Wendy Mphatswe

Challenges for Routine Health System Data Management in a Large Public Programme to Prevent Mother-to-Child HIV Transmission in South Africa

Background Recent changes to South Africas prevention of mother-to-child transmission of HIV (PMTCT) guidelines have raised hope that the national goal of reducing perinatal HIV transmission rates to less than 5% can be attained. While programmatic efforts to reach this target are underway, obtaining complete and accurate data from clinical sites to track progress presents a major challenge. We assessed the completeness and accuracy of routine PMTCT data submitted to the district health information system (DHIS) in three districts of Kwazulu-Natal province, South Africa. Methodology/Principal Findings We surveyed the completeness and accuracy of data reported for six key PMTCT data elements between January and December 2007 from all 316 clinics and hospitals in three districts. Through visits to randomly selected sites, we reconstructed reports for the same six PMTCT data elements from clinic registers and assessed accuracy of the monthly reports previously submitted to the DHIS. Data elements were reported only 50.3% of the time and were “accurate” (i.e. within 10% of reconstructed values) 12.8% of the time. The data element “Antenatal Clients Tested for HIV” was the most accurate data element (i.e. consistent with the reconstructed value) 19.8% of the time, while “HIV PCR testing of baby born to HIV positive mother” was the least accurate with only 5.3% of clinics meeting the definition of accuracy. Conclusions/Significance Data collected and reported in the public health system across three large, high HIV-prevalence Districts was neither complete nor accurate enough to track process performance or outcomes for PMTCT care. Systematic data evaluation can determine the magnitude of the data reporting failure and guide site-specific improvements in data management. Solutions are currently being developed and tested to improve data quality.

Safety and efficacy of corticosteroids for the treatment of septic shock: a systematic review and meta-analysis

BACKGROUND Septic shock is common and results in significant morbidity and mortality. Adjunctive treatment with corticosteroids is common, but definitive data are lacking. We aimed to determine the efficacy and safety of corticosteroid therapy among patients with septic shock. METHODS Medline, Embase, Cochrane Library, Web of Science, and Google Scholar were searched for randomized trials and observational studies published from January 1993 through December 2008. Studies were selected if they included adults with septic shock, discussed treatment with intravenous corticosteroids, and reported at least 1 outcome of interest (e.g., mortality, shock reversal, or incidence of superinfection). Two reviewers independently agreed on eligibility, assessed methodologic quality, and abstracted data. RESULTS Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated for 28-day all-cause mortality, shock reversal at 7 days, and incidence of superinfection with use of random-effects models. Analyses, stratified by adrenal responsiveness, were prespecified. Eight studies (6 randomized trials) involving a total of 1876 patients were selected. Overall, corticosteroid therapy did not result in a statistically significant difference in mortality (42.2% [369 of 875 patients] vs. 38.4% [384 of 1001]; RR, 1.00; 95% CI, 0.84-1.18). A statistically significant difference in the incidence of shock reversal at 7 days was observed between patients who received corticosteroids and those who did not (64.9% [314 of 484 patients] vs. 47.5% [228 of 480]; RR, 1.41; 95% CI, 1.22-1.64), with similar point estimates for both corticotropin stimulation test responders and nonresponders. No statistically significant difference was found in the incidence of superinfection between patients treated with corticosteroids and patients not treated with corticosteroids (25.3% [114 of 450 patients] vs. 22.7% [100 of 441]; RR, 1.11; 95% CI, 0.86-1.42). CONCLUSIONS In patients with septic shock, corticosteroid therapy appears to be safe but does not reduce 28-day all-cause mortality rates. It does, however, significantly reduce the incidence of vasopressor-dependent shock, which may be a clinically worthwhile goal.

Antiretroviral drugs in the cupboard are not enough: the impact of health systems' performance on mother-to-child transmission of HIV.

Objective:To model the effect of health systems performance on rates of mother-to-child HIV transmission. Methods:We modeled the effect of variation in performance of the multiple steps of different prevention of mother-to-child transmission (PMTCT) protocols using hypothetical and reported data. Setting:Data from a PMTCT program in a large province in South Africa was used to compare model predictions with reported outcomes for mother-to-child HIV transmission. Main Outcome Measure:Perinatal HIV transmission was predicted for infants of 6 weeks of age. Results:HIV-infected pregnant women who fulfill eligibility criteria are initiated on lifelong antiretroviral treatment, whereas noneligible HIV-infected women and their infants receive single-dose nevirapine in a health system functioning at reported performance levels, and the overall vertical transmission rate would be 19.5%. Adding azidothymidine for women not eligible for lifelong treatment would further decrease the overall transmission rates only marginally to 17%. If the same steps were accomplished at 95% reliability, then the overall transmission rates would be 9.4% and 4.1%, respectively. Conclusions:Introduction of more effective combination antiretroviral interventions will yield only marginal reductions in childhood HIV infections and mortality unless health systems achieve high levels of performance at each step of the PMTCT pathway. Investment in and support for the mechanisms of delivering and sustaining PMTCT interventions at scale are required if gains in maternal and child survival are to be realized in countries highly affected by HIV.

High frequency of rapid immunological progression in African infants infected in the era of perinatal Hiv prophylaxis

Objectives:To determine the natural history of HIV infection following peripartum single-dose nevirapine (sd-NVP) prophylaxis in a resource-limited country, and to assess implications for antiretroviral therapy (ART) roll-out programmes. Methods:Infants of HIV-infected mothers in KwaZulu-Natal, South Africa, were tested on days 1 and 28 to detect intrauterine (IU) and intrapartum (IP) infection. Infant follow-up included monthly viral load and CD4 cell measurement. ART was initiated at infant CD4 cell% ≤ 20%. Results:In 740 infants born to 719 HIV-infected women, mother-to-child transmission (MTCT) was 10.3% (69% IU, 31% IP). Median viral load was higher in mothers of infants infected IP than IU (279 000 versus 86 600 copies/ml; P = 0.039) and lower in mothers of uninfected infants (median 26 750 copies/ml; P < 0.001). Peak viraemia was higher in infants infected IP than IU (5 160 000 versus 984 000 copies/ml; P < 0.001). Median viral load at birth in IU-infected infants (155 000 copies/ml) fell 1.4 log to 6510 copies/ml by day 5 and was beneath the detection limit using dried blood spot analysis in 38% of infants. CD4 cell% declined rapidly, to ≤ 20% in 70% and ≤ 25% in 85% [current World Health Organization (WHO) criteria for initiating ART] of infants by 6 months. Conclusions:MTCT was reduced by sd-NVP through an effect on IP transmission. Where MTCT occurred despite NVP, two-thirds of transmissions arose IU; IP-infected babies were born to mothers with very high viral load. Disease progression was particularly rapid, 85% infants meeting WHO criteria for ART within 6 months. These findings argue for more effective MTCT-prevention programmes in resource-limited countries.

Improving public health information: a data quality intervention in KwaZulu-Natal, South Africa

OBJECTIVE To evaluate the effect of an intervention to improve the quality of data used to monitor the prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus in South Africa. METHODS The study involved 58 antenatal clinics and 20 delivery wards (37 urban, 21 rural and 20 semi-urban) in KwaZulu-Natal province that provided PMTCT services and reported data to the District Health Information System. The data improvement intervention, which was implemented between May 2008 and March 2009, involved training on data collection and feedback for health information personnel and programme managers, monthly data reviews and data audits at health-care facilities. Data on six data elements used to monitor PMTCT services and recorded in the information system were compared with source data from health facility registers before, during and after the intervention. Data completeness (i.e. their presence in the system) and accuracy (i.e. being within 10% of their true value) were evaluated. FINDINGS The level of data completeness increased from 26% before to 64% after the intervention. Similarly, the proportion of data in the information system considered accurate increased from 37% to 65% (P < 0.0001). Moreover, the correlation between data in the information system and those from facility registers rose from 0.54 to 0.92. CONCLUSION A simple, practical data improvement intervention significantly increased the completeness and accuracy of the data used to monitor PMTCT services in South Africa.

Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants.

Objectives:Infants infected with HIV-1 perinatally despite single-dose nevirapine progress rapidly. Data on treatment outcome in sub-Saharan African infants exposed to single-dose nevirapine are urgently required. This feasibility study addresses efficacy of infant antiretroviral therapy in this setting. Methods:HIV-infected infants in Durban, South Africa, received randomized immediate or deferred (when CD4 cell count reached <20%) four-drug antiretroviral therapy (zidovudine/lamivudine/nelfinavir/nevirapine). Genotyping for non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was undertaken pre-antiretroviral therapy. Monthly follow-up to 1-year post-antiretroviral therapy included viral load, CD4 cell count and verbal/measured adherence monitoring. Results:All 63 infants were exposed to single-dose nevirapine. Twenty-one out of 51 (39%) infants with baseline genotyping results had NNRTI resistance (most frequently Y181C; 20%). Forty-three infants were randomized to immediate antiretroviral therapy (ART): three withdrew pre-antiretroviral therapy; 36 out of 40 completed 1-year of ART. Twenty infants received deferred ART: 17 reached CD4 cell counts less than 20% (median d99) and 13 out of 17 started antiretroviral therapy in year 1. Verbal and measured adherence was 99% and 95%, respectively. One-year post-ART, 49 out of 49 (100%) infants had a viral load less than 400 copies/ml; 46 out of 49 (94%) had viral load less than 50 copies/ml. Ten infants (20%) required second-line ART due to virological failure or tuberculosis treatment, therefore 39 out of 49 (80%) achieved viral load less than 400 copies/ml by intention-to-treat. Time to viral load less than 50 copies/ml correlated with maternal CD4 cell count (r = −0.42; P = 0.005) and infant pre-ART viral load (r = 0.64; P < 0.001). NNRTI mutations had no significant effect on virological suppression. Infants starting immediate compared with deferred ART had fewer illness episodes (P = 0.003), but no significant difference in virological suppression. Conclusion:Excellent adherence and virological suppression are achievable in infants, despite high-frequency NNRTI mutations and rapid disease progression. Infants remain relatively neglected in roll-out programmes and ART provision must be expanded.

Human Immunodeficiency Virus-Specific CD8+ T-Cell Activity Is Detectable from Birth in the Majority of In Utero-Infected Infants

ABSTRACT Human immunodeficiency virus (HIV)-infected infants in sub-Saharan Africa typically progress to AIDS or death by 2 years of life in the absence of antiretroviral therapy. This rapid progression to HIV disease has been related to immaturity of the adaptive immune response in infants. We screened 740 infants born to HIV-infected mothers and tracked development and specificity of HIV-specific CD8+ T-cell responses in 63 HIV-infected infants identified using gamma interferon enzyme-linked immunospot assays and intracellular cytokine staining. Forty-four in utero-infected and 19 intrapartum-infected infants were compared to 45 chronically infected children >2 years of age. Seventy percent (14 of 20) in utero-infected infants tested within the first week of life demonstrated HIV-specific CD8+ T-cell responses. Gag, Pol, and Nef were the principally targeted regions in chronic pediatric infection. However, Env dominated the overall response in one-third (12/36) of the acutely infected infants, compared to only 2/45 (4%) of chronically infected children (P = 0.00083). Gag-specific CD4+ T-cell responses were minimal to undetectable in the first 6 months of pediatric infection. These data indicate that failure to control HIV replication in in utero-infected infants is not due to an inability to induce responses but instead suggest secondary failure of adaptive immunity in containing this infection. Moreover, the detection of virus-specific CD8+ T-cell responses in the first days of life in most in utero-infected infants is encouraging for HIV vaccine interventions in infants.

Detection of HIV Type 1 Gag-Specific CD4+ T Cell Responses in Acutely Infected Infants

Multiple HIV-1-specific cytokine and proliferative responses by CD4(+) T cells have not been studied in acutely infected infants. Using an intracellular cytokine staining assay, 34 untreated clade C HIV-1-infected infants (2-102 days old) were assessed for IFN-gamma, 28/34 for IL-2, and 26/34 for TNF-alpha responses to all HIV-1 proteins. Responses were detected in 29%, 36%, and 15% of infants, respectively. Twelve of the original 34 infants were then studied longitudinally for 14 months to determine the effect of viral load on IFN-gamma Gag-specific responses: seven infants were treated for 1 year, stopped treatment, and resumed when CD4% was < 20 and five infants were treated only when the CD4% was <20. Following treatment cessation, there was an immediate increase in viral load followed by an increase in the magnitude of CD4(+) Gag-specific responses. Despite this, the majority of infants (54%) had to restart treatment by 24 months of age, indicating that the immune responses were antigen driven but not associated with protection. Among untreated infants HIV-specific CD4(+) responses were detected sporadically indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia.

A case report of evaluating a large-scale health systems improvement project in an uncontrolled setting: a quality improvement initiative in KwaZulu-Natal, South Africa

Objective New approaches are needed to evaluate quality improvement (QI) within large-scale public health efforts. This case report details challenges to large-scale QI evaluation, and proposes solutions relying on adaptive study design. Study design We used two sequential evaluative methods to study a QI effort to improve delivery of HIV preventive care in public health facilities in three districts in KwaZulu-Natal, South Africa, over a 3-year period. We initially used a cluster randomised controlled trial (RCT) design. Principal findings During the RCT study period, tensions arose between intervention implementation and evaluation design due to loss of integrity of the randomisation unit over time, pressure to implement changes across the randomisation unit boundaries, and use of administrative rather than functional structures for the randomisation. In response to this loss of design integrity, we switched to a more flexible intervention design and a mixed-methods quasiexperimental evaluation relying on both a qualitative analysis and an interrupted time series quantitative analysis. Conclusions Cluster RCT designs may not be optimal for evaluating complex interventions to improve implementation in uncontrolled ‘real world’ settings. More flexible, context-sensitive evaluation designs offer a better balance of the need to adjust the intervention during the evaluation to meet implementation challenges while providing the data required to evaluate effectiveness. Our case study involved HIV care in a resource-limited setting, but these issues likely apply to complex improvement interventions in other settings.

From prevention of mother-to-child transmission to child survival... and back.

Purpose of reviewAt a time when highly effective drugs to prevent peripartum transmission of HIV are readily available and affordable, HIV remains the single most important cause of the death of infants and young children in southern and east Africa. Recent findingsEvidence from the past 5 years highlights four main points. The survival of children born to HIV-infected mothers relies on the mothers remaining well and alive. Suboptimal feeding practices of HIV-exposed infants can significantly increase infant mortality aside of any impact on postnatal transmission of HIV. Antiretroviral drugs are now available that can reduce morbidity and mortality in infected women as well as the transmission of HIV to their infants. Finally, the inability of health systems to deliver prevention of mother-to-child transmission services is the greatest obstacle to reducing HIV infection among infants and improving maternal and child survival. SummaryThe goal of improved maternal and child survival and not just the avoidance of HIV infection in infants must be the goal of prevention of mother-to-child transmission programmes. Research is needed to identify interventions that will improve the ability of health systems to deliver prevention of mother-to-child transmission services in addition to new and more effective therapeutic interventions.