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1.  Impact of Isoniazid Preventive Therapy for HIV-Infected Adults in Rio de Janeiro, Brazil: An Epidemiological Model 
Background
The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain.
Methods
We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of TB/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in tuberculosis (TB) incidence and mortality in the general population and among PLHIV specifically at the end of five years after implementing an IPT program.
Results
Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16%, 24%) of the 2,500 eligible individuals each year. By the end of year 5 after modeled program roll-out, IPT had reduced TB incidence by 3.0% (95% uncertainty range, UR: 1.6%, 7.2%) in the general population and by 15.6% (95%UR: 15.5%, 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95%UR: 2.2%, 10.3%) and 14.3% (14.6%, 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis.
Conclusions
TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.
doi:10.1097/QAI.0000000000000219
PMCID: PMC4257469  PMID: 24853308
Tuberculosis; Infectious Disease Transmission; HIV; Theoretical Models; Brazil; Isoniazid
2.  Assessing the impact of integrated community case management (iCCM) programs on child mortality: Review of early results and lessons learned in sub–Saharan Africa 
Journal of Global Health  2014;4(2):020411.
Aim
To accelerate progress in reducing child mortality, many countries in sub–Saharan Africa have adopted and scaled–up integrated community case management (iCCM) programs targeting the three major infectious killers of children under–five. The programs train lay community health workers to assess, classify and treat uncomplicated cases of pneumonia with antibiotics, malaria with antimalarial drugs and diarrhea with Oral Rehydration Salts (ORS) and zinc. Although management of these conditions with the respective appropriate drugs has proven efficacious in randomized trials, the effectiveness of large iCCM scale–up programs in reducing child mortality is yet to be demonstrated. This paper reviews recent experience in documenting and attributing changes in under–five mortality to the specific interventions of a variety of iCCM programs.
Methods
Eight recent studies have been identified and assessed in terms of design, mortality measurement and results. Impact of the iCCM program on mortality among children age 2–59 months was assessed through a difference in differences approach using random effect Poisson regression.
Results
Designs used by these studies include cluster randomized trials, randomized stepped–wedge and quasi–experimental trials. Child mortality is measured through demographic surveillance or household survey with full birth history conducted at the end of program implementation. Six of the eight studies showed a higher decline in mortality among children 2–59 months in program areas compared to comparison areas, although this acceleration was statistically significant in only one study with a decline of 76% larger in intervention than in comparison areas.
Conclusion
Studies that evaluate large scale iCCM programs and include assessment of mortality impact must ensure an appropriate design. This includes required sample sizes and sufficient number of program and comparison districts that allow adequate inference and attribution of impact. In addition, large–scale program utilization, and a significant increase in coverage of care seeking and treatment of targeted childhood illnesses are preconditions to measurable mortality impact. Those issues need to be addressed before large investments in assessing changes in child mortality is undertaken, or the results of mortality impact evaluation will most likely be inconclusive.
doi:10.7189/jogh.04.020411
PMCID: PMC4267100  PMID: 25520801
3.  Impact of tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV infection receiving care in public clinics in Rio de Janeiro, Brazil: the Tuberculosis/HIV in Rio de Janeiro (THRio) study: a stepped wedge, cluster randomized trial 
The Lancet infectious diseases  2013;13(10):852-858.
Summary
Background
Preventive therapy for tuberculosis among HIV-infected patients is effective but has not been widely implemented in moderate/high-burden settings.
Objectives
To determine the impact of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in HIV-infected individuals in Brazil.
Design
Stepped wedge, cluster randomized trial
Participants
Patients actively enrolled in 29 HIV clinics in Rio de Janeiro, Brazil
Control period
Standard of care
Intervention period
Staff training in tuberculosis screening, performance of tuberculin skin tests and use of isoniazid preventive therapy.
Randomization
Clinics were randomly allocated a date to begin the intervention period with two clinics beginning the intervention every 2 months starting September 1 2005.
Main outcome measures
Tuberculosis incidence alone or combined with death in the control versus intervention periods through August 31 2009.
Results
Among 17,413 patients in the THRio cohort, 12,816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19/100 person-years to 59/100 person-years, and from 36/100 person-years to 144/100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 tuberculosis cases were diagnosed (1·31/100 person-years) compared to 254 (1·10/100 person-years) in the intervention (unadjusted hazard ratio (HR)=0·87;95%CI:0·69–1·10). Rates of tuberculosis incidence or death were 3·64 and 3·04/100 person-years, respectively (HR=0·76; 95%CI:0·66–0·87). When adjusted for age, sex, entry CD4 count and use of antiretroviral therapy, the HR for tuberculosis was 0·73 (95%CI:0·54–0·99) and for tuberculosis or death was 0·69 (95%CI:0·57–0·83). Among 12,196 patients remaining in care (secondary analyses, 399 tuberculosis cases and 656 deaths), the adjusted HR of tuberculosis alone and combined with death were 0·42 (95%CI:0·29–0·60) and 0·45 (95%CI:0·35–0·56), respectively,
Conclusions
Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in moderate tuberculosis incident settings is achievable and should be strongly considered in Brazil and elsewhere.
Trial registration
This trial is registered at clinicaltrials.gov (NCT00107887)
Funding
Bill & Melinda Gates Foundation; National Institutes of Health
doi:10.1016/S1473-3099(13)70187-7
PMCID: PMC3899698  PMID: 23954450
4.  Point-of-Care Lateral Flow Assays for Tuberculosis and Cryptococcal Antigenuria Predict Death in HIV Infected Adults in Uganda 
PLoS ONE  2014;9(7):e101459.
Background
Mortality in hospitalized, febrile patients in Sub-Saharan Africa is high due to HIV-infected, severely immunosuppressed patients with opportunistic co-infection, particularly disseminated tuberculosis (TB) and cryptococcal disease. We sought to determine if a positive lateral flow assay (LFA) result for urine lipoarabinomannan (LAM) and cryptococcal antigenuria was associated with mortality.
Methods
351 hospitalized, HIV-positive adults with symptoms consistent with TB and who were able to provide both urine and sputum specimens were prospectively enrolled at Mulago National Referral Hospital in Uganda as part of a prospective accuracy evaluation of the lateral flow Determine TB LAM test. Stored frozen urine was retrospectively tested for cryptococcal antigen (CRAG) using the LFA. We fitted a multinomial logistic regression model to analyze factors associated with death within 2 months after initial presentation.
Results
The median CD4 of the participants was 57 (IQR: 14–179) cells/µl and 41% (145) were microbiologically confirmed TB cases. LAM LFA was positive in 38% (134), 7% (25) were CRAG positive, and 43% (151) were positive for either test in urine. Overall, 21% (75) died within the first 2 months, and a total of 32% (114) were confirmed dead by 6 months. At 2 months, 30% of LAM or CRAG positive patients were confirmed dead compared to 15.0% of those who were negative. In an adjusted model, LAM or CRAG positive results were associated with an increased risk of death (RRR 2.29, 95% CI: 1.29, 4.05; P = 0.005).
Conclusions
In hospitalized HIV-infected patients, LAM or CRAG LFA positivity was associated with subsequent death within 2 months. Further studies are warranted to examine the impact of POC diagnostic ‘test and treat’ approach on patient-centered outcomes.
doi:10.1371/journal.pone.0101459
PMCID: PMC4084886  PMID: 25000489
5.  CD4 and Viral Load Dynamics in Antiretroviral-Naïve HIV-Infected Adults from Soweto, South Africa: A Prospective Cohort 
PLoS ONE  2014;9(5):e96369.
Background
CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates.
Methods
HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored.
Results
1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm3 (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm3 per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml.
Conclusions
Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.
doi:10.1371/journal.pone.0096369
PMCID: PMC4022663  PMID: 24831447
6.  Stunting Is Characterized by Chronic Inflammation in Zimbabwean Infants 
PLoS ONE  2014;9(2):e86928.
Background
Stunting affects one-third of children in developing countries, but the causes remain unclear. We hypothesized that enteropathy leads to low-grade inflammation, which suppresses the growth hormone-IGF axis and mediates stunting.
Methods
We conducted a case-control study of 202 HIV-unexposed Zimbabwean infants who were stunted (height-for-age Z-score (HAZ) <−2; cases) or non-stunted (HAZ >−0.5; controls) at 18 months. We measured biomarkers of intestinal damage (I-FABP), inflammation (CRP, AGP, IL-6) and growth hormone-IGF axis (IGF-1, IGFBP3) in infant plasma at 6 weeks and 3, 6, 12 and 18 months, and in paired maternal-infant plasma at birth. Adjusted mean differences between biomarkers were estimated using regression models. Multivariate odds ratios of stunting were estimated by logistic regression.
Results
At birth, cases were shorter (median (IQR) HAZ −1.00 (−1.53, −0.08) vs 0.03 (−0.57, 0.62,); P<0.001) than controls and their mothers had lower levels of IGF-1 (adjusted mean difference (95%CI) −21.4 (−39.8, −3.1) ng/mL). From 6 weeks to 12 months of age, levels of CRP and AGP were consistently higher and IGF-1 and IGFBP3 lower in cases versus controls; IGF-1 correlated inversely with inflammatory markers at all time-points. I-FABP increased between 3–12 months, indicating extensive intestinal damage during infancy, which was similar in cases and controls. In multivariate analysis, higher log10 levels of CRP (aOR 3.06 (95%CI 1.34, 6.99); P = 0.008) and AGP (aOR 7.87 (95%CI 0.74, 83.74); P = 0.087) during infancy were associated with stunting. There were no associations between levels of I-FABP, IL-6, sCD14 or EndoCAb and stunting.
Conclusions
Stunting began in utero and was associated with low maternal IGF-1 levels at birth. Inflammatory markers were higher in cases than controls from 6 weeks of age and were associated with lower levels of IGF-1 throughout infancy. Higher levels of CRP and AGP during infancy were associated with stunting. These findings suggest that an extensive enteropathy occurs during infancy and that low-grade chronic inflammation may impair infant growth.
doi:10.1371/journal.pone.0086928
PMCID: PMC3928146  PMID: 24558364
7.  A common evaluation framework for the African Health Initiative 
BMC Health Services Research  2013;13(Suppl 2):S10.
Background
The African Health Initiative includes highly diverse partnerships in five countries (Ghana, Mozambique, Rwanda, Tanzania, and Zambia), each of which is working to improve population health by strengthening health systems and to evaluate the results. One aim of the Initiative is to generate cross-site learning that can inform implementation in the five partnerships during the project period and identify lessons that may be generalizable to other countries in the region. Collaborators in the Initiative developed a common evaluation framework as a basis for this cross-site learning.
Methods
This paper describes the components of the framework; this includes the conceptual model, core metrics to be measured in all sites, and standard guidelines for reporting on the implementation of partnership activities and contextual factors that may affect implementation, or the results it produces. We also describe the systems that have been put in place for data management, data quality assessments, and cross-site analysis of results.
Results and conclusions
The conceptual model for the Initiative highlights points in the causal chain between health system strengthening activities and health impact where evidence produced by the partnerships can contribute to learning. This model represents an important advance over its predecessors by including contextual factors and implementation strength as potential determinants, and explicitly including equity as a component of both outcomes and impact. Specific measurement challenges include the prospective documentation of program implementation and contextual factors. Methodological issues addressed in the development of the framework include the aggregation of data collected using different methods and the challenge of evaluating a complex set of interventions being improved over time based on continuous monitoring and intermediate results.
doi:10.1186/1472-6963-13-S2-S10
PMCID: PMC3668298  PMID: 23819778
8.  Training Laboratory Technicians from the Ethiopian Periphery in the MODS Technique Enables Rapid and Low-Cost Diagnosis of Mycobacterium tuberculosis Infection 
Tuberculosis (TB) is a leading cause of morbidity and mortality and is frequently complicated by emergence of drug-resistant strains. Diagnosis of TB in developing countries is often based on the relatively insensitive acid-fast staining that does not enable susceptibility profiling. Microscopic observation drug susceptibility assay (MODS) is an inexpensive, simple method that enables rapid TB culture coupled with susceptibility testing. A 3-week MODS training of three Ethiopian laboratory technicians was conducted at Hadassah-Hebrew University Medical Center, Israel. Results of the trainee readings were blindly assessed by an experienced instructor. Two hundred fifty-five (255) trainee culture readings were evaluated throughout the course. The sensitivity and specificity were 75–100% and 31.5–100%, respectively. Multivariate analysis revealed that sensitivity and duration of incubation were positively correlated, although specificity was positively correlated with the length of training. MODS can be reliably performed by laboratory technicians inexperienced in culture techniques in developing countries, with high sensitivity and specificity reached after a brief learning period.
doi:10.4269/ajtmh.2012.11-0516
PMCID: PMC3403761  PMID: 22492154
9.  Impact of More Than a Decade of Pneumococcal Conjugate Vaccine Use on Carriage and Invasive Potential in Native American Communities 
The Journal of Infectious Diseases  2011;205(2):280-288.
Background. We assessed the impact of 12 years of pneumococcal conjugate vaccine (PCV7) use on pneumococcal nasopharyngeal carriage and serotype-specific invasive disease potential among Native Americans.
Methods. Families were enrolled in a carriage study from 2006 to 2008; nasopharyngeal specimens and risk factor information were collected monthly for 7 visits. Pneumococcal carriage prevalence was compared with that before (1998–2000) and during (2001–2002) PCV7 introduction. We compared invasive disease incidence and carriage prevalence before and after PCV7 introduction to estimate changes in serotype-specific invasive potential.
Results. We enrolled 1077 subjects from 302 households. There was an absolute reduction in carriage prevalence of 8.0% (95% confidence interval [CI], 4.5%–11.4%) in children aged <5 years and 3.1% (95% CI, 1.1%–5.1%) in adults. In children aged <5 years, vaccine-serotype carriage prevalence decreased by 22.8% (95% CI, 20.1%–25.3%), and nonvaccine serotype (NVT) increased by 15.9% (95% CI, 12.4%–19.3%). No significant change was detected in serotype-specific invasive potential after PCV7 introduction.
Conclusions. Pneumococcal carriage prevalence decreased in all ages since PCV7 introduction; vaccine-serotype carriage has been nearly eliminated, whereas the prevalence of NVT carriage has increased. The increase in the NVT invasive disease rate seems to be proportional to the increase in colonization prevalence.
doi:10.1093/infdis/jir730
PMCID: PMC3244367  PMID: 22128315
10.  Safety and Efficacy of HIV Hyperimmune Globulin (HIVIGLOB) for Prevention of Mother-to-Child HIV Transmission in HIV-1 infected Pregnant Women and their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY) 
Background
This phase III randomized clinical trial compared single dose nevirapine (sdNVP) plus HIV immunoglobulin (HIVIGLOB) to sdNVP alone for preventing maternal-to-child transmission (PMTCT) of HIV.
Primary objectives were to determine rates of HIV infection among infants, and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants.
Methods
Mother-infant pairs were randomized to receive 200mg of NVP to women in labor and 2mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240ml dose of HIVIGLOB given to women at 36-38 weeks gestation and a single intravenous 24ml dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6 and 12 months of age.
Results
Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm versus the sdNVP arm (18.7% vs.15.0%; RR =1.240 [95% CI: 0.833-1.846]; p= 0.290). Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively for mothers (18.9% vs. 19.3%; p= 0.91) and infants (62.6% vs. 59.5%; p=0.51), were not significantly different.
Conclusion
Giving mother-infant pairs an infusion of peripartum HIV hyperimmunoglobulin in addition to sdNVP for PMTCT was as safe as sdNVP alone, but was no more effective than sdNVP alone in preventing HIV transmission.
doi:10.1097/QAI.0b013e31822f8914
PMCID: PMC3204156  PMID: 21826009
HIV; HIVIGLOB; sdNVP; breastfeeding; PMTCT; Uganda
11.  Predictive Value of Weight Loss on Mortality of HIV-Positive Mothers in a Prolonged Breastfeeding Setting 
AIDS Research and Human Retroviruses  2011;27(11):1141-1148.
Abstract
HIV-positive lactating women may be at high risk of weight loss due to increased caloric requirements and postpartum physiological weight loss. Ten percent weight loss is associated with a higher risk of mortality in HIV-positive patients and this alone is a criterion for highly active antiretroviral therapy (HAART) initiation where CD4 counts are not available. However, no study has investigated this association in lactating postpartum women. We investigated whether 10% weight loss predicts death in postpartum HIV-positive women. A total of 9207 HIV-negative and 4495 HIV-positive mothers were recruited at delivery. Women were weighed at 6 weeks, 3 months, and every 3 months thereafter for up to 24 months postpartum and data on mortality up to 2 years were collected. The median duration of breastfeeding was longer than 18 months. Among HIV-positive women, the independent predictors of ≥10% weight loss were CD4 cell count, body mass index, and household income. Mortality was up to 7.12 (95% CI 3.47–14.61) times higher in HIV-positive women with ≥10% weight loss than those without weight loss. Ten percent weight loss in postpartum lactating HIV-positive women was significantly predictive of death. Our findings suggest that 10% weight loss is an appropriate criterion for HAART initiation among postpartum breastfeeding women.
doi:10.1089/aid.2010.0293
PMCID: PMC3243462  PMID: 21226627
12.  Parents' Source of Vaccine Information and Impact on Vaccine Attitudes, Beliefs, and Nonmedical Exemptions 
In recent years, use of the Internet to obtain vaccine information has increased. Historical data are necessary to evaluate current vaccine information seeking trends in context. Between 2002 and 2003, surveys were mailed to 1,630 parents of fully vaccinated children and 815 parents of children with at least one vaccine exemption; 56.1% responded. Respondents were asked about their vaccine information sources, perceptions of these sources accuracy, and their beliefs about vaccination. Parents who did not view their child's healthcare provider as a reliable vaccine information source were more likely to obtain vaccine information using the Internet. Parents who were younger, more highly educated, and opposed to school immunization requirements were more likely than their counterparts to use the Internet for vaccine information. Compared to parents who did not use the Internet for vaccine information, those who sought vaccine information on the Internet were more likely to have lower perceptions of vaccine safety (adjusted odds ratio (aOR), 1.66; 95% CI, 1.18–2.35), vaccine effectiveness (aOR, 1.83; 95% CI, 1.32–2.53), and disease susceptibility (aOR, 2.08; 95% CI, 1.49–2.90) and were more likely to have a child with a nonmedical exemption (aOR 3.53, 95% CI, 2.61–4.76). These findings provide context to interpret recent vaccine information seeking research.
doi:10.1155/2012/932741
PMCID: PMC3469070  PMID: 23082253
13.  In utero and intra-partum HIV-1 transmission and acute HIV-1 infection during pregnancy: using the BED capture enzyme-immunoassay as a surrogate marker for acute infection 
Objective The BED assay was developed to estimate the proportion of recent HIV infections in a population. We used the BED assay as a proxy for acute infection to quantify the associated risk of mother-to-child-transmission (MTCT) during pregnancy and delivery.
Design A total of 3773 HIV-1 sero-positive women were tested within 96 h of delivery using the BED assay, and CD4 cell count measurements were taken. Mothers were classified according to their likelihood of having recently seroconverted.
Methods The risk of MTCT in utero and intra-partum was assessed comparing different groups defined by BED and CD4 cell count, adjusting for background factors using multinomial logistic models.
Results Compared with women with BED ≥ 0.8/CD4 ≥ 350 (typical of HIV-1 chronic patients) there was insufficient evidence to conclude that women presenting with BED < 0.8/CD4 ≥ 350 (typical of recent infections) were more likely to transmit in utero [adjusted odds ratio (aOR) = 1.37, 96% confidence interval (CI) 0.90–2.08, P = 0.14], whereas women with BED < 0.8/CD4 200–349 (possibly recently infected patients) had a 2.57 (95% CI 1.39–4.77, P-value < 0.01) odds of transmitting in utero. Women who had BED < 0.8/CD4 < 200 were most likely to transmit in utero (aOR 3.73, 95% CI 1.27–10.96, P = 0.02). BED and CD4 cell count were not predictive of intra-partum infections.
Conclusions These data provide evidence that in utero transmission of HIV might be higher among women who seroconvert during pregnancy.
doi:10.1093/ije/dyr055
PMCID: PMC3156369  PMID: 21471020
BED; CD4; in utero; intra-partum; seroconversion; HIV
14.  New Regimens to Prevent Tuberculosis in Adults with HIV Infection 
BACKGROUND
Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.
METHODS
We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.
RESULTS
The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.
CONCLUSIONS
On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid.
doi:10.1056/NEJMoa1005136
PMCID: PMC3407678  PMID: 21732833
15.  Net survival of perinatally and postnatally HIV-infected children: a pooled analysis of individual data from sub-Saharan Africa 
Background Previously, HIV epidemic models have used a double Weibull curve to represent high initial and late mortality of HIV-infected children, without distinguishing timing of infection (peri- or post-natally). With more data on timing of infection, which may be associated with disease progression, a separate representation of children infected early and late was proposed.
Methods Paediatric survival post-HIV infection without anti-retroviral treatment was calculated using pooled data from 12 studies with known timing of HIV infection. Children were grouped into perinatally or post-natally infected. Net mortality was calculated using cause-deleted life tables to give survival as if HIV was the only competing cause of death. To extend the curve beyond the available data, children surviving beyond 2.5 years post infection were assumed to have the same survival as young adults. Double Weibull curves were fitted to both extended survival curves to represent survival of children infected perinatally or through breastfeeding.
Results Those children infected perinatally had a much higher risk of dying than those infected through breastfeeding, even allowing for background mortality. The final-fitted double Weibull curves gave 75% survival at 5 months after infection for perinatally infected, and 1.1 years for post-natally infected children. An estimated 25% of the early infected children would still be alive at 10.6 years compared with 16.9 years for those infected through breastfeeding.
Conclusions The increase in available data has enabled separation of child mortality patterns by timing of infection allowing improvement and more flexibility in modelling of paediatric HIV infection and survival.
doi:10.1093/ije/dyq255
PMCID: PMC3140269  PMID: 21247884
HIV; survival; paediatric
16.  Children Who Acquire HIV Infection Perinatally Are at Higher Risk of Early Death than Those Acquiring Infection through Breastmilk: A Meta-Analysis 
PLoS ONE  2012;7(2):e28510.
Background
Assumptions about survival of HIV-infected children in Africa without antiretroviral therapy need to be updated to inform ongoing UNAIDS modelling of paediatric HIV epidemics among children. Improved estimates of infant survival by timing of HIV-infection (perinatally or postnatally) are thus needed.
Methodology/Principal Findings
A pooled analysis was conducted of individual data of all available intervention cohorts and randomized trials on prevention of HIV mother-to-child transmission in Africa. Studies were right-censored at the time of infant antiretroviral initiation. Overall mortality rate per 1000 child-years of follow-up was calculated by selected maternal and infant characteristics. The Kaplan-Meier method was used to estimate survival curves by child's HIV infection status and timing of HIV infection. Individual data from 12 studies were pooled, with 12,112 children of HIV-infected women. Mortality rates per 1,000 child-years follow-up were 39.3 and 381.6 for HIV-uninfected and infected children respectively. One year after acquisition of HIV infection, an estimated 26% postnatally and 52% perinatally infected children would have died; and 4% uninfected children by age 1 year. Mortality was independently associated with maternal death (adjusted hazard ratio 2.2, 95%CI 1.6–3.0), maternal CD4<350 cells/ml (1.4, 1.1–1.7), postnatal (3.1, 2.1–4.1) or peri-partum HIV-infection (12.4, 10.1–15.3).
Conclusions/Results
These results update previous work and inform future UNAIDS modelling by providing survival estimates for HIV-infected untreated African children by timing of infection. We highlight the urgent need for the prevention of peri-partum and postnatal transmission and timely assessment of HIV infection in infants to initiate antiretroviral care and support for HIV-infected children.
doi:10.1371/journal.pone.0028510
PMCID: PMC3285615  PMID: 22383946
17.  Estimating the Extent of Underreporting of Mortality Among HIV-Infected Individuals in Rio de Janeiro, Brazil 
Abstract
Non-HIV-related causes of death have been increasing after the introduction of highly active antiretroviral therapy. Underlying and contributing causes of death were assessed in respect to the presence/absence of HIV/AIDS among HIV-infected/AIDS patients in Rio de Janeiro, Brazil. Demographic variables (age, gender, ethnicity, and schooling) and CD4 cell counts closest to death were assessed through logistic regression models comparing those who did not have with those who had HIV/AIDS mentioned on the death certificate. The linkage with the two cohorts identified 1249 records, of which 370 (29.6%) did not have HIV/AIDS listed on any field of the death certificate [77 (20.8%) attributed to undefined and 72 (19.5%) to external causes]. After excluding external causes, 25.3% still did not have HIV/AIDS listed on the death certificate. Multiple logistic regression analysis showed that age >40 years (OR = 2.09; 95%CI = 1.49–2.93; p < 0.001) and CD4 cell count closest to the date of death (OR = 1.15; 95% CI = 1.07–1.23; p < 0.001 for 100 cell increase) were associated with an increased probability of not having HIV/AIDS mentioned on the death certificate, when external causes were excluded. Mortality among HIV-infected individuals is underreported in the Rio de Janeiro Mortality Registry, particularly among older individuals and those with higher CD4 counts. Physicians should be aware of the changing patterns of mortality among HIV individuals, and public health officials should regularly perform linkages between all-cause mortality and available HIV-infected patients databases, such as AIDS registries and large cohort studies.
doi:10.1089/aid.2010.0089
PMCID: PMC3026651  PMID: 20929394
18.  A modeling framework for the analysis of HPV incidence and persistence: a semi-parametric approach for clustered binary longitudinal data analysis 
Statistics in medicine  2010;29(28):2880-2889.
Human papillomavirus (HPV) infection is a common sexually transmitted disease of growing public health importance, and over 40 genotypes have been identified in genital infections. Current HPV cohort studies often follow participants at pre-determined visits, such as every 6-months, and data generated from such epidemiology studies can be described as clustered longitudinal binary data where correlation arises in two ways: the directionless clustering due to the multiple genotypes tested within an individual, and the temporal correlation among the repeated measurements on the same genotype along time. Current analyses for identification of risk factors associated with HPV incidence and persistence often either do not fully utilize information in the dataset or ignore the correlation between the multiple genotypes. Given the scientific definition of incidence and persistence, conditional probability modeling provides us a natural mathematical tool. We thus present a semi-parametric regression model for such data where full specification of the joint multivariate binary distribution is avoided by using conditioning argument to handle the temporal correlation and GEE to account for the correlation between the multiple genotypes. The model is applied to the HPV data from the Rakai male circumcision (MC) trial to evaluate the as-treated efficacy of MC and also identify modifiable risk factors for incidence and persistence of oncogenic HPV types in men. A simulation study is performed to provide empirical information on the number of individuals that is needed for satisfactory power and estimation accuracy of the association parameter estimates in future studies.
doi:10.1002/sim.4062
PMCID: PMC2991598  PMID: 20839368
clustered longitudinal binary data; conditional probability; semi-parametric model; HPV incidence; HPV persistence
19.  Circumcision of HIV-infected men: Effects on High Risk Human Papillomavirus Infections in a Randomized Trial in Rakai, Uganda 
The Journal of infectious diseases  2010;201(10):1463-1469.
In Rakai, Uganda, HIV+ men were randomized to immediate (intervention) or delayed circumcision (controls). Penile swabs were assayed for high risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and 24 months (intervention n=103, control n=107). Rate ratios (RR) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was intervention 55.3% and control 71.7% (RR=0.77, 95%CI 0.62–0.97). Multiple HR-HPV infections were intervention 22.4% and controls 42.5% (RR=0.53, 95%CI 0.33–0.83). New HR-HPV genotypes were acquired by 42.0% of intervention and 57.0% of control arm men (RR=0.74, 95%CI 0.54–1.01, p=0.06). Multiple new HR-HPV genotypes were acquired by 9.9% intervention and 24.7% control arm men (RR = 0.40, 95%CI 0.19–0.84, p = 0.01). Circumcision did not affect the acquisition of single HR-HPV infections (RR=1.00, 95%CI 0.65–1.53) or clearance of HR-HPV (RR=1.09, 95%CI 0.94–1.27). Circumcision of HIV+ men reduced the prevalence and incidence of multiple HR-HPV infections.
doi:10.1086/652185
PMCID: PMC2862639  PMID: 20370481
20.  Male circumcision decreases acquisition and increases clearance of high risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda 
The Journal of infectious diseases  2010;201(10):1455-1462.
Uncircumcised HIV-negative men aged 15-49 years were randomized to immediate circumcision (n=441) or delayed circumcision (n=399). HPV was detected by Roche HPV Linear Array at enrollment, 6, 12 and 24 months. Incident HR-HPV was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RR) and 95% confidence intervals (95%CI) of HR-HPV acquisition were estimated by Poisson multiple regression
Enrollment characteristics were comparable between groups. HR-HPV incidence was 19.7/100 py in the intervention (70/355.8 py) and 29.4/100 py (125/424.8 py) in the control arm (RR=0.67, 95%CI 0.51-0.89, p = 0.006.) The incidence of multiple HR-HPV infections was 6.7/100 py in the intervention and 14.8/100 py in control arm (RR = 0.45, 95%CI 0.28-0.73), but there was no significant effect on single infections (RR=0.89, 95%CI 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of pre-existing HR-HPV infections was 215.8/100py (205/95 py) in intervention and 159.1/100py (255/160.25 py) in control arm men (adjRR=1.39, 95%CI 1.17-1.64).
Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men.
The trial was registered with ClinicalTrials.gov numbers NCT00425984
doi:10.1086/652184
PMCID: PMC2882881  PMID: 20370483
21.  Risk Factors for Antibiotic-Resistant Escherichia coli Carriage in Young Children in Peru: Community-Based Cross-Sectional Prevalence Study 
Few studies have examined the influence of individual-, household-, and community-scale risk factors on carriage of resistant commensal bacteria. We determined children's medical, agricultural, and environmental exposures by household, pharmacy, and health facility surveys and Escherichia coli cultures of children, mothers' hands, household animals, and market chickens in Peru. Among 522 children with a positive stool culture, by log-binomial regression, using “any antibiotic” and 1–14 (versus 0) sulfa doses in the past 3 months increased children's risk, respectively, for ampicillin- and sulfamethoxazole-resistant E. coli carriage (P = 0.01–0.02). Each household member taking “any antibiotic” increased children's risk for sulfamethoxazole- and multidrug-resistant E. coli carriage (P < 0.0001). Residence in a zone where a larger proportion of households served home-raised chicken (as contrasted with intensively antibiotic-raised market chicken) protected against carrying E. coli resistant to all drugs (P = 0.0004–0.04). Environmental contamination with drug-resistant bacteria appeared to significantly contribute to children's carriage of antibiotic-resistant E. coli.
doi:10.4269/ajtmh.2010.09-0143
PMCID: PMC2861397  PMID: 20439971
22.  Postpartum Plasma CD4 Change in HIV-Positive Women: Implications for Timing of HAART Initiation 
Abstract
CD4 counts increase during the postpartum period and may not correctly identify HAART-eligible HIV-positive women. HAART eligibility when defined by two CD4 cutoffs (<200 and <350 cells/μl) measured at two time points (within 96 h of delivery and 6 weeks) in postpartum HIV-positive women was compared. Among HIV-positive women who had CD4 at delivery and 6 weeks (n = 423), time to Stage 3 or 4 opportunistic infection or death was compared using Cox regression between three groups of women: (1) CD4 <200 cells/μl at delivery and 6 weeks, (2) CD4 <200 cells/μl at delivery but ≥200 cells/μl at 6 weeks, and (3) CD4 ≥200 cells/μl at delivery and at 6 weeks. The analysis was repeated using the CD4 <350 cells/μl cut-off. CD4 counts increased by a median (IQR) of 70 (1–178) cells/μl between delivery and 6 weeks and decreased thereafter to approximately delivery levels at 12 months. Only 60% and 61% who had CD4 <200 cells/μl and CD4 <350 cells/μl, respectively, at delivery also had those levels at 6 weeks. Among those with CD4 <350 cells/μl at both delivery and 6 weeks, the risk of death or Stage 3 or 4 disease was 5.27 (95% CI 1.85–14.96) times higher than those with CD4 <350 at delivery but ≥350 cells/μl at 6 weeks. The use of CD4 counts immediately postpartum to define HAART eligibility may lead to substantial misclassification.
doi:10.1089/aid.2009.0138
PMCID: PMC3120221  PMID: 20455759
23.  The implementation of isoniazid preventive therapy in HIV clinics: the experience from the TB/HIV in Rio (THRio) Study 
AIDS (London, England)  2010;24(Suppl 5):S49-S56.
Objective
The TB/HIV in Rio (THRio) study was launched in September 2005 to assess the impact of integrated tuberculosis (TB) and HIV treatment strategies in 29 HIV clinics in Rio de Janeiro, Brazil.
Design
THRio is a cluster-randomized trial (CRT) to determine whether routine screening for and treatment of latent TB in HIV clinic patients with access to antiretroviral therapy will reduce TB incidence at the clinic level. THRio is part of the Consortium to Respond Effectively to AIDS/TB Epidemic that is implementing research studies to assess the impact of bold, new public health paradigms for controlling the AIDS/TB epidemic.
Methods
Twenty-nine public primary HIV clinics were randomly assigned a date to begin implementing TB screening procedures and provision of isoniazid preventive therapy (IPT) for TB/HIV coinfected patients. Final analysis of the CRT is expected in 2011.
Results
Starting at date of tuberculin skin test (TST)/IPT implementation at each clinic through August 2010, 1670 HIV-infected patients initiated IPT, of which 215 are still receiving treatment. Of the remaining 1455 patients, 1230 (85%) completed therapy and only 20 (1.2%) patients initiating IPT reported adverse reactions leading to discontinuation of therapy. IPT completion was higher among HIV-infected patients receiving HAART (87%) than those not yet receiving HAART (79%, P < 0.01). Times to TST and IPT have markedly decreased postintervention, but remain considerably long. The richness of the THRio database has resulted in several analyses of this expansive cohort of HIV-infected patients that are reviewed here.
Conclusions
The national implementation of TST and IPT for HIV-positive patients in Brazil has been invigorated partly due to THRio’s baseline results. Expanded use of IPT in HIV patients in Rio de Janeiro is achievable with high adherence and low adverse events, although this effort requires a package of activities including training, advocacy and reorganization of services.
doi:10.1097/01.aids.0000391022.95412.a6
PMCID: PMC3066070  PMID: 21079428
adherence; HIV; implementation; isoniazid preventive therapy; tuberculosis
24.  The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil 
AIDS (London, England)  2007;21(11):1441-1448.
Background
Tuberculosis is a common complication and leading cause of death in HIV infection. Antiretroviral therapy (ART) lowers the risk of tuberculosis, but may not be sufficient to control HIV-related tuberculosis. Isoniazid preventive therapy (IPT) reduces tuberculosis incidence significantly, but is not widely used.
Methods
We analysed tuberculosis incidence in 11 026 HIV-infected patients receiving medical care at 29 public clinics in Rio de Janeiro, Brazil, between 1 September 2003 and 1 September 2005. Data were collected through a retrospective medical record review. We determined rates of tuberculosis in patients who received neither ART nor IPT, only ART, only IPT, or both ART and IPT.
Results
The overall tuberculosis incidence was 2.28 cases/100 person-years (PY) [95% confidence interval (CI) 2.06–2.52]. Among patients who received neither ART nor IPT, incidence was 4.01/100 PY. Patients who received ART had an incidence of 1.90/100 PY (95% CI 1.66–2.17) and those treated with IPT had a rate of 1.27/100 PY (95% CI 0.41–2.95). The incidence among patients who received ART and IPT was 0.80/100 PY (95% CI 0.38–1.47). Multivariate Cox proportional hazards modeling revealed a 76% reduction in tuberculosis risk among patients receiving both ART and IPT (adjusted relative hazard 0.24; P < 0.001) after adjusting for age, previous tuberculosis diagnosis, and CD4 cell counts at baseline.
Conclusion
The use of both IPT and ART in HIV-infected patients is associated with significantly reduced tuberculosis incidence. In conjunction with expanded access to ART, the wider use of IPT in patients with HIV will improve tuberculosis control in high burden areas.
doi:10.1097/QAD.0b013e328216f441
PMCID: PMC3063947  PMID: 17589190
antiretroviral therapy; Brazil; HIV; isoniazid; tuberculosis
25.  Mother to child transmission of HIV among Zimbabwean women who seroconverted postnatally: prospective cohort study 
Objectives To estimate the rates and timing of mother to infant transmission of HIV associated with breast feeding in mothers who seroconvert postnatally, and their breast milk and plasma HIV loads during and following seroconversion, compared with women who tested HIV positive at delivery.
Design Prospective cohort study.
Setting Urban Zimbabwe.
Participants 14 110 women and infants enrolled in the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial (1997-2001).
Main outcome measures Mother to child transmission of HIV, and breast milk and maternal plasma HIV load during the postpartum period.
Results Among mothers who tested HIV positive at baseline and whose infant tested HIV negative with polymerase chain reaction (PCR) at six weeks (n=2870), breastfeeding associated transmission was responsible for an average of 8.96 infant infections per 100 child years of breast feeding (95% CI 7.92 to 10.14) and varied little over the breastfeeding period. Breastfeeding associated transmission for mothers who seroconverted postnatally (n=334) averaged 34.56 infant infections per 100 child years (95% CI 26.60 to 44.91) during the first nine months after maternal infection, declined to 9.50 (95% CI 3.07 to 29.47) during the next three months, and was zero thereafter. Among women who seroconverted postnatally and in whom the precise timing of infection was known (≤90 days between last negative and first positive test; n=51), 62% (8/13) of transmissions occurred in the first three months after maternal infection and breastfeeding associated transmission was 4.6 times higher than in mothers who tested HIV positive at baseline and whose infant tested HIV negative with PCR at six weeks. Median plasma HIV concentration in all mothers who seroconverted postnatally declined from 5.0 log10 copies/mL at the last negative enzyme linked immunosorbent assay (ELISA) to 4.1 log10 copies/mL at 9-12 months after infection. Breast milk HIV load in this group was 4.3 log10 copies/mL 0-30 days after infection, but rapidly declined to 2.0 log10 copies/mL and <1.5 log10 copies/mL by 31-90 days and more than 90 days, respectively. Among women whose plasma sample collected soon after delivery tested negative for HIV with ELISA but positive with PCR (n=17), 75% of their infants were infected or had died by 12 months. An estimated 18.6% to 20.4% of all breastfeeding associated transmission observed in the ZVITAMBO trial occurred among mothers who seroconverted postnatally.
Conclusions Breastfeeding associated transmission is high during primary maternal HIV infection and is mirrored by a high but transient peak in breast milk HIV load. Around two thirds of breastfeeding associated transmission by women who seroconvert postnatally may occur while the mother is still in the “window period” of an antibody based test, when she would test HIV negative using one of these tests.
Trial registration Clinical trials.gov NCT00198718.
doi:10.1136/bmj.c6580
PMCID: PMC3007097  PMID: 21177735

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