Scott Dryden-Peterson

Highly Active Antiretroviral Therapy and Adverse Birth Outcomes Among HIV-Infected Women in Botswana

BACKGROUND It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings. METHODS We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)-infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4(+) lymphocyte cell count. RESULTS Of 33,148 women, 32,113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4(+) was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB. CONCLUSIONS HAART receipt during pregnancy was associated with increased PTD, SGA, and SB.

Variability of Infectious Aerosols Produced during Coughing by Patients with Pulmonary Tuberculosis

RATIONALE Mycobacterium tuberculosis is transmitted by infectious aerosols, but assessing infectiousness currently relies on sputum microscopy that does not accurately predict the variability in transmission. OBJECTIVES To evaluate the feasibility of collecting cough aerosols and the risk factors for infectious aerosol production from patients with pulmonary tuberculosis (TB) in a resource-limited setting. METHODS We enrolled subjects with suspected TB in Kampala, Uganda and collected clinical, radiographic, and microbiological data in addition to cough aerosol cultures. A subset of 38 subjects was studied on 2 or 3 consecutive days to assess reproducibility. MEASUREMENTS AND MAIN RESULTS M. tuberculosis was cultured from cough aerosols of 28 of 101 (27.7%; 95% confidence interval [CI], 19.9-37.1%) subjects with culture-confirmed TB, with a median 16 aerosol cfu (range, 1-701) in 10 minutes of coughing. Nearly all (96.4%) cultivable particles were 0.65 to 4.7 μm in size. Positive aerosol cultures were associated with higher Karnofsky performance scores (P = 0.016), higher sputum acid-fast bacilli smear microscopy grades (P = 0.007), lower days to positive in liquid culture (P = 0.004), stronger cough (P = 0.016), and fewer days on TB treatment (P = 0.047). In multivariable analyses, cough aerosol cultures were associated with a salivary/mucosalivary (compared with purulent/mucopurulent) appearance of sputum (odds ratio, 4.42; 95% CI, 1.23-21.43) and low days to positive (per 1-d decrease; odds ratio, 1.17; 95% CI, 1.07-1.33). The within-test (kappa, 0.81; 95% CI, 0.68-0.94) and interday test (kappa, 0.62; 95% CI, 0.43-0.82) reproducibility were high. CONCLUSIONS A minority of patients with TB (28%) produced culturable cough aerosols. Collection of cough aerosol cultures is feasible and reproducible in a resource-limited setting.

Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey

BACKGROUND HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswanas progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90-90-90). METHODS A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. FINDINGS 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83·3%, 95% CI 81·4-85·2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87·4%, 95% CI 85·8-89·0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96·5%, 95% CI 96·0-97·0) had viral load of 400 copies per mL or less. Overall, 70·2% (95% CI 67·5-73·0) of HIV-infected people had virological suppression, close to the UNAIDS target of 73%. INTERPRETATION UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden. FUNDING US Presidents Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana

Background:The impact of in utero exposure to highly active antiretroviral therapy (HAART) on longitudinal growth of HIV-uninfected infants is unknown. Methods:The Mashi and Mma Bana PMTCT intervention trials enrolled HIV-infected pregnant women at four sites in Botswana. Breast-fed (BF), HIV-uninfected infants born at 37 weeks or greater were included in this analysis. Weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores were calculated using World Health Organization Child Growth Standards. Mean z-scores were compared between in utero antiretroviral exposure groups using Student t test, response profiles analysis, and general linear mixed effects modeling. Results:Growth of 619 HAART-exposed and 440 zidovudine-exposed, HIV-uninfected infants was evaluated. Mean birth weights were 3.01 kg for HAART and 3.15 kg for zidovudine-exposed infants (P < 0.001) with lower mean birth WAZ, length-for-age (LAZ), and weight-for-length (WLZ) among HAART-exposed infants (all P < 0.001). HAART-exposed infants had greater improvement in WAZ and weight-for-length (WLZ) from birth through 2 months (P = 0.03, P < 0.001, respectively). The WAZ did not differ between groups from 3 through 6 months (P = 0.26). Length-for-age (LAZ) remained lower in HAART-exposed infants but the incidence of wasting or stunting did not differ between exposure groups. Conclusions:Lower weights in HAART-exposed uninfected infants at birth were rapidly corrected during the first 6 months of life.

Effectiveness of the Standard WHO Recommended Retreatment Regimen (Category II) for Tuberculosis in Kampala, Uganda: A Prospective Cohort Study

Prospective evaluation of the effectiveness of the WHO-recommended standardized retreatment regimen for tuberculosis by Edward Jones-López and colleagues reveals an unacceptable proportion of unsuccessful outcomes.

Increased risk of severe infant anemia after exposure to maternal HAART, Botswana.

Background:Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission but may increase the risk for infant anemia. Methods:The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). Results:A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Conclusions:Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.

Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana.

Background:Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana. Methods:We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009–2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013–2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB). Results:Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7). Conclusions:Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.

Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4+ cell counts in Gaborone, Botswana.

Background:Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4+ cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4+ cell count testing, and HAART initiation during pregnancy. Methods:From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana. Results:We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4+ cell counts, of whom 62 (16%) had a CD4+ cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy. Conclusions:We observed low rates of CD4+ cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4+ cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.

Addressing the growing cancer burden in the wake of the AIDS epidemic in Botswana: The BOTSOGO collaborative partnership.

Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources.

Cancer Incidence following Expansion of HIV Treatment in Botswana.

Background The expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa. Methods We included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003–2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage. Findings During this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi’s sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%). Interpretation Expansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.