Prevention of vertical transmission of HIV in Khayelitsha, South Africa: A contemporary review of services after 20 years.

BACKGROUND: The first vertical transmission of HIV prevention (VTP) programme in South Africa was launched in 1999 in Khayelitsha, Western Cape Province (WC). Since then, VTP guidelines have expanded in complexity and scope. OBJECTIVES: To describe contemporary VTP uptake in Khayelitsha and quantify vertical transmission (VT) risk factors based on linked routine electronic health data. METHODS: In the WC, all patients at public health facilities have a unique identifier allowing linkage across electronic health platforms through a health information exchange hosted within the WC Department of Health. We conducted a cohort analysis of mother-infant pairs where the mother was living with HIV and attended any obstetric care in Khayelitsha in 2017. Descriptive statistics assessed VTP coverage along the care cascade, including maternal viral load (VL) testing and early infant diagnosis (EID). Logistic regression analysis quantified a priori-defined risk factors associated with VT. RESULTS: Antenatal HIV prevalence in the cohort was 31.3%, and VT was 1.8% by 12 months. Of women living with HIV, 88.3% knew of their positive status at the first antenatal visit and 77.9% were already receiving antiretroviral therapy (ART). Most women diagnosed prior to delivery (94.5%) were initiated on ART; 85.0% received an antenatal VL test, of whom 88.0% were virologically suppressed. Women who were not virally suppressed had a five-fold (adjusted odds ratio (aOR) 5.3; 95% confidence interval (CI) 2.5 - 12.3) increased VT risk compared with those who were suppressed. Women who attended no antenatal care were at higher risk of VT (aOR 1.6; 95% CI 0.7 - 3.6) than those who did attend. EID coverage was suboptimal: a birth HIV polymerase chain reaction (PCR) test was available for 79.2% of infants, and a low proportion with a negative birth test had a repeat test around 10 weeks (57.9%). Data linkage identified an additional 15 infants living with HIV who were not detected by HIV-PCR testing alone. CONCLUSION: Although most women presented to care already knowing their HIV status, ART initiation was suboptimal prior to the first antenatal visit but improved over the course of pregnancy. The VT rate based on laboratory HIV-PCR testing alone underestimated HIV transmission: linked data from multiple sources suggested higher VT than programme-reported rates based on HIV-PCR testing alone.

Best practices for the care of pregnant people living with TB.

BACKGROUND: Each year more than 200,000 pregnant people become sick with TB, but little is known about how to optimize their diagnosis and therapy. Although there is a need for further research in this population, it is important to recognize that much can be done to improve the services they currently receive.METHODS: Following a systematic review of the literature and the input of a global team of health professionals, a series of best practices for the diagnosis, prevention and treatment of TB during pregnancy were developed.RESULTS: Best practices were developed for each of the following areas: 1) screening and diagnosis; 2) reproductive health services and family planning; 3) treatment of drug-susceptible TB; 4) treatment of rifampicin-resistant/multidrug-resistant TB; 5) compassionate infection control practices; 6) feeding considerations; 7) counseling and support; 8) treatment of TB infection/TB preventive therapy; and 9) research considerations.CONCLUSION: Effective strategies for the care of pregnant people across the TB spectrum are readily achievable and will greatly improve the lives and health of this under-served population.

Neurodevelopmental and behavioural outcomes of HIV-exposed uninfected and HIV-unexposed children at 2-3 years of age in Cape Town, South Africa.

Successful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2-3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30-42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children's performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.

Assessing the value of Western Cape Provincial Government health administrative data and electronic pharmacy records in ascertaining medicine use during pregnancy.

BACKGROUND: In African settings, where there is a high disease burden, there is a need to improve the science of documenting and analysing accurate information regarding medicine exposures in women immediately before and during pregnancy to assess the extent of use and safety in pregnant women and their unborn children. OBJECTIVES: To compare evidence of medicine use during pregnancy, as documented in paper-based clinical records (maternity case records (MCRs)) against electronic health information resources (Provincial Health Data Centre (PHDC)) and assess the level of concordance between the two as part of baseline investigations before piloting a provincial pregnancy exposure registry and birth defect surveillance system. The PHDC consolidates electronic clinical and pharmacy data. METHODS: A folder review of completed pregnancies between November 2013 and January 2016 was conducted on randomly selected MCRs from midwife-run obstetric units and a secondary maternity hospital in Cape Town, South Africa. Medication exposures in the MCR were captured and compared with a customised PHDC data extract. The type and timing of drug exposures were compared. Total exposures were compiled from all data sources. RESULTS: Two hundred and six MCRs from three facilities were sampled: 83 women had documented antiretroviral therapy (ART) exposure; all but 1 (1%) had been recorded in the PHDC extract. There was no evidence of ART use in the MCRs of 4 (5%) cases, despite evidence in the PHDC. There were imprecise drug names in the MCRs of 14 (17%) ART patients, discordant dates of onset between the MCRs and PHDC extracts in 10/83 (12%) and inaccurate medicine names and incorrect dates in 1 (1%) case each. Nine of 10 (90%) women who were administered antituberculosis medication were recorded in the PHDC extract. Ten of 21 (48%) isoniazid preventive therapy treatments appeared in the MCRs and PHDC; 9 (42%) in the PHDC only and 2 (10%) in the MCRs only. Half (n=18/36) of all antibiotic use was reflected only in the MCRs, while 13/36 (36%) appeared only in the PHDC extract. In the former cases, antibiotics used for treatment of sexually transmitted infections and urinary tract infections were dispensed from ward stock and not captured electronically. Antibiotics reflected only in the PHDC were either dispensed at a referral facility or before the first recorded antenatal clinic visit. Folic acid and iron were mostly documented in the MCR only (n=79/99 (80%) and n=107/128 (84%), respectively). However, analgesics and antihistamines more often appeared in the PHDC extract only (n=11/16 (73%) and n=5/5 (100%), respectively). CONCLUSIONS: The PHDC extract provided a better and more complete reflection of chronic drug exposures compared with the MCRs, especially when women sought care at facilities other than the antenatal care unit where they first attended, or when exposures occurred before the initial antenatal visit. The exception was antibiotics dispensed from ward stock to treat sexually transmitted and urinary tract infections.

Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells.

Advanced chronic lymphocytic leukaemia (CLL) is associated with profound immunodeficiency, including changes in T regulatory cells (T(regs)). We determined the pattern of expression of forkhead box P3 (FoxP3), CD25, CD27 and CD127 and showed that the frequency of CD4+ FoxP3+ T cells was increased in CLL patients (12% versus 8% in controls). This increase was seen only in advanced disease, with selective expansion of FoxP3-expressing cells in the CD4+ CD25(low) population, whereas the number of CD4+ CD25(high) FoxP3+ cells was unchanged. CD4+ CD25(low) cells showed reduced expression of CD127 and increased CD27, and this regulatory phenotype was also seen on all CD4 T cells subsets in CLL patients, irrespective of CD25 or FoxP3 expression. Incubation of CD4+ T cells with primary CLL tumours led to a sixfold increase in the expression of FoxP3 in CD4+ CD25- T cells. Patients undergoing treatment with fludarabine demonstrated a transient increase in the percentage of CD4+ FoxP3+ T cells, but this reduced to normal levels post-treatment. This work demonstrates that patients with CLL exhibit a systemic T cell dysregulation leading to the accumulation of CD4+ FoxP3+ T cells. This appears to be driven by interaction with malignant cells, and increased understanding of the mechanisms that are involved could provide novel avenues for treatment.

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens.

We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

Acute arterial thrombosis in acute promyelocytic leukaemia.

INTRODUCTION: Localized large vessel thrombosis in acute leukaemia is rare, haemorrhagic complications being more common. METHOD: We present a patient with acute promyelocytic leukaemia (APL) presenting with an acutely ischaemic lower limb. Large vessel thrombosis is a rare presentation of APL. We reviewed the literature on the coagulopathy of APL and discuss the pathology and current treatment options. DISCUSSION: Disordered haemostasis is typical of acute promyelocytic leukaemia (FAB M3) and relates to the intrinsic properties of the blast cells as well as thrombocytopenia from bone marrow involvement. Expression of procoagulants, stimulation of cytokines and alterations in endothelial cell anticoagulant properties initiate a disseminated intravascular coagulation (DIC) resulting in the typical clinical and laboratory findings in APL. The promyelocytes are characterized by the balanced reciprocal translocation between chromosomes 15 and 17. All-trans-retinoic acid (ATRA) induces differentiation in these cells, revolutionizing the treatment of APL. CONCLUSION: Unexpected limb ischaemia in a young, apparently healthy patient might be the presenting symptom of an underlying haematological disorder such as APL. A thorough haematological investigation should be performed prior to contemplating surgery. New treatment strategies based on knowledge of the molecular biology of APL has improved the prognosis of patients suffering from APL.