART) to HIV positive women from pregnancy throughout breastfeeding were reviewed. cART is capable of reducing vertical transmission to less than 5% at 24 months of age, as well as maternal mortality and infant mortality in both HIV infected and exposed populations to levels similar to those of uninfected individuals. The challenge for programs targeting eMTCT in developing countries is retention in care and treatment adherence. Both are intrinsically related to the model of care. The drop-out from eMTCT programs before cART initiation ranges from 33%–88% while retention rates at 18–24 months are less than 50%. Comprehensive strategies including peer-to-peer education, social support and laboratory monitoring can reduce refusals to less than 5% and attain retention rates approaching 90%. Several components of the model of care for reduction of HIV-1 MTCT are feasible and implementable in scale-up strategies. A review of this model of care for HIV eMTCT is provided.

Predictors of Adverse Outcomes in HIV-1 Infected Children Receiving Combination Antiretroviral Treatment: Results from a DREAM Cohort in Sub-Saharan Africa

Background: HIV-infected children have less access to combination antiretroviral therapy as compared with adults in resource-limited settings. Growth faltering, loss to follow-up (LTFU) and high mortality are frequently seen. Methods: A retrospective cohort study was performed with parameters extracted from the Drug Resource Enhancement against AIDS and Malnutrition database for HIV-infected, antiretroviral naïve children under 15 years presenting for care at 17 Drug Resource Enhancement against AIDS and Malnutrition centers in Mozambique, Malawi and Guinea between January 2005 to December 2008. Predictors of time-to-death, time-to-LTFU and persistence of malnutrition by Cox’s regression and Kaplan–Meier were determined. Results: 2215 children presented to care with 1343 (61%) being ⩽5 years. At baseline, stunting and malnutrition occurred in 40% and 25%, respectively; 75% of 2149 children had CD4 cell percentages less than 20; median HIV RNA, log10 cp/mL, was 4.97 in 1927 patients. Over time 238 children died (10.7%; 2.7% person-years [PY]) 63 were LTFU (2.8%; 0.7% PY). By multivariate analysis, mortality was associated with virus load (hazards ratio: 1.19; confidence interval: 1.01–1.402, P = 0.038) and reduced weight-for-age Z scores (hazards ratio: 0.590; confidence interval: 0.53–0.66, P < 0.001). LTFU was associated with low weight-for-height Z scores (hazards ratio: 0.71; confidence interval: 0.51–0.97, P = 0.031). At 12 months after combination antiretroviral therapy, anthropometric parameters significantly improved in 1226 children (P < 0.001); virus load declined to <400 copies/mL in over 60%. Conclusions: Despite advanced HIV disease, children initiating combination antiretroviral therapy had mortality rates of 2.7% p/PY with overall attrition rates of 11.7% p/100 PY, with significant reversal of negative anthropometric markers, and improvement of immunological and virological parameters in children with 12 months of follow-up.