Many randomized and cohort studies have reported a survival benefit with cotrimoxazole prophylaxis without detecting a difference in tuberculosis (TB) incidence by cotrimoxazole status. However, several in vitro studies have reported that cotrimoxazole possesses anti-TB activity. We sought to compare TB incidence and TB diagnostic yield by cotrimoxazole use among participants in a well characterized cohort of HIV-infected adults living in a high TB prevalence region.
We analyzed prospective data from a long-term longitudinal cohort of adults receiving HIV care and TB investigations in Soweto, South Africa. Using longitudinal analysis, we compared total and laboratory confirmed TB incidence by cotrimoxazole status as well as all-cause mortality. In addition, we compared TB culture results by cotrimoxazole status.
In a multivariable analysis, adjusted for sex, body mass index, WHO clinical stage, time-updated CD4 count, and antiretroviral therapy status, we observed an association between cotrimoxazole and an increase in TB incidence (hazard ratio 1.7, 95% CI: 1.2, 2.2). However, when restricted to laboratory-confirmed TB, there was no association between cotrimoxazole and TB incidence (hazard ratio: 0.97, 95% CI: 0.39, 2.4). In TB cases, we found no difference in the proportion of positive sputum cultures or days to culture positivity by cotrimoxazole status. Cotrimoxazole was associated with a reduction in mortality.
In this cohort with a mortality benefit from cotrimoxazole, we found an increased risk of all TB among individuals using cotrimoxazole, likely a result of residual confounding, but no association between use of cotrimoxazole and laboratory-confirmed TB. Cotrimoxazole did not compromise TB diagnosis.
The reduction of HIV transmission risk behaviors among those infected with HIV remains a major global health priority. Psychosocial characteristics have proven to be important correlates of sexual transmission risk behaviors in high-income countries, but little attention has focused on the influence of psychosocial and psychological factors on sexual transmission risk behaviors in African cohorts.
Methodology and Principal Findings
The CHAT Study enrolled a representative sample of 499 HIV-infected patients in established HIV care and 267 newly diagnosed HIV-infected individuals from the Kilimanjaro Region of Tanzania. Participants completed in-person interviews every 6 months for 3 years. Using logistic random effects models to account for repeated observations, we assessed sociodemographic, physical health, and psychosocial predictors of self-reported unprotected sexual intercourse. Among established patients, the proportion reporting any recent unprotected sex was stable, ranging between 6–13% over 3 years. Among newly diagnosed patients, the proportion reporting any unprotected sex dropped from 43% at baseline to 11–21% at 6–36 months. In multivariable models, higher odds of reported unprotected sex was associated with female gender, younger age, being married, better physical health, and greater post-traumatic stress symptoms. In addition, within-individual changes in post-traumatic stress over time coincided with increases in unprotected sex.
Conclusions and Significance
Changes in post-traumatic stress symptomatology were associated with changes in sexual transmission risk behaviors in this sample of HIV-infected adults in Tanzania, suggesting the importance of investing in appropriate mental health screening and intervention services for HIV-infected patients, both to improve mental health and to support secondary prevention efforts.
Efforts to scale-up maternal and child health services in lower and middle income countries will fail if services delivered are not of good quality. Although there is evidence of strategies to increase the quality of health services, less is known about the way these strategies affect health system goals and outcomes. We conducted a systematic review of the literature to examine this relationship.
We undertook a search of MEDLINE, SCOPUS and CINAHL databases, limiting the results to studies including strategies specifically aimed at improving quality that also reported a measure of quality and at least one indicator related to health system outcomes. Variation in study methodologies prevented further quantitative analysis; instead we present a narrative review of the evidence.
Methodologically, the quality of evidence was poor, and dominated by studies of individual facilities. Studies relied heavily on service utilisation as a measure of strategy success, which did not always correspond to improved quality. The majority of studies targeted the competency of staff and adequacy of facilities. No strategies addressed distribution systems, public-private partnership or equity. Key themes identified were the conflict between perceptions of patients and clinical measures of quality and the need for holistic approaches to health system interventions.
Existing evidence linking quality improvement strategies to improved MNCH outcomes is extremely limited. Future research would benefit from the inclusion of more appropriate indicators and additional focus on non-facility determinants of health service quality such as health policy, supply distribution, community acceptability and equity of care.
tuberculin skin test; HIV; TB transmission; children; annual risk of TB infection
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 (ART) has expanded within the region, early pessimism concerning the delivery of ART 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 ART, with most deaths occurring in the first few months. Patients typically access ART with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count <50 cells/μL 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 ART programmes, but more fundamentally on how advanced disease is at programme enrolment and the quality of preceding health-care. In addition to improving delivery of ART and providing this 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 ART. Health systems delays in ART initiation must be minimised, especially in patients who present with advanced immunodeficiency.
HIV; AIDS; antiretroviral treatment; HAART; ART; mortality; death; Africa
There is scant evidence on the association between diagnosis delays and the receipt of test results in HIV Early Infant Diagnosis (EID) programs. We determine the association between diagnosis delays and other health care system and patient factors on result receipt.
We reviewed 703 infant HIV test records for tests performed between January 2008 and February 2009 at a regional referral hospital and level four health center in Uganda. The main outcome was caregiver receipt of the test result. The primary study variable was turnaround time (time between sample collection and result availability at the health facility). Additional variables included clinic entry point, infant age at sample collection, reported HIV status and receipt of antiretroviral prophylaxis for prevention of mother-to-child transmission. We conducted a pooled analysis in addition to separate analyses for each facility. We estimated the relative risk of result receipt using modified Poisson regression with robust standard errors.
Overall, the median result turnaround time, was 38 days. 59% of caregivers received infant test results. Caregivers were less likely to receive results at turnaround times greater than 49 days compared to 28 days or fewer (ARR = 0.83; 95% CI = 0.70–0.98). Caregivers were more likely to receive results at the PMTCT clinic (ARR = 1.81; 95% CI = 1.40–2.33) and less likely at the pediatric ward (ARR = 0.54; 95% CI = 0.37–0.81) compared to the immunization clinic. At the level four health center, result receipt was half as likely among infants older than 9 months compared to 3 months and younger (ARR= 0.47; 95% CI = 0.25–0.93).
In this study setting, we find evidence that longer turnaround times, clinic entry point and age at sample collection may be associated with receipt of infant HIV test results.
To determine the short-term and long-term risks of tuberculosis (TB) associated with CD4 cell recovery during antiretroviral therapy (ART).
Observational community-based ART cohort in South Africa.
TB incidence was determined among patients (n = 1480) receiving ART for up to 4.5 years in a South African community-based service. Updated CD4 cell counts were measured 4-monthly. Person-time accrued within a range of CD4 cell count strata (CD4 cell strata) was calculated and used to derive CD4 cell-stratified TB rates. Factors associated with incident TB were identified using Poisson regression models.
Two hundred and three cases of TB were diagnosed during 2785 person-years of observation (overall incidence, 7.3 cases/100 person-years). During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500 and more than 500 cells/µl unadjusted TB incidence rates were 16.8, 9.3, 5.5, 4.6, 4.2 and 1.5 cases/100 person-years, respectively (P < 0.001). During early ART (first 4 months), adjusted TB rates among those with CD4 cell counts 0–200 cells/µl were 1.7-fold higher than during long-term ART (P = 0.026). Updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk.
Updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. Among those with baseline CD4 cell counts less than 200 cells/µl, the excess adjusted risk of TB during early ART was consistent with ‘unmasking’ of disease missed at baseline screening. TB incidence rates at CD4 cell counts of 200–500 cells/µl remained high and adjunctive interventions are required. TB prevention would be improved by ART policies that minimized the time patients spend with CD4 cell counts below a threshold of 500 cells/µl.
Africa; antiretroviral; CD4 cell; HIV; immune reconstitution; resource-limited country; tuberculosis
Antiretroviral therapy (ART) has been proposed as an intervention for reducing tuberculosis (TB) burdens in areas with high HIV prevalence. However, little data is available on the impact of ART on population-level TB.
Trends in adult TB case fatality and notifications were assessed prior to and during increasing ART coverage in a well-defined peri-urban community, from 1997 to 2008. Mean changes in TB rates were measured using linear autoregression models. ART coverage increased from 1% in 2003, to 5%, 13% and 21% of HIV-infected population in 2004, 2005 and 2008 respectively.
From 1997 to end of 2004 TB notification rates increased by an average of 187 cases/100,000/yr (p<0.001), reaching a peak of 2,536/100,000 in 2005. From 2005 to 2008, TB notification rates declined by approximately 183 cases/100,000/yr (p<0.001). TB rates were initially stable in HIV-uninfected individuals, but declined moderately from 2005. TB rates declined in HIV-infected adults from 6,513/100,000 in 2005 to 4,741/100,000 in 2008. The predominant decline in TB notifications occurred among HIV-infected patients receiving ART (1,156 cases/100,000/yr) and was less marked in those not receiving ART (416cases/100,000/yr). Similarly, TB case fatality was constant for HIV-uninfected individuals but declined in HIV-infected individuals from 23% in 2002 to 8% in 2008 (p=0.01).
In this community heavily affected by both HIV and TB epidemics, rapid and high ART coverage was associated with significant reductions in TB notifications and TB-associated case fatality.
tuberculosis; notification rates; HIV; antiretroviral; community
Women of reproductive age in parts of sub-Saharan Africa are faced both with high levels of HIV and the threat of dying from the direct complications of pregnancy. Clinicians practicing in such settings have reported a high incidence of direct obstetric complications among HIV-infected women, but the evidence supporting this is unclear. The aim of this systematic review is to establish whether HIV-infected women are at increased risk of direct obstetric complications.
Methods and findings
Studies comparing the frequency of obstetric haemorrhage, hypertensive disorders of pregnancy, dystocia and intrauterine infections in HIV-infected and uninfected women were identified. Summary estimates of the odds ratio (OR) for the association between HIV and each obstetric complication were calculated through meta-analyses. In total, 44 studies were included providing 66 data sets; 17 on haemorrhage, 19 on hypertensive disorders, five on dystocia and 25 on intrauterine infections. Meta-analysis of the OR from studies including vaginal deliveries indicated that HIV-infected women had over three times the risk of a puerperal sepsis compared with HIV-uninfected women [pooled OR: 3.43, 95% confidence interval (CI): 2.00–5.85]; this figure increased to nearly six amongst studies only including women who delivered by caesarean (pooled OR: 5.81, 95% CI: 2.42–13.97). For other obstetric complications the evidence was weak and inconsistent.
The higher risk of intrauterine infections in HIV-infected pregnant and postpartum women may require targeted strategies involving the prophylactic use of antibiotics during labour. However, as the huge excess of pregnancy-related mortality in HIV-infected women is unlikely to be due to a higher risk of direct obstetric complications, reducing this mortality will require non obstetric interventions involving access to ART in both pregnant and non-pregnant women.
Rates of pregnancy and HIV infection are high among South African adolescents, yet little is known about rates of mother-to-child transmission of HIV (MTCT) in this group. We report a comparison of the characteristics of adolescent mothers and adult mothers, including HIV prevalence and MTCT rates.
We examined patterns of health service utilization during the antenatal and early postnatal period, HIV prevalence and MTCT amongst adolescent (<20-years-old) and adult (20 to 39-years-old) mothers with infants aged ≤16 weeks attending immunization clinics in six districts of KwaZulu-Natal between May 2008 and April 2009.
Interviews were conducted with 19,093 mothers aged between 12 and 39 years whose infants were aged ≤16 weeks. Most mothers had attended antenatal care four or more times during their last pregnancy (80.3%), and reported having an HIV test (98.2%). A greater proportion of HIV-infected adult mothers, compared to adolescent mothers, reported themselves as HIV-positive (41.2% vs. 15.9%, p<0.0001), reported having a CD4 count taken during their pregnancy (81.0% vs. 66.5%, p<0.0001), and having received the CD4 count result (84.4% vs. 75.7%, p<0.0001). Significantly fewer adolescent mothers received the recommended PMTCT regimen. HIV antibody was detected in 40.4% of 7,800 infants aged 4–8 weeks tested for HIV, indicating HIV exposure. This was higher among infants of adult mothers (47.4%) compared to adolescent mothers (17.9%, p<0.0001). The MTCT rate at 4–8 weeks of age was significantly higher amongst infants of adolescent mothers compared to adult mothers (35/325 [10.8%] vs. 185/2,800 [6.1%], OR 1.7, 95% CI 1.2–2.4).
Despite high levels of antenatal clinic attendance among pregnant adolescents in KwaZulu-Natal, the MTCT risk is higher among infants of HIV-infected adolescent mothers compared to adult mothers. Access to adolescent-friendly family planning and PMTCT services should be prioritised for this vulnerable group.
Early initiation of antiretroviral therapy (ART) in eligible pregnant women is a key intervention for prevention of mother-to-child transmission (PMTCT) of HIV. However, in many settings in sub-Saharan Africa where ART-eligibility is determined by CD4 cell counts, limited access to laboratories presents a significant barrier to rapid ART initiation. Point-of-care (POC) CD4 cell count testing has been suggested as one approach to overcome this challenge, but there are few data on the agreement between POC CD4 cell enumeration and standard laboratory-based testing.
Working in a large antenatal clinic in Cape Town, South Africa, we compared POC CD4 cell enumeration (using the Alere PimaTM Analyzer) to laboratory-based flow cytometry in consecutive HIV-positive pregnant women. Bland–Altman methods were used to compare the two methods, including analyses by subgroups of participant gestational age.
Among the 521 women participating, the median gestational age was 23 weeks, and the median CD4 cell count according to POC and laboratory-based methods was 388 and 402 cells/µL, respectively. On average, the Pima POC test underestimated CD4 cell count relative to flow cytometry: the mean difference (laboratory test minus Pima POC) was 22.7 cells/µL (95% CI, 16.1 to 29.2), and the limits of agreement were −129.2 to 174.6 cells/µL. When analysed by gestational age categories, there was a trend towards increasing differences between laboratory and POC testing with increasing gestational age; in women more than 36 weeks’ gestation, the mean difference was 45.0 cells/µL (p=0.04).
These data suggest reasonable overall agreement between Pima POC CD4 testing and laboratory-based flow cytometry among HIV-positive pregnant women. The finding for decreasing agreement with increasing gestational age requires further investigation, as does the operational role of POC CD4 testing to increase access to ART within PMTCT programmes.
point-of-care test; CD4 cell count; reliability; pregnancy; HIV; antiretroviral therapy; South Africa
Universal HIV pediatric screening offered at postnatal points of care (PPOC) is an entry point for early infant diagnosis (EID). We assessed the parents' acceptability of this approach in Abidjan, Côte d'Ivoire.
In this cross-sectional study, trained counselors offered systematic HIV screening to all children aged 6–26 weeks attending PPOC in three community health centers with existing access to HAART during 2008, as well as their parents/caregivers. HIV-testing acceptability was measured for parents and children; rapid HIV tests were used for parents. Both parents' consent was required according to the Ivorian Ethical Committee to perform a HIV test on HIV-exposed children. Free HIV care was offered to those who were diagnosed HIV-infected.
We provided 3,013 HIV tests for infants and their 2,986 mothers. While 1,731 mothers (58%) accepted the principle of EID, only 447 infants had formal parental consent 15%; 95% confidence interval (CI): [14%–16%]. Overall, 1,817 mothers (61%) accepted to test for HIV, of whom 81 were HIV-infected (4.5%; 95% CI: [3.5%–5.4%]). Among the 81 HIV-exposed children, 42 (52%) had provided parental consent and were tested: five were HIV-infected (11.9%; 95% CI: [2.1%–21.7%]). Only 46 fathers (2%) came to diagnose their child. Parental acceptance of EID was strongly correlated with prenatal self-reported HIV status: HIV-infected mothers were six times more likely to provide EID parental acceptance than mothers reporting unknown or negative prenatal HIV status (aOR: 5.9; 95% CI: [3.3–10.6], p = 0.0001).
Although the principle of EID was moderately accepted by mothers, fathers' acceptance rate remained very low. Routine HIV screening of all infants was inefficient for EID at a community level in Abidjan in 2008. Our results suggest the need of focusing on increasing the PMTCT coverage, involving fathers and tracing children issued from PMTCT programs in low HIV prevalence countries.
Data are reported on the background and performance of the K6 screening scale for serious mental illness (SMI) in the World Health Organization (WHO) World Mental Health (WMH) surveys. The K6 is a 6-item scale developed to provide a brief valid screen for DSM-IV SMI based on the criteria in the US ADAMHA Reorganization Act. Although methodological studies have documented good K6 validity in a number of countries, optimal scoring rules have never been proposed. Such rules are presented here based on analysis of K6 data in nationally or regionally representative WMH surveys in 14 countries (combined n = 41,770 respondents). Twelve-month prevalence of DSM-IV SMI was assessed with the fully-structured WHO Composite International Diagnostic Interview. Nested logistic regression analysis was used to generate estimates of the predicted probability of SMI for each respondent from K6 scores taking into consideration the possibility of variable concordance as a function of respondent age, gender, education, and country. Concordance, assessed by calculating the area under the receiver operating characteristic curve (AUC), was generally substantial (Median .83; Range .76-.89; Inter-quartile range .81-.85). Based on this result, optimal scaling rules are presented for use by investigators working with the K6 scale in the countries studied.
K6 screening scale; psychiatric epidemiology; serious mental illness (SMI)
Initiation of antiretroviral therapy (ART) during pregnancy is critical to promote maternal health and prevent mother-to-child HIV transmission (PMTCT). The separation of services for antenatal care (ANC) and ART may hinder antenatal ART initiation. We evaluated ART initiation during pregnancy under different service delivery models in Cape Town, South Africa.
A retrospective cohort study was conducted using routinely collected clinic data. Three models for ART initiation in pregnancy were evaluated ART ‘integrated’ into ANC, ART located ‘proximal’ to ANC, and ART located some distance away from ANC (‘distal’). Kaplan-Meier methods and Poisson regression were used to examine the association between service delivery model and antenatal ART initiation.
Among 14 617 women seeking antenatal care in the three services, 30% were HIV-infected and 17% were eligible for ART based on CD4 cell count <200 cells/µL. A higher proportion of women started ART antenatally in the integrated model compared to the proximal or distal models (55% vs 38% vs 45%, respectively, global p = 0.003). After adjusting for age and gestation at first ANC visit, women who at the integrated service were significantly more likely to initiate ART antenatally (rate ratio 1.33; 95% confidence interval: 1.09–1.64) compared to women attending the distal model; there was no difference between the proximal and distal models in antenatal ART initiation however (p = 0.704).
Integration of ART initiation into ANC is associated with higher levels of ART initiation in pregnancy. This and other forms of service integration may represent a valuable intervention to enhance PMTCT and maternal health.
The World Health Organisation and the Joint United Nations Programme in 2006 reaffirmed the earlier recommendation of 2000 that all HIV-exposed infants in resource-poor countries should commence cotrimoxazole (CTX) prophylaxis at 6-weeks of life. CTX prophylaxis should be continued until the child is confirmed HIV-uninfected and there is no further exposure to breastmilk transmission. We determined CTX coverage and explored factors associated with CTX administration in HIV-exposed infants at a primary health clinic in South Africa.
In a cross-sectional study of HIV-exposed infants 6–18 months of age attending a child immunisation clinic, data from the current visit and previous visits related to CTX prophylaxis, feeding practice and infant HIV testing were extracted from the child's immunisation record. Further information related to the administration of CTX prophylaxis was obtained from an interview with the child's mother.
One-third (33.0%) HIV-exposed infants had not initiated CTX at all and breastfed infants were more likely to have commenced CTX prophylaxis as compared to their non-breastfed counterparts (78.7% vs 63.4%) (p = 0.008). Availability of infant's HIV status was strongly associated with continuation or discontinuation of CTX after 6 months of age or after breastfeeding cessation. Maternal self-reports indicated that only 52.5% (95%CI 47.5–57.5) understood the reason for CTX prophylaxis, 126 (47%) did not dose during weekends; 55 (21%) dosed their infants 3 times a day and 70 (26%) dosed their infants twice daily.
A third of HIV-exposed children attending a primary health care facility in this South African setting did not receive CTX prophylaxis. Not commencing CTX prophylaxis was strongly associated with infants not breastfeeding and unnecessary continued exposure to CTX in this paediatric population was due to limited availability of early infant diagnosis. Attendance at immunization clinics can be seen as missed opportunities for early infant diagnosis of HIV and related care.
Cardiovascular disease (CVD) and premature aging have been hypothesized as new risk factors for HIV associated neurocognitive disorders (HAND) in adults with virally-suppressed HIV infection. Moreover, their significance and relation to more classical HAND biomarkers remain unclear.
92 HIV− infected (HIV+) adults stable on combined antiretroviral therapy (cART) and 30 age-comparable HIV-negative (HIV−) subjects underwent 1H Magnetic Resonance Spectroscopy (MRS) of the frontal white matter (targeting HIV, normal aging or CVD-related neurochemical injury), caudate nucleus (targeting HIV neurochemical injury), and posterior cingulate cortex (targeting normal/pathological aging, CVD-related neurochemical changes). All also underwent standard neuropsychological (NP) testing. CVD risk scores were calculated. HIV disease biomarkers were collected and cerebrospinal fluid (CSF) neuroinflammation biomarkers were obtained in 38 HIV+ individuals.
Relative to HIV− individuals, HIV+ individuals presented mild MRS alterations: in the frontal white matter: lower N-Acetyl-Aspartate (NAA) (p<.04) and higher myo-inositol (mIo) (p<.04); in the caudate: lower NAA (p = .01); and in the posterior cingulate cortex: higher mIo (p<.008– also significant when Holm-Sidak corrected) and higher Choline/NAA (p<.04). Regression models showed that an HIV*age interaction was associated with lower frontal white matter NAA. CVD risk factors were associated with lower posterior cingulate cortex and caudate NAA in both groups. Past acute CVD events in the HIV+ group were associated with increased mIo in the posterior cingulate cortex. HIV duration was associated with lower caudate NAA; greater CNS cART penetration was associated with lower mIo in the posterior cingulate cortex and the degree of immune recovery on cART was associated with higher NAA in the frontal white matter. CSF neopterin was associated with higher mIo in the posterior cingulate cortex and frontal white matter.
In chronically HIV+ adults with long-term viral suppression, current CVD risk, past CVD and age are independent factors for neuronal injury and inflammation. This suggests a tripartite model of HIV, CVD and age likely driven by chronic inflammation.
An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth.
Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3–5 hours were calculated.
All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3–5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3–5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3–5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3–5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG.
The encephalopathy assessment described by the Thompson score at age 3–5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.
Asphyxia; Neonate; Hypoxic ischemic encephalopathy; Electroencephalogram; aEEG; Prognostic
Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART.
We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models.
The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75).
Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.
To determine the proportion, characteristics and outcomes of patients who transfer-out from an antiretroviral therapy (ART) service in a South African township.
This retrospective cohort study included all patients aged ≥15 years who enrolled between September 2002 and December 2009. Follow-up data were censored in December 2010. Kaplan-Meier survival analysis was used to describe time to transfer-out and cox proportional hazard analysis was used to determine associated risk factors.
4511 patients (4003 ART-naïve and 508 non-naïve at baseline) received ART during the study period. Overall, 597 (13.2%) transferred out. The probability of transferring out by one year of ART steadily increased from 1.4% in 2002/2004 cohort to 8.9% for the 2009 cohort. Independent risk factors for transfer-out were more recent calendar year of enrolment, younger age (≤25 years) and being ART non-naïve at baseline (i.e., having previously transferred into this clinic from another facility). The proportions of patients transferred out who had a CD4 cell count <200 cells/µL and/or a viral load ≥1000 copies/mL were 19% and 20%, respectively.
With scale-up of ART over time, an increasing proportion of patients are transferring between ART services and information systems are needed to track patients. Approximately one-fifth of these have viral loads >1000 copies/mL around the time of transfer, suggesting the need for careful adherence counseling and assessment of medication supplies among those planning transfer.
HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.
Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded.
Between May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm3 (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%.
High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1st three months following ART initiation.
Tanzanian guidelines for prevention of mother-to-child-transmission of HIV (PMTCT) recommend an antiretroviral combination regimen involving zidovudine (AZT) during pregnancy, single-dosed nevirapine at labor onset, AZT plus Lamivudine (3TC) during delivery, and AZT/3TC for 1–4 weeks postpartum. As drug toxicities are a relevant concern, we assessed hematological alterations in AZT-exposed women and their infants.
Methods and Materials
A cohort of HIV-positive women, either with AZT intake (n = 82, group 1) or without AZT intake (n = 62, group 2) for PMTCT during pregnancy, was established at Kyela District Hospital, Tanzania. The cohort also included the infants of group 1 with an in-utero AZT exposure ≥4 weeks, receiving AZT for 1 week postpartum (n = 41), and infants of group 2 without in-utero AZT exposure, receiving a prolonged 4-week AZT tail (n = 58). Complete blood counts were evaluated during pregnancy, birth, weeks 4–6 and 12.
For women of group 1 with antenatal AZT intake, we found a statistically significant decrease in hemoglobin level, red blood cells, white blood cells, granulocytes, as well as an increase in red cell distribution width and platelet count. At delivery, the median red blood cell count was significantly lower and the median platelet count was significantly higher in women of group 1 compared to group 2. At birth, infants from group 1 showed a lower median hemoglobin level and granulocyte count and a higher frequency of anemia and granulocytopenia. At 4–6 weeks postpartum, the mean neutrophil granulocyte count was significantly lower and neutropenia was significantly more frequent in infants of group 2.
AZT exposure during pregnancy as well as after birth resulted in significant hematological alterations for women and their newborns, although these changes were mostly mild and transient in nature. Research involving larger cohorts is needed to further analyze the impact of AZT-containing regimens on maternal and infant health.
Early infant diagnosis (EID) of HIV infection is an important service to reduce paediatric morbidity and mortality related to HIV/AIDS. Although South Africa has a national EID programme based on PCR testing, there are no population-wide data on the linkage of infants testing HIV PCR-positive to HIV care and treatment services.
We conducted a retrospective analysis of all public sector laboratory data from across the Western Cape province between 2005 and 2011. We linked positive HIV PCR results to subsequent HIV viral load testing to determine the proportion of infants who were successfully linked to HIV care.
A total of 83 698 unique infant HIV PCR tests were documented, of which 6322 (8%) were PCR positive. The proportion of PCR-positive children declined from 12% in 2005 to 3% in 2011. Of the children testing PCR-positive, 4105 (65%) had subsequent viral load testing indicating successful linkage to care. The proportion of successfully linked infants increased from 54% in 2005 to 71% in 2010, while the median delay in days to successful linkage decreased from 146 days in 2005 to 33 days in 2010.
From 2005 to 2011 there has been a reduction in the proportion of children testing HIV PCR-positive, and an increase in the proportion of infected infants successfully linked to HIV care and treatment, in this setting. However a large proportion of infected infants remain unlinked to antiretroviral therapy services and there is a clear need for interventions to further strengthen EID programmes.
Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.
Materials and Methods
Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.
There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].
The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.
In order to achieve Millennium Development Goals 4, 5 and 6, it is essential to address adolescents’ health.
To estimate the additional resources required to scale up adolescent friendly health service interventions with the objective to reduce mortality and morbidity among individuals aged 10 to 19 years in 74 low- and middle- income countries.
A costing model was developed to estimate the financial resources needed to scale-up delivery of a set of interventions including contraception, maternity care, management of sexually transmitted infections, HIV testing and counseling, safe abortion services, HIV harm reduction, HIV care and treatment and care of injuries due to intimate partner physical and sexual violence. Financial costs were estimated for each intervention, country and year using a bottom-up ingredients approach, defining costs at different levels of delivery (i.e., community, health centre, and hospital level). Programme activity costs to improve quality of care were also estimated, including activities undertaken at national-, district- and facility level in order to improve adolescents’ use of health services (i.e., to render health services adolescent friendly).
Costs of achieving universal coverage are estimated at an additional US$ 15.41 billion for the period 2011–2015, increasing from US$ 1.86 billion in 2011 to US$ 4,31 billion in 2015. This corresponds to approximately US$ 1.02 per adolescent in 2011, increasing to 4.70 in 2015. On average, for all 74 countries, an annual additional expenditure per capita ranging from of US$ 0.38 in 2011 to US$ 0.82 in 2015, would be required to support the scale-up of key adolescent friendly health services.
The estimated costs show a substantial investment gap and are indicative of the additional investments required to scale up health service delivery to adolescents towards universal coverage by 2015.