Leonardo Palombi

Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV.

Background: The Drug Resource Enhancement against AIDS and Malnutrition (DREAM) program is a large antiretroviral therapy treatment program financed by the Treatment Acceleration Program (TAP) of the World Bank. In addition to provision of antiretroviral treatment to individuals infected with human immunodeficiency virus (HIV) in sub-Saharan Africa, one major aspect of the DREAM program is nutritional supplementation and prevention of mother-to-child transmission (PMTCT) of HIV. Methods: HIV-positive pregnant women enrolled in the DREAM program receive highly active antiretroviral therapy (HAART) free of charge from the 25th week of gestation, irrespective of clinical stage, CD4 count, and viral load. Their infants receive post-exposure prophylaxis. From 2004 to 2006, women enrolled in the DREAM program in Mozambique, Tanzania, and Malawi received water filters and formula for the first 6 months of lactation. In a second cohort starting in 2005 until 2006 in Mozambique, women received HAART for up to 6 months after delivery and were given the option to breastfeed. We conducted a comparative analysis of the two cohorts of HIV-positive pregnant women followed prospectively and evaluated HIV-1 mother-to-child transmission rates, infant morbidity, and mortality in both cohorts. Results: In the first cohort, 879 live-born children were delivered, with 809 evaluable infants at 1 and 6 months. In the second cohort, 341 infants were delivered and evaluable at 1 month, and 251 infants were evaluable at 6 months. At age 1 month, HIV-1 transmission rates were 4/341 (1.2%) among breastfed infants and 7/809 (0.8%) among formula-fed infants. At age 6 months, HIV-1 mother-to-child transmission rates were 2/251 (0.8%) among breastfed infants of women receiving HAART and 15/809 (1.8%) among formula-fed infants (χ2 = 0.77, P = 0.38 [NS]). The cumulative incidence rate at 6 months of age was 2.7% for formula-fed infants and 2.2% for breastfed infants (χ2 = 0.27, P = 0.60 [NS]). There was a trend for HIV-1 infection rates to be slightly greater among formula-fed infants, but overall mother-to-child transmission rates in both cohorts were extremely low. Most infants did relatively well on both feeding regimens. Observed Z scores were greater than among the general infant population in the community. Z scores ≤2.0 for weight by age occurred in 92/809 formula-fed infants (11.4%) and in 28/251 breastfed infants (11.1%). The rates of anemia in the study infant population were also lower than that of the general population. A hemoglobin value <8 g/dl was found in 40/809 formula-fed infants (4.9%) and in 17/251 breastfed infants (6.8%) (χ2 = 0.92, P = 0.33). The mortality rate at 6 months of age was 27 per 1000 person-years among formula-fed infants and 28.5 per 1000 person-years in breastfed infants – both considerably lower than the rates of 101 per 1000 person-years observed in Mozambique. Conclusions: The DREAM HIV-1 PMTCT protocol was safe and efficacious in reducing transmission in infants of 1 and 6 months of age. Results were comparable to those from developed countries. Breastfeeding among HIV-1 infected mothers receiving HAART posed no additional risk of late postnatal HIV-1 transmission to the infant by 6 months of age.

Predicting Stroke Inpatient Rehabilitation Outcome: The Prominent Role of Neuropsychological Disorders

This study was designed to determine the role of demographic, medical and cognitive factors in the results of rehabilitation in first stroke patients. In a prospective study on 273 consecutive patients admitted to a rehabilitation hospital for sequelae of first stroke, we used multiple regressions to assess the relationship between 11 independent variables and a battery of outcome measures: mortality, length of hospital stay, Barthel Index (BI) and Rivermead Mobility Index (RMI) scores at discharge and their effectiveness. Severity of stroke at admission and hemineglect were the strongest prognostic factors. In a logistic model, cognitive impairment was a significant independent predictor (OR = 4.10) also after adjusting for age and severity of stroke. Patients with hemineglect had a significantly higher relative risk of poor autonomy [RR = 7.30, 95% confidence interval (CI) 4.04-13.18] and impaired mobility (RR = 9.25, CI 4.63-18.45). Global aphasic patients had similar risks for both autonomy (RR = 4.51, CI 2.74-7.41) and mobility (RR = 4.71, CI 2.79-7.97). This study underlines the crucial role of cognitive disorders as predictors of poor functional outcome in stroke survivors and confirms the need for early neuropsychological screening.

Excessive Early Mortality in the First Year of Treatment in HIV Type 1-Infected Patients Initiating Antiretroviral Therapy in Resource-Limited Settings

The response to treatment and risk factors for early mortality following initiation of combination antiretrovirals(ARVs) in a cohort of African patients are described in a retrospective cohort design. Medical history, laboratory parameters, and mortality data were reviewed for patients initiating ARVs in 12 clinical centers in Mozambique, Tanzania, and Malawi. Among 3456 HIV-1-infected patients who received ARVs for more than 6 months, at baseline 72% had WHO clinical stages 3/4, 7% had a viral load 400 copies/ml, and 38% had a CD4 cell count >200/microl. One year later, 78% had undetectable virus loads and 79% had CD4 cell counts >200 cells/mm3. In the first year of HAART 260 deaths occurred (97 per 1000 person/years) with mortality peaking in the first 3 months. The highest mortality was observed in patients with low BMI, low hemoglobin levels, and CD4 values <200 cells/microl at baseline. Mortality rates following initiation of HAART are higher in patients in resource-limited areas, particularly in the first 90 days following treatment initiation.HAART initiated at higher CD4 cell count levels, especially among malnourished and/or anemic patients, will carry significant public health impact.

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.

Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique

AIMS Nevirapine is widely used to treat HIV-1 infection to prevent mother-to-child transmission; unfortunately adverse drug reactions have been reported. Our aim was to identify genes/variants involved in nevirapine-induced hepatotoxicity. MATERIALS & METHODS Patients from Mozambique, 78 with nevirapine-induced hepatotoxicity and 78 without adverse events, were genotyped for ABCB1, CYP2B6, CYP3A4 and CYP3A5 gene variants. We conducted a case-control association study and a genotype/phenotype correlation analysis. RESULTS The ABCB1 c.3435C>T SNP was associated with hepatotoxicity (p = 0.038), with the variant T allele showing a protective effect (odds ratio: 0.42). Moreover, four SNPs in the CYP2B6 and CYP3A5 genes resulted significantly correlated with transaminase values. In particular, for the CYP2B6 c.983T>C SNP, the difference in the alanine aminotransferase mean values were highly significant between TT and TC genotypes (p < 0.001). CONCLUSION Our preliminary results confirm the contribution of the ABCB1 c.3435C>T SNP in nevirapine-induced hepatotoxicity risk and, at the same time, suggest the necessity for further studies.

Safety of nevirapine-containing antiretroviral triple therapy regimens to prevent vertical transmission in an African cohort of HIV-1-infected pregnant women.

To assess the incidence and consequences of adverse reactions among African HIV‐positive pregnant women treated with fixed‐dose combinations of a nevirapine‐containing antiretroviral (ARV) triple therapy.

Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: A study within the Drug Resource Enhancement Against AIDS and Malnutrition Program.

Background:The administration of antiretroviral therapy to lactating women could represent a possible strategy to reduce postnatal HIV transmission. In this study, we assessed the effect of antiretroviral treatment on breast milk viral load and determined plasma and breast milk drug concentrations in pregnant women receiving highly active antiretroviral therapy (HAART). Methods:We studied 40 women receiving zidovudine, lamivudine, and nevirapine from 28 weeks of gestation to 1 month postpartum (group A) and 40 untreated pregnant women (group B). Blood and breast milk samples were collected at delivery and 7 days postpartum. Results:Women in group A had received a median of 85 days of therapy before delivery. Median breast milk concentrations of nevirapine, lamivudine, and zidovudine were 0.6, 1.8, and 1.1 times, respectively, those in maternal plasma. HIV RNA levels in breast milk were significantly lower in group A than in group B (median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at day 7; P < 0.001 for both comparisons). Conclusions:Antiretroviral drugs administered during the last trimester of pregnancy and after delivery reach levels similar to or higher than plasma concentrations in breast milk and can significantly reduce HIV RNA levels. Our data support the potential role of maternal HAART prophylaxis in reducing the risk of breast-feeding-associated transmission.

Ebola Virus Disease 2013-2014 Outbreak in West Africa: An Analysis of the Epidemic Spread and Response

The Ebola virus epidemic burst in West Africa in late 2013, started in Guinea, reached in a few months an alarming diffusion, actually involving several countries (Liberia, Sierra Leone, Nigeria, Senegal, and Mali). Guinea and Liberia, the first nations affected by the outbreak, have put in place measures to contain the spread, supported by international organizations; then they were followed by the other nations affected. In the present EVD outbreak, the geographical spread of the virus has followed a new route: the achievement of large urban areas at an early stage of the epidemic has led to an unprecedented diffusion, featuring the largest outbreak of EVD of all time. This has caused significant concerns all over the world: the potential reaching of far countries from endemic areas, mainly through fast transports, induced several countries to issue information documents and health supervision for individuals going to or coming from the areas at risk. In this paper the geographical spread of the epidemic was analyzed, assessing the sequential appearance of cases by geographic area, considering the increase in cases and mortality according to affected nations. The measures implemented by each government and international organizations to contain the outbreak, and their effectiveness, were also evaluated.