Challenges and successes in the implementation of option B+ to prevent mother-to-child transmission of HIV in southern Swaziland

This was a prospective PMTCTB+ implementation cohort study in Nhlangano health zone, southern Swaziland. Predominantly rural, it comprises one secondary and 8 primary care facilities providing HIV diagnosis and ART integrated into maternal and child health care services. Full details of the setting and the study have been described elsewhere [20].

From 28 January 2013 to 30 June 2014 newly diagnosed and previously known HIV+ pregnant women aged ≥16 years were enrolled into the study and offered lifelong ART at the first ante-natal care (ANC) visit. At completion of study enrolment, PMTCTB+ was adopted as the standard of care nationally, and the study follow-up period coincided with the national roll out. Trained HIV testing counsellors (HTCs) performed HIV testing, treatment preparation, and ART follow-up counselling. A serial rapid testing algorithm was applied using the Alere Determine™ HIV-1/2 rapid test followed by the Uni-Gold™ test on whole blood. Trained nurses initiated ART and performed follow-up visits and ART refills, while mobile medical doctors attended clinically complicated HIV patients. Because PMTCTA remained the standard of care nationally and per the guidance from the Ministry of Health, women were still allowed to opt for AZT in the PMTCTB+ study. Treatment response was monitored through routine VL testing at 6 and 12 months and annually thereafter using the Biocentric (Bandol, France) multi-manufacturer open platform for HIV-1 VL quantification on plasma samples. Stepped-up adherence counselling was performed in case of an elevated VL > 1000 copies/ml [13]. EID testing was performed using the Cobas® AmpliPrep/Cobas® TaqMan® v2.0 for the qualitative detection of HIV-1 from heel prick dried blood spots. Women missing their scheduled ART refill visits or their EID appointment at 6 weeks after birth were traced by phone as per national protocol.

First, for HIV+ pregnant treatment naïve women, the primary outcome was time from first ANC visit to ART initiation. Censoring occurred on the date of AZT initiation, transfer out of the study facilities, death, loss to follow-up (LTFU), and latest at 6 months after the first ANC visit. Second, for women commencing ART, the primary outcome was time to occurrence of the composite unfavourable endpoint LTFU (defined as ≥4.5 months without visit) or death. Censoring occurred at the last recorded clinic visit for transfer out and latest at the end of the observation period (18 September 2015). Six-month VL test utilization was defined as the proportion of women being on ART for at least 6 months who received a VL test between 6 to 12 months after the commencement of ART. Finally, EID utilization and HIV mother to infant transmission were described. Because the date of birth was often not recorded, EID was defined as any PCR measurement done between birth and the end of the observation period. HIV transmission was described for infants who had EID test results available. For all analyses, baseline variables were measured at the time of the first ANC visit. Same-day ART initiation was defined as patients starting ART on the day of HIV diagnosis. The study enrolment period was divided into 3 phases (early: 01–06/2013, mid: 07–12/2013 and late: 01–06/2014) to account for temporal trends.

Trained data clerks entered patient information into an electronic study database. Clinical and socio-demographic data were obtained from facility-based registers and patient files. VL test results were obtained from the laboratory based electronic VL database, and birth outcomes and EID data from maternity records and child welfare registers. Baseline characteristics were described using frequency statistics and proportions. Kaplan-Meier estimates were computed and uni- and multivariate Cox proportional-hazards regression models built for time to ART initiation and treatment outcome analyses. All regression models were adjusted for baseline socio-demographic and clinical covariate information, and the final models were obtained through backwards stepwise regression and elimination of covariates with p > 0.15. All analyses were performed using STATA (version 12.1) [21].

Overall, 665 HIV-positive pregnant women attended a first ANC visit (Table 1) and 354 (53.2%) at primary care facilities. The median age was 26 years (IQR: 23, 30), the median CD4 count was 387 cells/μl (IQR: 264, 539), 506 (76.1%) had combined WHO stage I/II and 408 (61.4%) were newly diagnosed HIV+. The median gestational age was 22 weeks (IQR: 17, 26) and 131 (19.8%) were primigravida. Overall one third of patients were enrolled during each of the enrolment phases.

Of 665 HIV+ pregnant women, 496 (74.6%) initiated ART (of whom 47 transitioned from single AZT therapy), 70 (10.5%) opted for AZT and 99 (14.9%) received neither. Of the 496 who initiated ART, 454 (91.5%) were on a Tenofovir+Lamivudine+Efavirenz, 3 (0.6%) were on Zidovudine+Lamivudine+Nevirapine, 3 (0.6%) were on Zidovudine+Lamivudune+Efavirenz and 36 (7.3%)) were missing ART regimen data. The proportion of women initiating ART among all individuals increased from 150 (64.7%) to 198 (85.7%) between early to late study implementation phases. Kaplan-Meier estimates for same-day ART initiation was 34.1% (95%CI: 30.7–37.9) and for three-month ART initiation was 74.4% (95%CI: 71.1-77.7). The same-day and six-month ART initiation rate increased from 8.6% (95%CI: 5.6–13.0) to 58.4% (95%CI: 52.2–64.8) and 64.2% (95%CI 58.1–70.4) to 85.7% (95%CI 80.8–89.9; p < 0.001) respectively between early and late enrolment phases (Fig. 1).

In multivariate analysis (Table 1), women with CD4 ≥ 500 (aHR: 0.69, 95%CI 0.56–0.87), missing CD4 (aHR: 0.31, 95% 0.2–0.49) and missing WHO staging result (aHR: 0.40, 95% 0.31–0.52) were less likely to initiate ART. The only positive predictor of ART initiation was entry into the study in later phases (mid: aHR: 1.41, 95% 1.12–1.77; late: aHR: 2.36, 95% 1.89–2.94).

Of 496 women initiated on ART, 250 (50.4%) were in care in the study clinics at the end of the observation period, 4 (0.8%) had died and 37 (7.5%) had transferred out. Of 205 (41.3%) women LTFU, 44/205 (21.5%) never returned for the first drug refill visit. Of 94/205 (45.9%) with recorded delivery date, 34 (36.2%) had the last drug refill visit before delivery. Kaplan-Meier estimated retention was 79.9% (95% CI 76–83.2), 70.7% (95% CI 66.4–74.6) and 52.9% (95% CI 47.6–57.9) at 6, 12 and 24 months. Retention between the CD4 categories was different only for the first 3 months after ART initiation (p = 0.01) but similar thereafter (p = 0.187). In the multivariate model (Table 2), ANC visit in the third trimester (aHR: 2.37, 95% CI 1.39–4.01), secondary care facility (aHR: 1.98, 95% CI 1.50–2.60) and later enrolment phases (mid aHR: 1.48, 95% CI 1.05–2.08; late aHR: 1.67, 95% CI 1.18–2.37) were associated with an increased risk of attrition while the risk was reduced for the age-group 25–34 years (aHR: 0.75, 95% 0.57–0.99). Following defaulter tracing, 34 (40.5%) of 84 mothers traced from those LTFU re-started ART after completion of the retention analysis, and their median time of treatment interruption was 5 months (IQR: 4.0, 7.3).

Of 496 women initiated on ART, 373 were retained in care for at least 6 months, making them eligible for a first VL test. Of these 251 (67.3%) received a first VL test and 223/251 (88.8%) were virologically suppressed (< 1000 copies/mL).

Of 670 infants, 359 (53.6%) received a PCR EID HIV test. A test result was available for 320 (89.1%) infants, of whom 7 (2.2%) were HIV-positive: 3/278 (1.1%) for women on ART, 2/34 (5.9%) for women on AZT and 2/31 (6.5%) for women without ART/AZT; 4/141 (2.8%) for women with CD4 < 350, 1/94 (1.1%) for CD4 350-499 and 1/85 (1.2%) for CD4 ≥ 500. For the 3 infants who tested positive with their mothers on ART, all three women had a suppressed VL test at the time of delivery and the 3 infants received the EID test more than 2 months after delivery and were exclusively breastfed.