In Botswana, where almost all pregnant women known to have HIV receive antiretroviral therapy, a large proportion of vertical HIV transmission may occur among women with incident undiagnosed HIV infection during pregnancy. Botswana guidelines recommend repeat HIV testing every 3 months in pregnancy, with at least one test in the third trimester. We evaluated the rate of repeat HIV testing, calculated HIV incidence during pregnancy and estimated missed seroconversions.
To the Editors: In the January 2019 issue of this journal, Dadabhai et al1 presented an analysis of birth outcomes, including preterm birth (PTB), low birth weight, and small for gestational age (SGA) among infants born to women living with HIV (WLHIV) on antiretroviral therapy (ART) compared with women without HIV, enrolled in the Pregnancy Outcomes and Infant Survival in the Era of Universal HAART in Africa (POISE) study. This comparison is crucial to understand whether the previously observed disparity in birth outcomes between women with and without HIV is being narrowed by maternal ART.2 In POISE, WLHIV were included if they were on ART for at least 1 week before delivery and had a delivery CD4 count ≥350 cells/mm3. Women were enrolled in the maternity ward either just before or after delivery, at one teaching hospital and 4 major health centers in Blantyre, Malawi, during 2016 and 2017. Of 5423 women approached, 614 WLHIV and 685 women without HIV were ultimately enrolled. Within the cohort of infants born to enrolled women, there was no difference in PTB, low birth weight, or SGA by maternal HIV status, and the paper concludes that “ART use has reduced the high rates of adverse pregnancy outcomes among HIV-infected women.”1 The authors considered the possibility of selection bias and thought it unlikely to be present or at least not to be differential between women with and without HIV. However, the methodology used for participant selection is likely to preferentially exclude women with adverse birth outcomes, particularly severe outcomes. Women approached in the postpartum period whose newborns were acutely ill or who died shortly after birth (often due to severe prematurity) may have been less likely to enroll in a 1-year prospective study of infant survival and may also not have been readily accessible for recruitment. For the same reasons, women approached before delivery in preterm labor, or with serious pregnancy complications, may have been less inclined to enroll and less accessible. Evidence for this type of selection bias is observed in the POISE study population, as the lowest birth weight of enrolled infants was 1.9 kg and the minimum gestational age was 34 weeks, highlighting the fact that no infant with very low birth weight (<1.5 kg) or born very preterm was included. Although lower enrollment with severe outcomes may have occurred regardless of maternal HIV-infection status, the included study population is no longer representative of the entire population. If PTB and lower birth weights occur more frequently in the newborns of WLHIV, then selection bias in the POISE study sample would lead to a bias toward the null in the comparison of PTB and low birth weight between WLHIV and women without HIV. Interestingly, the POISE study did find differences in some of the SGA outcomes by HIV status. SGA, which is associated with less immediate morbidity than very PTB or very low birth weight among neonates, may therefore be less susceptible to selection bias. Recent studies from Botswana and South Africa have indeed shown that compared with women without HIV, WLHIV and on ART have an increased risk of adverse birth outcomes, particularly PTB.3,4 There are important methodological differences between these studies and POISE. The Tsepamo study in Botswana reported increased risk of PTB [adjusted risk ratio 1.18; 95% confidence interval (CI): 1.12 to 1.25] and SGA (adjusted risk ratio 1.30; 95% CI: 1.23 to 1.38) among women on efavirenz-based ART compared with women without HIV.3 Like POISE, Tsepamo collected maternal pregnancy and birth outcome data shortly after delivery, but in Botswana, the data were abstracted on all consecutive deliveries at 8 government hospitals.3 By including all deliveries at the study facilities and not a selected sample as in POISE, the risk of selection bias was minimized. The South African study, which enrolled pregnant women at their first antenatal care visit, observed double the odds of PTB in WLHIV initiating ART during pregnancy compared with women without HIV (adjusted odds ratio 2.03; 95% CI: 1.33 to 3.10).4 Antenatal enrollment well before the end of pregnancy with prospective follow-up for complete outcome ascertainment guards against noninclusion of women with worse birth outcomes. The likely selection bias introduced by the design of the POISE study and conducted in a single African country should not provide stakeholders with definitive reassurance or causal evidence that maternal ART has mitigated adverse pregnancy outcomes among WLHIV in sub-Saharan Africa.
Women with vertically acquired HIV (VHIV) may have a greater risk of adverse birth outcomes than women with horizontally acquired HIV (HHIV).The Tsepamo study performed birth outcomes surveillance at 8 government delivery sites in Botswana from July 2014 through March 2019. Pregnant women diagnosed with HIV before their 11th birthday received VHIV status, and other women had HHIV. Small for gestational age (SGA), preterm delivery (PTD), stillbirth, and neonatal death were compared using χ2 and Fisher's exact tests. Log-binomial regression models determined risk ratios (RRs).VHIV women (n = 402) aged 15-27 years were identified over 4 years of surveillance and compared with HHIV women (n = 8465) of the same age. VHIV women were more likely to use nevirapine (NVP)-based antiretroviral treatment (ART) in pregnancy and to have SGA and very SGA infants, but less likely to have very PTD infants. In unadjusted analyses, VHIV women had a higher risk of any adverse birth outcome combined (RR = 1.21, 95% confidence interval [CI], 1.08-1.36). After adjusting for potential confounders, particularly use of NVP-based regimens, the risk of adverse birth outcomes among VHIV and HHIV women was similar.NVP-based ART is a primary and modifiable risk factor for adverse birth outcomes. Updating ART regimens could improve birth outcomes for women with HIV.
Diarrhoea and pneumonia are common causes of childhood death in sub-Saharan Africa but there are few studies describing specific pathogens.The study aimed to describe the pathogens associated with diarrhoea, pneumonia and oropharyngeal colonization in children born to HIV-infected women (HIV-exposed infants).The Mashi Study randomized 1200 HIV-infected women and their infants to breastfeed for 6 months with ZDV prophylaxis or formula-feed with 4 weeks of ZDV. Children were tested for HIV by PCR at 1, 4, 7, 9 and 12 months and by ELISA at 18 months. Pre-defined subsets of children were sampled during episodes of diarrhoea (n = 300) and pneumonia (n = 85). Stool was tested for bacterial pathogens, rotavirus and parasites. Children with pneumonia underwent bacterial blood culture, and testing of nasopharyngeal aspirates for viral pathogens by PCR. Oropharyngeal swabs were collected from a consecutive subset of 561 infants at the routine 3-month visit for bacterial culture.The median age (range) at sampling was 181 days for diarrhoea (0-730) and 140 days for pneumonia (2-551). Pathogens were identified in 55 (18%) children with diarrhoea and 32 (38%) with pneumonia. No differences in pathogens by child HIV status (HIV-infected vs HIV-uninfected) or feeding strategy were identified. Campylobacter was the most common diarrhoeal pathogen (7%). Adenovirus (22%) and other viruses (19%) were the primary pathogens isolated during pneumonias. More formula-fed infants had oropharyngeal colonization by pathogenic Gram-negative bacteria (16.8% vs 6.2%, P = 0.003), which was associated with a non-significant increased risk of pneumonia (OR 2.2, 95% CI 0.8-5.7).A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.
To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.
Antiretroviral therapy (ART) has significantly improved survival in Africa in recent years. In Botswana, where adult HIV prevalence is 21.9%, AIDS-related mortality is estimated to have declined by 58% between 2005 and 2013 following the initial wide-spread introduction of ART, and ART coverage has steadily increased reaching 84% in 2016. However, there remains little data about the burden of HIV and its impact on mortality in the hospital setting where most deaths occur. We aimed to describe the burden of HIV and related morbidity and mortality among hospitalized medical patients in a district hospital in southern Botswana in the era of widespread ART coverage.We prospectively reviewed medical admissions to Scottish Livingstone Hospital from December 2015 to November 2017 and recorded HIV status, demographics, clinical characteristics and final diagnoses at discharge, death or transfer. We ascertained outcomes and determined factors associated with mortality. Results were compared with similar surveillance data collected at the same facility in 2011 to 2012.A total of 2316 admissions occurred involving 1969 patients; 42.4% were of HIV-positive patients, 46.9% of HIV-negative patients and 10.7% of patients with unknown HIV status. Compared to HIV-negative patients, HIV-positive patients had younger age (mean 42 vs. 64 years, p < 0.0001) and higher mortality (22.2% vs. 18.0%, p = 0.03). Tuberculosis was the leading diagnosis among mortality cases in both groups but accounted for a higher proportion of deaths among HIV-positive admissions (44.5%) compared with HIV-negative admissions (19.4%, p < 0.0001). Compared with similar surveillance in 2011 to 2012, HIV prevalence was lower (42.4% vs. 47.6%, p < 0.01), and among HIV-positive admissions: ART coverage was higher (72.2% vs. 56.2%, p < 0.0001), viral load suppression was similar (78.6% vs. 80.3%, p = 0.77), CD4 counts were higher (55.0% vs. 44.6% with CD4 ≥200 cells/mm3 , p < 0.001), mortality was similar (22.2 vs. 22.7%, p = 0.93), tuberculosis diagnoses increased (27.5% vs. 20.1%, p < 0.01) and tuberculosis-associated mortality was higher (35.9% vs. 24.7%, p = 0.05).Despite high ART-coverage in Botswana, HIV-positive patients continue to be disproportionately represented among hospital admissions and deaths. Deaths from tuberculosis may be contributing to lack of reduction in inpatient mortality. Our findings suggest that control of HIV and tuberculosis remain top priorities for reducing inpatient mortality in Botswana.
Among human immunodeficiency virus-positive women in Botswana on the recommended first-line antiretroviral therapy regimen, tenofovir-emtricitabine-efavirenz, initiated within the first or early second trimester, we found no increased risk of stillbirth, neonatal death, preterm/very preterm delivery, or the infant being born small or very small for gestational age. Treatment with tenofovir-emtricitabine-efavirenz <1 year before conception increased the risk of preterm delivery slightly over late-second-trimester treatment initiation (adjusted risk ratio, 1.33 [95% confidence interval, 1.04-1.70]).
In May 2018, regulatory authorities released cautionary statements about the possible association between neural tube defects (NTDs) and dolutegravir (DTG)-based antiretroviral therapy (ART) exposure at conception, based on data from the Tsepamo study in Botswana which reported four NTDs among 426 pregnancies exposed to DTG at conception, compared with 11 among 11 300 who were exposed to ART at conception that did not contain DTG (Zash et al. NEJM 2019;379:979–81). Given the small number of events from a single study, more data are needed to confirm or refute this association. Difficulty finding these additional data highlights limitations of existing pharmacovigilance systems and challenges of combining disparate sources of data to understand rare but important events. Money et al. (BJOG 2019;126:1338–45) report on birth defects among infants born to HIV-infected women in Canada from 2007 to 2017. During this 10-year period, there were 69 exposures to DTG at conception; no NTDs were identified. In Canada, a country with mandated grain folate fortification, overall NTD prevalence is 4 per 10 000 births. Given this low NTD prevalence and only 69 exposures to DTG at conception, the Money study has approximately 8% power to detect a ten-fold NTD increase with DTG conception exposure. Power is further reduced because of lack of birth defect ascertainment among stillbirths or pregnancy terminations; in Botswana, where termination of pregnancy is not legal, 25% of NTDs were detected in stillborn infants. Since May 2018, the Money et al. study is among the largest to evaluate NTDs with DTG exposure, but the chance of a false-negative result (type 2 error) remains >90%. Given low overall NTD prevalence, negative results from small studies provide insufficient evidence to refute the signal. Future meta-analyses may improve power, but uncertainty will remain because of methodological variability, incomplete outcome ascertainment, and differences between countries in preconception folate repletion and baseline NTD prevalence. Outside of Botswana, accrual of sufficient data to confirm or refute the signal will take time. Expanding pharmacovigilance in low-resource settings with high HIV prevalence, where the majority of fetal ART exposures occur, is essential as DTG is further rolled-out and new drugs become available. Ongoing uncertainly about the NTD signal makes ART treatment decisions more challenging but does not necessarily preclude DTG use among women of reproductive potential. DTG-based ART has many advantages (Vitoria et al. AIDS 2018;32:1551–61), and modelling suggests large public health benefits of DTG use in low- and middle-income countries when weighed against small possible absolute NTD risks (Dugdale et al. Ann Intern Med 2019;170:614–25). With the exception of efavirenz, there are insufficient data on the safety of conception exposure to acceptable DTG alternatives, including other integrase inhibitors, protease inhibitors such as darunavir and atazanavir, and newer non-nucleoside reverse transcriptase inhibitors such as rilpivirine and doravirine. A focus on expanding pharmacovigilance systems, improving comprehensive sexual and reproductive health service access, and developing effective risk communication to assist informed, patient-centred treatment choices will benefit people living with HIV, whether the signal is ultimately confirmed or refuted. Additionally, although it is not yet known whether folate could mitigate the possible DTG-associated NTD risk, implementation of folate food fortification and pre-conception folate supplementation in settings where these important interventions are lacking would benefit persons living both with and without HIV (Kancherla. Birth Defects Res 2018;110:965). RMZ reports grants from NIH/NICHD during the conduct of the study. There are no other potential conflicts of interest. A completed disclosure of interests form is available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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