Over the 6 months before rollout of Option B+, 34 (24%) women initiating ART were pregnant/breastfeeding, including 3 early Option B+ initiations at the hospital; excluding these 3 and 1 woman who was not WHO staged, 21 of 30 (70%) had WHO stage 3/4 disease. In contrast, in the first quarter after Option B+ rollout, initiations rose to 269 among pregnant/breastfeeding women (corresponding to a 16-fold increase) and then reduced to 82, 42, and 42 in the subsequent 3 quarters (a 6-fold increase over the first year after Option B+). After Option B+, 59 of 435 (13%) pregnant/breastfeeding women were WHO stage 3 at ART initiation and none had stage 4 disease. CD4 data were incomplete [only 190 of 376 (51%) with WHO stage 1/2 had a CD4 recorded]; 64 (34%) stage 1/2 women had ≤350 cells per cubic millimeter and 47 (25%) had 351–500 cells per cubic millimeter, implying that overall, 43% of pregnant/breastfeeding women would have been eligible for treatment of their own health based on WHO 2010 disease progression criteria (WHO stage 3/4 or CD4 ≤350 cells per cubic millimeter) or 64% based on WHO 2013 criteria (WHO stage 3/4 or CD4 ≤500 cells per cubic millimeter). Median age at ART initiation in pregnant/breastfeeding women was similar pre- and post-Option B+ (Table 1); but the proportion of adolescents younger than 20 years increased from 1 (3%) before Option B+ to 25 (7%) in the first 6 months and 13 (15%) in the second 6 months post-Option B+ (trend P = 0.008).
In Zowa, a primary care facility, where ART provision was started later and alongside Option B+ rollout (from April 2014), there were 54 ART initiations, including 6 in children younger than 15 years (Fig. 1).
Median follow-up in individuals newly initiating ART was 8 (3–11) months. Retention on ART in 1140 adults who started ART for disease progression (all patients pre-Option B+ implementation; pregnant/breastfeeding women with WHO stage 3/4 disease, and nonpregnant/breastfeeding patients post-Option B+ implementation) was 95% (95% confidence interval: 93% to 96%) at 6 months, including 12 deaths and 39 losses to follow-up (LTFU); 12-month retention was 93% (91%–95%) (18 deaths, 40 LTFU). Figure 2A shows the cumulative incidence of death and default across all sites. Retention varied between sites (Table 2; P < 0.001); 12-month retention in the primary care facilities was 86% (80%–90%) compared with 98% (96%–99%) at the hospital. There was no evidence that retention-in-care was worse when ART was initiated after Option B+ had rolled out compared with before Option B+ (Table 2). Retention was higher in patients with higher CD4 and lower in pregnant/breastfeeding patients (pre-Option B+ or also WHO stage 3/4); when we looked at the risks of death and LTFU separately, the CD4 effect was predominantly because of an increased risk of death in patients with low CD4, whereas pregnancy/breastfeeding predicted higher LTFU but not higher mortality (Table 3). Among WHO stage 1/2 patients, those with CD4 >350 had similar retention to those with CD4 ≤350 [HR: 1.11 (0.63–1.94)].
Retention on ART in 386 women who newly started ART for Option B+ was 85% (81%–88%) at 6 months (1 death, 53 LTFU) and 79% (69%–87%) at 12 months (3 deaths, 55 LTFU); this was significantly lower than retention in the adults starting ART for WHO 3/4 or CD4<threshold [across all periods: HR 3.09 (2.15–4.46), P < 0.001; restricted to March 2014 onward: HR 4.00 (2.59–6.09), P < 0.001]. Retention differed markedly by age at initiation, being lower in younger women (Table 2 and Fig. 2B). Retention did not differ by pre-ART CD4 (Table 2). Although 32 women were LTFU by 1 month, 20 of 32 attended 1 post-ART initiation visit (median 14 days after starting ART). Importantly, in the subgroup of women who started ART during pregnancy/breastfeeding with WHO stage 3/4 or CD4 ≤350, there was no evidence for worse retention after Option B+ implementation than before [HR: 0.78 (0.28–2.16)].
Among 145 children younger than 15 years at ART initiation, there were 3 (2%) deaths, 16 (11%) LTFU, and 10 (7%) transfers-out. The 3 children who died were all seen at the hospital; two 3-year-olds died very soon after starting ART (13 days; 45 days) and one 2-year-old died 12 months after initiation. At 6 months, retention on ART was 87% (80%–92%) and at 12 months it was 85% (77%–91%). We found no evidence that retention at 12 months in the primary care facilities [94% (83%–98%)] was worse than at the hospital [79% (67%–88%)].
Retention on ART in the 402 individuals who transferred into one of the facilities already on ART was 95% (92%–97%) 6 months after transfer (0 death, 18 LTFU) and 94% (90%–96%) (0 death, 20 LTFU) at 12 months. Over half the individuals LTFU (11/20) did not return after their first registration visit.
The last 5 years have seen rapid changes in both PMTCT guidance and practice and CD4 threshold recommendations for ART initiation. The Lablite project13 was working with Ministries of Health in Malawi, Zimbabwe, and Uganda between 2011 and 2015 and collating routine data on ART rollout in nonresearch facilities in rural areas. In Zimbabwe, this provided an important opportunity to compare ART initiations and retention on ART before and after introduction of Option B+ and the increase in CD4 threshold.
We found that after Option B+ implementation and the increased CD4 threshold, greater numbers of all patients started ART, including children. Patients who started ART at CD4 >350 or for Option B+ (with high CD4) inevitably did so as a result of guideline changes; however, increases in other patient groups may have occurred anyway. Devolvement of ART care to the primary care staff with support from MOHCW allowed management of increasing patient numbers. However, drug supply remains a concern; although no stock-outs of ART were reported, there were anecdotal reports of patients having to return to clinic in between scheduled visits to collect ART because of low supplies, and stock-outs of cotrimoxazole did occur.
Overall mortality was low and retention in care was extremely good in patients starting ART for disease progression (93% at 12 months), better than reported for the ART program in Zimbabwe between 2007 and 201015 and in other settings.16 Retention was higher at the hospital than in the primary care facilities, possibly because of the Lablite model of training whereby hub staff received additional training to mentor staff at primary care facilities. Encouragingly, we found no evidence that introduction of Option B+ had a detrimental effect on retention of patients starting ART for disease progression. Retention on ART was poorer in Option B+ women than in other adults starting ART, as found in Malawi,17 but similar to retention reported in other rural districts of Zimbabwe (83%).18 At all 4 Lablite facilities, women were asked to start ART immediately; for many, HIV is a new diagnosis after routine testing during antenatal care, and qualitative work suggests that immediate treatment may be difficult because of the limited time available to digest a positive HIV diagnosis and understand and form decisions around the uptake of a new lifelong treatment.17,19
CD4 counts were obtained for 85% of men and nonpregnant/breastfeeding women before ART with no drop in testing after Option B+ implementation or increase in CD4 threshold. Numbers of men and nonpregnant/breastfeeding women starting ART with CD4 >350 were encouraging, suggesting these individuals can be identified, although we could not distinguish individuals newly diagnosed from those already in pre-ART HIV care. Despite this, a significant proportion of individuals still start ART with low CD4s, particularly men, who are more likely to present later than women.20,21 Around half Option B+ women had a pre-ART CD4 recorded; facilities were asked to continue providing CD4s (unlike in Malawi where CD4s are not offered to pregnant/breastfeeding women13); it is unclear whether remaining women had no CD4 measured or whether it was not recorded. Assuming recorded CD4s were representative in Option B+ women, importantly >40% pregnant/breastfeeding women needed ART for their own disease (either WHO stage 3/4 or CD4 ≤350), consistent with other studies.22 It is important that these women are retained on ART for their own health and to prevent MTCT; health care workers may need focused training to support retention of Option B+ women with low CD4 counts.
Among Option B+ women, almost all attrition was recorded as LTFU; unrecorded deaths are unlikely to be a major contributor but we cannot distinguish between women who have “silently” transferred to other health facilities and those who have dropped out of care completely. Age was a clear factor in predicting LTFU, with younger women more likely to be lost. This corroborates findings in Malawi23,24 and Zimbabwe.18 Targeted support measures are needed for the increasing numbers of HIV-infected adolescent and young pregnant women starting ART. We were only able to look at retention on ART to 12 months, and it is important to recognize that losses in this period, most of which were very early, are likely to have been during pregnancy or breastfeeding. In Malawi, it is estimated that half of those lost in the first 6 months may never have started ART.8 In Zimbabwe, patients are asked to return to clinic 2 weeks after starting ART, which is earlier than elsewhere (including Malawi). We found that around 2/3 of women who were lost by 1 month had returned for their 2-week visit; this raises concerns that they took ART for only a short time and may now have developed resistance as the half-life of efavirenz may be much longer than other drugs. Data from Malawi suggest that the risk of LTFU is much lower after the first year24; however, it will be some time before comparable data are available for Zimbabwe.
In Zimbabwe since Option B+ rollout, policy has been to encourage male partners to attend antenatal care with pregnant women and to provide them with ART, irrespective of their own CD4 count. However, this seems to have happened very rarely (only 3 men). Initiatives to engage men are critical as lack of male involvement and the complex dynamics between the women and their partners including concerns about stigma are cited by health care workers as a common reason for nonretention among women on Option B+.25,26
Historically, HIV-infected children have been seen in secondary and tertiary health care facilities in Zimbabwe,27 so it was encouraging to see ART initiations in under 15's at all facilities, including the new primary care facility (where ART provision was introduced alongside Option B+). However, similar to other studies,28 children younger than 24 months were treated almost exclusively at the hospital, suggesting possible reluctance to test and treat infants in primary care. Retention on ART was also somewhat lower in children than in adults starting ART outside of Option B+. Previous studies of retention in care of HIV-exposed and HIV-infected children have identified a range of possible risk factors, including characteristics of the carer for mortality and LTFU29−31; further research is needed to develop strategies to mitigate losses.
After the START and TEMPRANO trials,32,33 WHO released new guidelines recommending that all HIV-infected individuals should start treatment as soon as possible after a positive diagnosis.34 It is unclear how quickly this recommendation will be taken up in sub-Saharan Africa. Our early data on uptake of treatment in individuals with CD4 >350 after the rise in threshold suggest that there will be demand. If adopted, lessons may be learned from Option B+ rollout; immediate treatment after provider-initiated testing in “well” patients may not be dissimilar. In particular, adopting treatment for all may facilitate retention of pregnant/breastfeeding women by reducing the current disparity in access to ART between women and their partners.
Strengths of the Lablite project include the study of rural MOHCW facilities with little/no research experience and use of routine data collected from paper records. This contrasts with much of the existing Option B+ operations research, which primarily focuses on larger health facilities with electronic data capture. Additionally, we have data before and after the introduction of Option B+ and changes in WHO CD4 threshold guidelines and across all patient groups. The primary weaknesses include lack of information on the underlying causes of patients LTFU (common to most studies) and use of a retrospective definition of LTFU (often used in analysis of routinely collected data where visit data may be incomplete). Our study is limited to 4 facilities and it remains important to collate further data to determine how generalizable our findings are.
The Lablite Team comprises: Dignitas International, Zomba, Malawi: F.C., A.K.C., L. Chiwaula, M.J.N., J. J. van Oosterhout, G.Mateyu, M. Willie; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: F. Mirimo, S. Kiwuwa, J.S.; Joint Clinical Research Centre, Kampala, Uganda: G.A., C.K., Harriet Namata; University of Zimbabwe, Harare, Zimbabwe: J.H., T.M., M.M., A.R., M.N.; Infectious Diseases Institute, Makerere University, Mulago, Uganda: S. Kaggwa, E.K., I. Mambule. School of Population Health, University of Queensland, Australia: C.F.G.; Centre for Health Economics, University of York, UK: P. Revill; MRC Clinical Trials Unit at UCL, London, United Kingdom: D.F., D.M.G., C.G., S. Hoskins, S.J., A. South, M. Thomason. Independent Chair of the Project Management Group: I. Weller. The Lablite Zimbabwe team acknowledges the guiding role of the Central Ministry of Health and Child Care including Provincial Medical Directorates, City of Harare Directorate of Health Services, District Health Executive Teams, and all facility staff involved. The authors also extend their gratitude to the former DART staff at the University of Zimbabwe Clinical Research Centre.
1. World Health Organization 2013. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection. Available at: http://http://www.who.int
/hiv/pub/guidelines/arv2013/download/en/index.html. Accessed October 21, 2015.
2. Fowler MG, Qin M, Fiscus SA, et al. PROMISE: efficacy and saftey of 2 strategies to prevent perinatal HIV transmission. CROI 2015. Available at: http://http://www.croiconference.org
/sessions/promise-efficacy-and-safety-2-strategies-prevent-perinatal-hiv-transmission. Accessed January 12, 2016. 2015.
3. Clinical Management of HIV in Children and Adults. Malawi Integrated Guidelines: Malawi: Ministry of Health; 2011.
4. World Health Organization 2015. Global Health Sector Response to HIV, 2000–2015: Focus on Innovations in Africa: Progress Report. Available at: http://apps.who.int/iris/bitstream/10665/198065/1/9789241509824_eng.pdf?ua=1. Accessed January 12, 2016.
5. Schouten EJ, Jahn A, Midiani D, et al. Prevention of mother-to-child transmission of HIV and the health-related Millennium Development Goals: time for a public health approach. Lancet. 2011;378:282–284.
6. Kieffer MP, Mattingly M, Giphart A, et al. Lessons learned from early implementation of option B
+: the Elizabeth Glaser Pediatric AIDS Foundation experience in 11 African countries. J Acquir Immune Defic Syndr. 2014;67(suppl 4):S188–S194.
7. Impact of an innovative approach to prevent mother-to-child transmission of HIV–Malawi, July 2011–September 2012. MMWR Morb Mortal Wkly Rep. 2013;62:148–151. See ref. https://http://www.cdc.gov
8. Integrated HIV Program Report January–March 2015. Government of Malawi: Malawi: Ministry of Health; 2015.
9. An Operational Plan for the Nationwide Transition to Option B
+ in Zimbabwe. Zimbabwe: Ministry of Health and Child Care; 2013.
10. National Medicine and Therapeutics Policy Advisory Committee (NMTPAC) and The AIDS and TB Directorate. Guidelines for Antiretroviral Therapy
for the Prevention and Treatment of HIV in Zimbabwe: Zimbabwe: Ministry of Health and Child Care; 2013.
11. World Health Organization 2014. Global Update on the Health Sector Response to HIV, 2014. Available at: http://apps.who.int/iris/bitstream/10665/128494/1/9789241507585_eng.pdf?ua=1. Accessed January 5, 2016.
12. National AIDS Council of Zimbabwe. 2015. Global AIDS Response Country Progress Report Zimbabwe 2014. Available at: http://http://www.nac.org.zw
/sites/default/files/Zimbabwe%20Country%20report2014_0.pdf. Accessed January 12, 2016.
13. The Lablite Project. Available at: http://lablite.org/Accessed January 5, 2016.
14. Tai BC, White IR, Gebski V, et al. On the issue of “multiple” first failures in competing risks analysis. Stat Med. 2002;21:2243–2255.
15. Mutasa-Apollo T, Shiraishi RW, Takarinda KC, et al. Patient retention, clinical outcomes and attrition-associated factors of HIV-infected patients enrolled in Zimbabwe's National Antiretroviral Therapy
Programme, 2007–2010. PLoS One. 2014;9:e86305.
16. Tassie JM, Baijal P, Vitoria MA, et al. Trends in retention on antiretroviral therapy
in national programs in low-income and middle-income countries. J Acquir Immune Defic Syndr. 2010;54:437–441.
17. Tenthani L, Haas AD, Tweya H, et al. Retention in care under universal antiretroviral therapy
for HIV-infected pregnant and breastfeeding women (“Option B
+”) in Malawi. AIDS. 2014;28:589–598.
18. Dzangare J, Takarinda KC, Harries AD, et al. HIV testing uptake and retention in care of HIV-infected pregnant and breastfeeding women initiated on “Option B
+” in rural Zimbabwe. Trop Med Int Health. 2015;21:202–209.
19. Cataldo F. Exploring women and health care workers experiences in the context of PMTCT Option B
Plus in Malawi. Oral presentation at ICASA; December 7–11, 2013; Capetown. Abstract 2429707.
20. Cornell M, Schomaker M, Garone DB, et al. Gender differences in survival among adult patients starting antiretroviral therapy
in South Africa: a multicentre cohort study. PLoS Med. 2012;9:e1001304.
21. Takarinda KC, Harries AD, Shiraishi RW, et al. Gender-related differences in outcomes and attrition on antiretroviral treatment among an HIV-infected patient cohort in Zimbabwe: 2007–2010. Int J Infect Dis. 2015;30:98–105.
22. Carter RJ, Dugan K, El-Sadr WM, et al. CD4+ cell count testing more effective than HIV disease clinical staging in identifying pregnant and postpartum women eligible for antiretroviral therapy
in resource-limited settings. J Acquir Immune Defic Syndr. 2010;55:404–410.
23. Tweya H, Gugsa S, Hosseinipour M, et al. Understanding factors, outcomes and reasons for loss to follow-up among women in Option B
+ PMTCT programme in Lilongwe, Malawi. Trop Med Int Health. 2014;19:1360–1366.
24. Haas AD, Tenthani L, Msukwa MT, et al. Retention in care during the first 3 years of antiretroviral therapy
for women in Malawi's option B
+ programme: an observational cohort study. Lancet HIV. 2016;3:e175–182.
25. Mills EJ, Beyrer C, Birungi J, et al. Engaging men in prevention and care for HIV/AIDS in Africa. PLoS Med. 2012;9:e1001167.
26. Sonke Gender Justice Project 2015. Available at: http://http://www.genderjustice.org.za
/publication/unaids-2015-discussion-paper/. Accessed March 5, 2016.
27. AIDS and TB Unit. The National OI/ART Programme Annual Report, 2009. Zimbabwe: Ministry of Health and Child Welfare; 2009.
28. Fayorsey RN, Saito S, Carter RJ, et al. Decentralization
of pediatric HIV care and treatment in five sub-Saharan African countries. J Acquir Immune Defic Syndr. 2013;62:e124–130.
29. Tene G, Lahuerta M, Teasdale C, et al. High retention among HIV-infected children in Rwanda during scale-up and decentralization
of HIV care and treatment programs, 2004 to 2010. Pediatr Infect Dis J. 2013;32:e341–347.
30. Sengayi M, Dwane N, Marinda E, et al. Predictors of loss to follow-up among children in the first and second years of antiretroviral treatment in Johannesburg, South Africa. Glob Health Action. 2013;6:19248.
31. Bigna JJ, Noubiap JJ, Plottel CS, et al. Factors associated with non-adherence to scheduled medical follow-up appointments among Cameroonian children requiring HIV care: a case-control analysis of the usual-care group in the MORE CARE trial. Infect Dis Poverty. 2014;3:44.
32. Group ISS; Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy
in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807.
33. Group TAS, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373:808–822.
34. World Health Orgnaization September 2015. Guideline on when to Start Antiretroviral Therapy
and on Pre-exposure Prophylaxis for HIV. Available at: http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1. Accessed January 12, 2016.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
antiretroviral therapy; Option B+; CD4 threshold; decentralization; primary health care