Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per µL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050). INTERPRETATION: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Evolution of HIV-1 drug resistance after virological failure of first-line antiretroviral therapy in Lusaka, Zambia.

BACKGROUND: HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolution of drug resistance mutations among adults failing first-line ART in Zambia. METHODS: We analysed data from a trial of VL monitoring in Lusaka, Zambia. From 2006 to 2011, 12 randomized sites provided either routine VL monitoring (intervention) or discretionary (control) after ART initiation. Samples were collected prospectively following the same schedule in each arm but analysed retrospectively in the control group. For those with virological failure (VF; >400 copies/ml), HIV genotyping was performed retrospectively on baseline (BL) and on all subsequent specimens until censored due to study completion, withdrawal or death. RESULTS: Of 1,973 enrollees, 165 (8.4%) developed VF. 464 genotype results were available including 132 (80%) at BL, 116 (70%) at VF and 125 (76%) had at least one result between VF and censoring. Major nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations increased from 26% (BL) to 82% (VF) to 89% at last genotype (LG). M184 mutations increased from 2% to 59% to 71%; K65R from 2% to 11% to 13%; 2 or more thymidine analogue mutations from 1% to 3% to 12%. Among those on a failing tenofovir disoproxil fumarate (TDF)-based regimen, TDF resistance increased from 42% to 58%. CONCLUSIONS: We found substantial resistance to NRTIs and NNRTIs at VF with incremental increases after VF while still on a failing first-line ART; this resistance may compromise attainment of the UNAIDS 90-90-90 goals.

Adverse birth outcomes and their clinical phenotypes in an urban Zambian cohort.

Background: Few cohort studies of pregnancy in sub-Saharan Africa use rigorous gestational age dating and clinical phenotyping. As a result, incidence and risk factors of adverse birth outcomes are inadequately characterized. Methods: The Zambian Preterm Birth Prevention Study (ZAPPS) is a prospective observational cohort established to investigate adverse birth outcomes at a referral hospital in urban Lusaka. This report describes ZAPPS phase I, enrolled August 2015 to September 2017. Women were followed through pregnancy and 42 days postpartum. At delivery, study staff assessed neonatal vital status, birthweight, and sex, and assigned a delivery phenotype. Primary outcomes were: (1) preterm birth (PTB; delivery <37 weeks), (2) small-for-gestational-age (SGA; <10 th percentile weight-for-age at birth), and (3) stillbirth (SB; delivery of an infant without signs of life). Results: ZAPPS phase I enrolled 1450 women with median age 27 years (IQR 23-32). Most participants (68%) were multiparous, of whom 41% reported a prior PTB and 14% reported a prior stillbirth. Twins were present in 3% of pregnancies, 3% of women had short cervix (<25mm), 24% of women were HIV seropositive, and 5% were syphilis seropositive. Of 1216 (84%) retained at delivery, 15% were preterm, 18% small-for-gestational-age, and 4% stillborn. PTB risk was higher with prior PTB (aRR 1.88; 95%CI 1.32-2.68), short cervix (aRR 2.62; 95%CI 1.68-4.09), twins (aRR 5.22; 95%CI 3.67-7.43), and antenatal hypertension (aRR 2.04; 95%CI 1.43-2.91). SGA risk was higher with twins (aRR 2.75; 95%CI 1.81-4.18) and antenatal hypertension (aRR 1.62; 95%CI 1.16-2.26). SB risk was higher with short cervix (aRR 6.42; 95%CI 2.56-16.1). Conclusio ns: This study confirms high rates of PTB, SGA, and SB among pregnant women in Lusaka, Zambia. Accurate gestational age dating and careful ascertainment of delivery data are critical to understanding the scope of adverse birth outcomes in low-resource settings.

A risk score to identify HIV-infected women most likely to become lost to follow-up in the postpartum period.

Access to lifelong combination antiretroviral therapy (cART) is expanding among HIV-infected pregnant and breastfeeding women throughout sub-Saharan Africa (SSA). For this strategy to meaningfully improve maternal HIV outcomes, retention in HIV care is essential. We developed a risk score to identify women with high likelihood of loss to follow-up (LTFU) at 6 months postpartum from HIV care, using data from public health facilities in Lusaka, Zambia. LTFU was defined as not presenting for HIV care within 60 days of the last scheduled appointment. We used logistic regression to assess demographic, obstetric and HIV predictors of LTFU and to develop a simple risk score. Sensitivity and specificity were assessed at each risk score cut-point. Among 2029 pregnant women initiating cART between 2009 and 2011, 507 (25%) were LTFU by 6 months postpartum. Parity, education, employment status, WHO clinical stage, duration of cART during pregnancy and number of antenatal care visits were associated with LTFU (p-value < .10). A risk score cut-point of 11 (42nd percentile) had 85% sensitivity (95% CI 82%, 88%) and 22% specificity (95% CI 20%, 24%) to detect women LTFU and would exclude 20% of women from a retention intervention. A risk score cut-point of 18 (69th percentile) identified the 23% of women with the highest probability of LTFU and had sensitivity 32% (95% CI 28%, 36%) and specificity 80% (95% CI 78%, 82%). A risk score approach may be useful to triage a subset of women most likely to be LTFU for targeted retention interventions.

Prevalence of hypertension and its treatment among adults presenting to primary health clinics in rural Zambia: analysis of an observational database.

BACKGROUND: Hypertension constitutes a growing burden of illness in developing countries like Zambia. Adequately screening and treating hypertension could greatly reduce the complications of stroke and coronary disease. Our objective was to determine the prevalence of hypertension and identify current treatment practices among adult patients presenting for routine care to rural health facilities in the Better Health Outcomes through Mentoring and Assessments (BHOMA) project. METHODS: We conducted a retrospective analysis of routinely collected clinical data from 46 rural government clinics in Zambia. Our analysis cohort comprised patients ≥ 25 years with recorded blood pressure measurements, who sought care at primary health centers. Consistent with prior research, in our primary analysis, we only included data from first visits. Hypertension was defined as a systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or reported use of antihypertensive medication. A sensitivity analysis was performed using median blood pressure for individuals with multiple visits. RESULTS AND DISCUSSION: From January 2011 to December 2014, 116,130 first visits by adult patients met eligibility criteria. The crude prevalence of hypertension by onsite measurement or reported use of antihypertensive medication was 23.1% [95% CI: 22.8-23.3] (23.6% in females, 22.3% in males). The age standardized prevalence of hypertension across participating sites was 28.0 [95% CI: 27.7-28.3] (29.7% in females, 25.8% in males). Sensitivity analysis revealed a similar prevalence using data from all visits. Only 5.6% of patients had a diagnosis of hypertension documented in their medical record. Among patients with hypertension, only 18.0% had any antihypertensive drug prescribed, with nifedipine (8.9%), furosemide (8.3%), and propranolol (2.4%) as the most common. CONCLUSIONS: Age standardized prevalence of hypertension in rural primary health clinics in Zambia was high compared to other studies in rural Africa; however, we diagnosed hypertension with only one measurement and this may have biased our findings. Future efforts to improve hypertension control should focus on population preventive care and primary healthcare provider education on individual management.

Utilization of cervical cancer screening services and trends in screening positivity rates in a 'screen-and-treat' program integrated with HIV/AIDS care in Zambia.

BACKGROUND: In the absence of stand-alone infrastructures for delivering cervical cancer screening services, efforts are underway in sub-Saharan Africa to dovetail screening with ongoing vertical health initiatives like HIV/AIDS care programs. Yet, evidence demonstrating the utilization of cervical cancer prevention services in such integrated programs by women of the general population is lacking. METHODS: We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia (CCPPZ), the largest public sector programs of its kind in sub-Saharan Africa. We evaluated patterns of utilization of screening services by HIV serostatus, examined contemporaneous trends in screening outcomes, and used multivariable modeling to identify factors associated with screening test positivity. RESULTS: Between January 2006 and April 2011, CCPPZ services were utilized by 56,247 women who underwent cervical cancer screening with visual inspection with acetic acid (VIA), aided by digital cervicography. The proportion of women accessing these services who were HIV-seropositive declined from 54% to 23% between 2006-2010, which coincided with increasing proportions of HIV-seronegative women (from 22% to 38%) and women whose HIV serostatus was unknown (from 24% to 39%) (all p-for trend<0.001). The rates of VIA screening positivity declined from 47% to 17% during the same period (p-for trend <0.001), and this decline was consistent across all HIV serostatus categories. After adjusting for demographic and sexual/reproductive factors, HIV-seropositive women were more than twice as likely (Odds ratio 2.62, 95% CI 2.49, 2.76) to screen VIA-positive than HIV-seronegative women. CONCLUSIONS: This is the first 'real world' demonstration in a public sector implementation program in a sub-Saharan African setting that with successful program scale-up efforts, nurse-led cervical cancer screening programs targeting women with HIV can expand and serve all women, regardless of HIV serostatus. Screening program performance can improve with adequate emphasis on training, quality control, and telemedicine-support for nurse-providers in clinical decision making.

Implementation of cervical cancer prevention services for HIV-infected women in Zambia: measuring program effectiveness.

BACKGROUND: Cervical cancer kills more women in low-income nations than any other malignancy. A variety of research and demonstration efforts have proven the efficacy and effectiveness of low-cost cervical cancer prevention methods but none in routine program implementation settings of the developing world, particularly in HIV-infected women. METHODS: In our public sector cervical cancer prevention program in Zambia, nurses conduct screening using visual inspection with acetic acid aided by digital cervicography. Women with visible lesions are offered same-visit cryotherapy or referred for histologic evaluation and clinical management. We analyzed clinical outcomes and modeled program effectiveness among HIV-infected women by estimating the total number of cervical cancer deaths prevented through screening and treatment. RESULTS: Between 2006 and 2008, 6572 HIV-infected women were screened, 53.6% (3523) had visible lesions, 58.5% (2062) were eligible for cryotherapy and 41.5% (1461) were referred for histologic evaluation. A total of 75% (1095 out of 1462) of patients who were referred for evaluation complied. Pathology results from 65% (715 out of 1095) of women revealed benign abnormalities in 21% (151), cervical intraepithelial neoplasia (CIN) I in 30% (214), CIN 2/3 in 33% (235) and invasive cervical cancer in 16.1% (115, of which 69% were early stage). Using a conditional probability model, we estimated that our program prevented 142 cervical cancer deaths (high/low range: 238-96) among the 6572 HIV-infected women screened, or one cervical cancer death prevented per 46 (corresponding range: 28-68) HIV-infected women screened. CONCLUSION: Our prevention efforts using setting-appropriate human resources and technology have reduced morbidity and mortality from cervical cancer among HIV-infected women in Zambia. Financial support for implementing cervical cancer prevention programs integrated within HIV/AIDS care programs is warranted. Our prevention model can serve as the implementation platform for future low-cost HPV-based screening methods, and our results may provide the basis for comparison of programmatic effectiveness of future prevention efforts.

A cluster-randomized trial of enhanced labor ward-based PMTCT services to increase nevirapine coverage in Lusaka, Zambia.

OBJECTIVE: Determine whether enhanced labor ward-based services for prevention of mother-to-child transmission of HIV (PMTCT) would improve nevirapine (NVP) coverage. DESIGN: Cluster-randomized trial at 12 public-sector delivery centers in Lusaka, Zambia. METHODS: Following a baseline surveillance period, 12 labor wards were randomized, six to offer opt-in HIV testing to women of unknown serostatus (with NVP administration as indicated) and to assess NVP adherence among known HIV-infected women. The six control labor wards provided the standard of care. The NVP coverage endpoint was defined as the proportion of HIV-infected/exposed women/infant pairs with confirmed NVP ingestion. We used generalized estimating equations (GEE) to determine the odds of coverage associated with the intervention and ultimately used the parameters for the estimated GEE model to estimate relative risk. RESULTS: Between October 2005 and January 2006, 7664 women gave birth at participating clinics. We collected anonymous-linked blood from 7592 (99%) umbilical cords; tested 7438 (97%) for HIV, 1618 (22%) were seropositive, and of these, 1279 (79%) were tested for NVP. At baseline (preintervention), the probability of HIV-infected/exposed women/infant pairs receiving NVP in treatment clinics (42%) was 0.89 times the probability of being covered in control clinics (53%) whereas during the intervention period the probability of treatment clinic coverage (52%) was 1.22 the probability control clinic coverage (43%), representing a multiplicative effect of 1.37 upon the RR at baseline (ratio of relative risks 1.37, bootstrapped 95% CI, 1.04-1.77). CONCLUSION: Labor ward-based PMTCT programs are feasible and can have a significant, positive impact on NVP coverage.

Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation.

BACKGROUND: The objective of the study was to evaluate whether providing antiretroviral therapy (ART) integrated in antenatal care (ANC) clinics resulted in a greater proportion of treatment-eligible women initiating ART during pregnancy compared with the existing approach of referral to ART. ANALYSIS DESIGN AND METHODS: The evaluation used a stepped-wedge design and included all HIV-infected, ART-eligible pregnant women in eight public sector clinics in Lusaka district, Zambia. Main outcome indicators were the proportion of treatment-eligible pregnant women enrolling into HIV care within 60 days of HIV diagnosis, and of these, the proportion initiating ART during pregnancy. Adjusted odds ratios (AORs) and confidence intervals (CIs) for enrollment and initiation proportions were estimated through a logistic regression model accounting for clinical site cluster and time effects. RESULTS: Between 16 July 2007 and 31 July 2008, 13,917 women started antenatal care more than 60 days before the intervention rollout and constituted the control cohort; 17 619 started antenatal care after ART integrated into ANC and constituted the intervention cohort. Of the 1566 patients found eligible for ART, a greater proportion enrolled while pregnant and within the 60 days of HIV diagnosis in the intervention cohort (376/846, 44.4%) compared with the control cohort (181/716, 25.3%), AOR 2.06, 95% CI (1.27-3.34); and initiated ART while pregnant in the intervention cohort (278/846, 32.9%) compared with the control cohort (103/716, 14.4%), AOR 2.01, 95% CI (1.37-2.95). CONCLUSION: An integrated ART in ANC strategy doubled the proportion of treatment-eligible women initiating ART while pregnant.

Hormonal contraception and HIV disease progression: a multicountry cohort analysis of the MTCT-Plus Initiative.

OBJECTIVE: HIV-infected women need access to safe and effective contraception. Recent animal and human data suggest that hormonal contraception may accelerate HIV disease progression. METHODS: We compared the incidence of HIV disease progression among antiretroviral therapy-naive women with and without exposure to hormonal contraception at 13 sites in Africa and Asia. Disease progression was defined as becoming eligible for antiretroviral therapy or death. RESULTS: Between 1 August 2002 and 31 December 2007, the MTCT-Plus programs enrolled 7846 women. In total, 4109 (52%) women met eligibility criteria for this analysis and contributed 5911 person-years of follow-up (median follow-up, 379 days; interquartile range, 121-833). At baseline, 3064 (75%) women reported using either no contraception or a nonhormonal method, whereas 823 (20%) reported using implants/injectables and 222 (5%) reported using oral contraceptive pills. The disease progression outcome was met by 944 (29%) women (rate, 18.3/100 woman-years). Neither implants/injectables (adjusted hazard ratio 1.0, 95% confidence interval 0.8-1.1) nor oral contraceptive pills (adjusted hazard ratio 0.8, 95% confidence interval 0.6-1.1) were associated with disease progression. Treating contraceptive method as a time-varying exposure did not change this negative finding. CONCLUSION: This multicountry cohort analysis provides some reassurance that hormonal contraception is not associated with HIV disease progression. Further research is needed to address the contraceptive needs of HIV-infected women.

Effectiveness of a city-wide program to prevent mother-to-child HIV transmission in Lusaka, Zambia.

OBJECTIVE: To determine the population effectiveness of a city-wide perinatal HIV prevention program. DESIGN: An anonymous surveillance of newborn cord blood for HIV serology and nevirapine (NVP). METHODS: All 10 public-sector delivery centers in Lusaka, Zambia participated. All mother-infant pairs delivering during the 12-week surveillance period at the participating centers and who received antenatal care at a public-sector facility in Lusaka were included in the study. The main outcome measure was population NVP coverage, defined as the proportion of HIV-infected women and HIV-exposed infants in the population that ingested NVP. RESULTS: Of 8787 women in the surveillance population, 7204 (82%) had been offered antenatal HIV testing, of which 5149 (71%) had accepted, and of which 5129 (99%) had received a result. Overall, 2257 of 8787 (26%) were cord seropositive. Of the 1246 (55%) cord blood seropositive women who received an antenatal HIV test result, 1112 (89%) received a positive result; the other 134 comprise seroconverters and clerical errors. Only 751 of 1112 (68%) women who received a positive antenatal test result and a NVP tablet for ingestion at labor onset had NVP detected in the cord blood (i.e., maternal non-adherence rate was 32%). A total of 675 infants born to 751 adherent mothers (90%) received NVP before discharge. Thus, only 675 of 2257 (30%) seropositive mother-infant pairs in the surveillance population received both a maternal and infant dose of NVP. CONCLUSIONS: Successful perinatal HIV prevention requires each mother-infant pair to negotiate a cascade of events that begins with offering HIV testing and continues through adherence to the prescribed regimen. This novel surveillance demonstrates that failures occur at each step, resulting in reduced coverage and diminished program effectiveness.