van der Merwe, Karin MBBCh*; Chersich, Matthew F MD, MPH†‡; Technau, Karl MBBCh*; Umurungi, Yvonne MBBCh*; Conradie, Francesca MBBCh§‖; Coovadia, Ashraf MBBCh, FCPaeds*
Triple-antiretroviral (ARV) regimens for pregnant women reduce maternal mortality and morbidity; are the most effective method of preventing mother-to-child transmission (MTCT) of HIV; and, by securing the health of women, improve child survival.1,2 ARV treatment, used in high-income countries for a decade, is increasingly becoming available in resource-constrained settings.3 It is anticipated that antenatal clinics can provide entry into HIV treatment and care, together with interventions to reduce MTCT.4
There is widespread consensus that pregnant women with indications for ARV treatment should start treatment during pregnancy.1,5,6 In high-income countries and, increasingly, in Latin America and the Caribbean, triple-ARV prophylaxis is provided during pregnancy and discontinued after childbirth for an HIV-infected woman without indications for ARV treatment.5-7 Data, mostly from high-income countries, have shown that these regimens, initiated as early as 12 weeks of pregnancy, reduce the risk of MTCT to approximately 2%.8-12 Almost all pregnant women with HIV in these settings are offered triple-ARV prophylaxis, regardless of their plasma viral load or CD4 cell count.6,11 Consequently, in 2005, only an estimated 700 children were newly infected with HIV in North America and Western Europe combined.13 This near-elimination of MTCT risk has not been achieved in resource-constrained settings, where less effective regimens are used for MTCT prophylaxis-commonly, single-dose maternal and infant nevirapine (sd-NVP) for HIV-infected women without indications for ARV treatment.
Several factors hinder the uptake of ARV treatment for pregnant women in resource-constrained settings. These include weak linkages between antenatal and ARV treatment services and missed opportunities to identify pregnant women with indications for treatment, mostly because of inadequate access to CD4 cell counts. Further, initiation may be delayed, because many women present late for antenatal care14 and treatment preparation requires several visits. To reduce MTCT maximally, it is necessary for pregnant women to receive ARV treatment for an adequate duration of pregnancy, with consequent virologic suppression, which is particularly important around the time of childbirth.11
The study investigated the effectiveness of interventions to increase the uptake of ARV treatment and reduce delays in initiating treatment during pregnancy. Specifically, effects of strengthening linkages and integrating key components of ARV treatment within antenatal care were examined. Findings of this study could inform ongoing initiatives to provide timely ARV treatment for pregnant women.1,15
The study took place at Coronation Women and Children Hospital, a public health care facility providing secondary-level pediatric and obstetric and gynecology services in Gauteng Province, South Africa. Approval for the study was obtained from the University of the Witwatersrand Human Research Ethics Committee.
As part of routine care, HIV testing and counseling are offered to all pregnant women at their first antenatal visit. Rapid HIV tests (First Response HIV Card test 1-2.0 [Kachigam, Daman, India] and Pareekshak HIV Triline card test [Bangalore, Karnataka, India]) are used for HIV diagnosis, with results available the same day. Women are considered medically eligible for ARV treatment if they have World Health Organization (WHO) clinical stage 4 conditions or a CD4 cell count <250 cells/mm3, which is determined using a Beckman Coulter (Fullerton, CA) Epics XL MCL cytometer and Beckman Coulter TQ PREP. Women who present late in pregnancy and are medically eligible are started on treatment, irrespective of the gestational age of the fetus. HIV-infected pregnant women without indications for ARV treatment receive sd-NVP.
Gestation is determined from a maternal history of the last menstrual period, clinical assessment, and ultrasound, where available. Elective cesarean section for reducing MTCT risk is not considered part of standard care. Women receive infant feeding counseling and support for their choice, including being offered free replacement feeding.
When ARV treatment in the public sector became available in April 2004, pregnant women with indications for ARV treatment were given a referral letter for the Themba Lethu Clinic, Helen Joseph Hospital, located approximately 1 km away, for preparation and initiation of treatment and long-term follow-up. From the outset of the program, pregnant women presenting at Helen Joseph Hospital have been “fast-tracked” into treatment. During the study period, ARV treatment for adults was not available at Coronation Women and Children Hospital.
Evaluation of Service Delivery
The study includes HIV-infected women attending the antenatal clinic between June 2004 and July 2005. In January 2005, an audit evaluated time between HIV diagnosis and ARV treatment initiation and related aspects of service delivery for pregnant women. Hospital records from the ARV treatment clinic were reviewed as well as the records of all women attending the antenatal clinic in the 6-week period from December 1, 2004 to January 13, 2005. Information was extracted on maternal demographics and the number of days between HIV diagnosis and treatment initiation.
Changes in Service Delivery
Changes in service delivery were made to address weaknesses identified in the audit. These interventions, beginning January 15, 2005, aimed to strengthen linkages between antenatal clinics and ARV treatment and to integrate key aspects of ARV treatment within antenatal care (Box 1).
To determine the effectiveness of these interventions, we compared outcomes for women attending the antenatal clinic before and after changes to service delivery. Time-to-treatment initiation before these changes (June 1, 2004-January 13, 2005) is compared with the subsequent 6-month period (January 15, 2005-July 15, 2005). Time-to-treatment initiation is the number of days between HIV diagnosis (made at the first antenatal visit) and initiation of ARV treatment. Other process indicators include time to receiving CD4 cell count results, mean gestation at treatment initiation, and number of weeks ARV treatment is received before childbirth. For the period after changes to service delivery, uptake of ARV treatment is reported (proportion of medically eligible pregnant women who initiate ARV treatment).
Risk of HIV infection among infants born to women receiving ARV treatment during pregnancy is compared with that of woman-infant pairs participating in the sd-NVP program. Using a locally validated protocol,16 HIV diagnosis was determined in infants aged 6 weeks or older with a DNA polymerase chain reaction (PCR) test (Amplicor HIV-1 DNA PCR version 1.5 assay; Roche Diagnostics, Inc., Alameda, CA).
After data checking and cleaning, Intercooled Stata 8.0 (Stata Corporation, College Station, TX) was used for statistical analysis. During analysis, World Health Organization (WHO) clinical stages 3 and 4 were combined. HIV infection in a single or both twins was counted as 1 transmission. Univariate comparisons for categoric variables were tested using a χ2 test or χ2 test for trend. For continuous variables, the Student t test and Wilcoxon rank-sum test were used for comparing data with normal and nonnormal distributions, respectively.
In total, 164 women initiated ARV treatment during pregnancy and 863 women-infant pairs received sd-NVP. Women initiating ARV treatment and those receiving sd-NVP had similar gravidity, mode of delivery, and infant weight (Table 1). Differences in maternal age were detected; women receiving ARV treatment were, on average, 1.3 years older (95% confidence interval [CI]: 0.4 to 2.1 years; P = 0.005) than women in the sd-NVP program. Most women chose replacement feeding: 95.9% (589 of 614) of women receiving sd-NVP and 99.1% (107 of 108) of women taking ARV treatment (P = 0.12).
Most women (88 [76%] of 116) who initiated ARV treatment were asymptomatic (WHO clinical stage 1), 15% (17 of 116) had WHO clinical stage 2 disease, and 9% (11 of 116) had WHO clinical stage 3 or 4 conditions. Of pregnant women who initiated ARV treatment, 9% would have been identified as medically eligible for treatment if the presence of WHO clinical stage 3 or 4 disease were the only criterion for eligibility. The first-line treatment regimen for most women was lopinavir with a ritonavir boost, along with lamivudine and stavudine (155 [94.5%] of 164), with fewer women receiving a combination of NVP (5 [3.1%] of 164) or efavirenz (4 [2.4%] of 164) plus lamivudine and stavudine.
Time-to-Treatment Initiation and Effectiveness of the Program
No differences in baseline maternal characteristics or pregnancy outcomes were detected between women attending the antenatal clinic before and after changes in service delivery. Time-to-treatment initiation, reduced from a median of 56 days before interventions (interquartile range [IQR]: 30-103), was implemented to 37 days thereafter (IQR: 22-63; P = 0.041; Table 2). The median number of days between HIV diagnosis and receiving CD4 cell count results also decreased (50 vs. 29 days; P = 0.047).
HIV diagnosis is not available for 21.3% (219 of 1027) of infants in the study. Five (4.3%) of 116 infants born to women receiving ARV treatment were infected with HIV. This risk of transmission was lower than among women-infant pairs in the sd-NVP program (74 [10.7%] of 692 woman-infant pairs; P = 0.032 by χ2 test). Infants born to women receiving ARV treatment were 2.66 times less likely (95% CI: 1.05 to 6.75; P = 0.032) to be infected with HIV compared with woman-infant pairs in the sd-NVP program.
During the second time period (January 15, 2005-July 15, 2005), 75.4% of eligible women (129 of 171) initiated treatment. Of the 42 women with indications for ARV treatment who declined such treatment, 23 (55%) continued to attend follow-up visits and received sd-NVP. Seventeen percent (4 of 23) of their infants were infected with HIV. To determine whether uptake increased during this period, 2-month intervals were examined; no increase was observed (odds ratio = 1.00; P = 0.78 by χ2 test for trend), however.
In this study, strengthening linkages and integrating key aspects of ARV treatment within antenatal care reduced delays between HIV diagnosis and treatment initiation for pregnant women. Measuring CD4 cell counts at the first antenatal visit seems to be particularly important in reducing delays. Several interventions occurred simultaneously, however, making it difficult to determine the relative importance of each intervention. Inclusion of health workers from ARV treatment services within antenatal clinics aimed to streamline the transition from antenatal care to long-term ARV treatment services, to ensure consistent counseling and messages, and to provide necessary oversight of the program. Despite improvements in service delivery, only three quarters of medically eligible pregnant women initiated ARV treatment. Further improvements in service delivery may be needed to optimize uptake. Similarly, additional attention and resources may be required to achieve high levels of uptake and well-functioning linkages between ARV treatment and other key entry points, such as voluntary testing and counseling sites and clinics for tuberculosis (TB) and sexually transmitted infections. Additional evidence is needed of the specific practical steps necessary for establishing such linkages and reducing missed opportunities for facilitating entry into HIV-related services after an HIV diagnosis.
CD4 cell counts formed a vital link between antenatal and ARV treatment services; approximately three quarters of pregnant women who initiated ARV treatment were asymptomatic, and using clinical criteria alone, few women would have received ARV treatment. To identify pregnant women who require ARV treatment, it may be necessary to include CD4 cell count testing in minimum care packages for pregnant women with HIV. Women with a low CD4 cell count require ARV treatment for their own health as well as having a higher risk for MTCT (even with sd-NVP17 or short-course zidovudine combined with sd-NVP18) and a higher risk of viral resistance after receiving sd-NVP.19 Identifying these women and facilitating their entry into ARV treatment is a high priority for prevention of MTCT programs.1,15,20 In this setting, triple-ARV regimens were highly effective in reducing MTCT among women with indications for ARV treatment. Women with a CD4 cell count >250 cells/mm3 and at lower baseline risk for MTCT were given sd-NVP but had a 2.7-fold higher MTCT risk than immunosuppressed women who received ARV treatment.
Initiation of ARV treatment is not a clinical emergency, and adequate preparation is required. For pregnant women, accelerated initiation is necessary to decrease MTCT risk, however. Difficulties with timely initiation of ARV treatment during pregnancy are compounded by health-seeking patterns in these settings. In Latin America, the Caribbean, the Middle East, and North Africa, two thirds of women present for antenatal care in the first trimester of pregnancy; in Asia, nearly half of women present for antenatal care at this time.14 In contrast, most women in sub-Saharan Africa present for antenatal care in the second trimester of pregnancy, and a substantial proportion are only seen in the third trimester.14 Given these patterns, to ensure timely initiation of ARV treatment, particular attention is needed to optimize each contact with pregnant women.
Data on effectiveness of prevention of MTCT services at Coronation Women and Children Hospital and interventions to improve these services have previously been published.21,22 The findings of this study are consistent with those of previous reports, showing that regular audits and monitoring, accompanied by corrective action, can substantially improve service delivery.22 Inherent limitations of comparing outcomes of service delivery before and after an intervention restrict the ability to interpret and generalize study findings, however. In particular, it is possible that changes observed between the 2 time periods are attributable to improvements that occur naturally over time as new services become established. Nevertheless, given the magnitude of improvements in service outcomes, this seems unlikely to be solely attributable to changes over time. A further study limitation is the amount of unavailable data. Information in hospital records was recorded for other purposes, thus limiting data extraction and resulting in missing information. A substantial proportion of infants have an unknown HIV status. Similar difficulties with infant follow-up have been reported from other settings.23-25
Implementation of ARV treatment is an important opportunity to strengthen existing health systems, including services for HIV-related prevention and care.26 This study further demonstrates that additional inputs available for implementing ARV treatment may, with adequate planning, have positive spin-offs, such as preventing HIV infection in infants.
Study activities took place as part of routine hospital services in collaboration with staff from the Gauteng Province Department of Health. The authors acknowledge Professor K. Bolton and Ms. S. Jordaan for supporting this program and the interhospital collaboration. Dr. S. Luchters and Professor M. Temmerman provided incisive revisions on several manuscript drafts. The authors thank the antenatal clinic staff at Coronation Women and Children Hospital who implemented study activities, particularly Jeffrey Mhlauli, the counselor coordinator.
1. WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Available at: http://www.who.int/hiv/pub/mtct/guidelines/en/
. Accessed September 28, 2006.
2. Tuomala RE, Watts DH, Li D, et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr
4. Askew I, Berer M. The contribution of sexual and reproductive health services to the fight against HIV/AIDS: a review. Reprod Health Matters
6. Public Health Service Task Force. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. Available at: http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf
. Accessed September 28, 2006.
7. Ministério da Saudé, Brasil. Recomendações para Profilaxia da Transmissão Vertical do HIV e Terapia Anti-retroviral em Gestantes
8. Marazzi M, Germano P, Liotta G, et al. Safety of nevirapine-containing antiretroviral triple therapy regimens to prevent vertical transmission in an African cohort of HIV-1-infected pregnant women. HIV Med
9. Read J, Cahn P, Losso M, et al. A prospective cohort study of HIV-1-infected pregnant women and their infants in Latin America and the Caribbean: the NICHD International Site Development Initiative Perinatal Study [abstract 790]. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; 2005; Boston.
10. Morris AB, Dobles AR, Cu-Uvin S, et al. Protease inhibitor use in 233 pregnancies. J Acquir Immune Defic Syndr
11. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis
12. Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA
15. Ekpini RE, Gilks C. Antiretroviral regimens for preventing HIV infection in infants. Bull World Health Organ
16. Sherman GG, Cooper PA, Coovadia AH, et al. Polymerase chain reaction for diagnosis of human immunodeficiency virus infection in infancy in low resource settings. Pediatr Infect Dis J
17. Nakabiito C, Guay LA, Musoke P, et al. Effect of nevirapine (NVP) for perinatal HIV prevention appears strong among women with advanced disease: subgroup analyses of HIVNET 012 [abstract TuOrB1174]. Presented at: XIV International AIDS Conference; 2002; Barcelona.
18. Dabis F, Bequent L, Ekouevi DK, et al. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS
19. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS
20. Chersich MF, Gray GE. Progress and emerging challenges in preventing mother-to-child transmission. Curr Infect Dis Rep
21. Sherman GG, Jones SA, Coovadia AH, et al. PMTCT from research to reality-results from a routine service. S Afr Med J
22. Urban M, Chersich M. Acceptability and utilisation of voluntary HIV testing and nevirapine to reduce mother-to-child transmission of HIV-1 integrated into routine clinical care. S Afr Med J
23. Kagaayi J, Dreyfuss ML, Kigozi G, et al. Maternal self-medication and provision of nevirapine to newborns by women in Rakai, Uganda. J Acquir Immune Defic Syndr
24. Perez F, Mukotekwa T, Miller A, et al. Implementing a rural programme of prevention of mother-to-child transmission of HIV in Zimbabwe: first 18 months of experience. Trop Med Int Health
25. Quaghebeur A, Mutunga L, Mwanyumba F, et al. Low efficacy of nevirapine (HIVNET012) in preventing perinatal HIV-1 transmission in a real-life situation. AIDS
26. Gayle H, Lange JM. Seizing the opportunity to capitalise on the growing access to HIV treatment to expand HIV prevention. Lancet
© 2006 Lippincott Williams & Wilkins, Inc.