Prevention of mother-to-child transmission services as a gateway to family-based human immunodeficiency virus care and treatment in resource-limited settings: rationale and international experiences

Article Outline

• Abstract
• The rationale for linking PMTCT and HIV treatment services
• PMTCT services as a gateway to family-based HIV care and treatment
• The MTCT-Plus Initiative
• Conclusion
• Acknowledgments
• References
• Copyright

In many developing countries, services to prevent the mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) operate with limited contact with HIV care and treatment programs, despite significant advances in the accessibility of both services. There is a need to deliver more complex multidrug PMTCT interventions that extend beyond single-dose nevirapine, particularly for pregnant women with advanced HIV disease who are at high risk of transmitting HIV to their children and require rapid initiation of life-long highly active antiretroviral therapy. We argue for strengthened ties between PMTCT services and HIV care and treatment programs in resource-limited settings, viewing PMTCT programs as a gateway to family-based HIV care and treatment. Existing experiences from the multicountry MTCT-Plus Initiative suggest that close ties between PMTCT services and HIV care and treatment programs are feasible and can lead to significant advances in reducing the vertical transmission of HIV and promoting the health of HIV-infected women, children, and families.

Key words: antiretroviral therapy, child health, health systems, human immunodeficiency virus, mother-to-child transmission, women’s health

With more than 15 million human immunodeficiency virus (HIV)-infected women living in developing countries and more than 500,000 HIV-infected infants born each year, the HIV/Acquired Immunodeficiency Syndrome (AIDS) epidemic presents an unprecedented challenge to maternal and child health.¹ In response, there have been important steps in the areas of HIV prevention and treatment towards mitigating the impact of the epidemic among women and children in developing countries.

Efforts to identify HIV-infected women during pregnancy and prevent the mother-to-child transmission (PMTCT) of HIV have made important inroads in the prevention of pediatric HIV, primarily through the use of single-dose nevirapine (SD-NVP).² Although SD-NVP programs have proven feasible to implement in a wide range of antenatal care settings, further efforts to prevent the vertical transmission of HIV face significant hurdles. In many countries, low levels of uptake of antenatal and obstetric services mean that only a fraction of HIV-infected women can receive PMTCT interventions.³ There is also evidence to suggest that the effectiveness of PMTCT programs in preventing pediatric HIV may be somewhat less than that demonstrated in clinical trials. This may be due in large part to difficulties in maintaining high levels of compliance with SD-NVP protocols in busy public sector services where HIV-infected pregnant women do not receive intensive education and adherence support. One analysis of an urban PMTCT service in Zambia suggested that approximately one-third of HIV-infected women who were dispensed SD-NVP did not take it.⁴ In this light, initiatives to further reduce the vertical transmission of HIV around the world will require more intensive interventions delivered on a broader scale.

There have also been recent advances in many developing countries in the accessibility of HIV care and antiretroviral treatment services. A number of reports have demonstrated that the use of highly active antiretroviral therapy (HAART) in these settings can achieve outcomes comparable to those in United States and Europe,⁵, ⁶ and experience in the use of antiretroviral drugs is increasing rapidly in many developing countries.

The parallel expansion of PMTCT and HIV treatment around the world has challenged many national and international health programs to consider the practical interactions between these services. In many local health services and national health systems, PMTCT is the concern of maternal and child health. HIV care and treatment services have generally been developed as stand-alone clinical services, often with limited integration with HIV prevention efforts or existing primary health care services.

This separation may prevent both services from achieving their overall aims of preventing new HIV infections and providing optimal care to individuals who are HIV-infected. Here, we review the potential interface between PMTCT services and HIV treatment programs in developing countries. After discussing the benefits of integrating these services, we argue for an approach in which PMTCT services are viewed as a gateway for HIV-infected women and their families to comprehensive HIV care and treatment.

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The rationale for linking PMTCT and HIV treatment services 

In many developing countries, particularly in sub-Saharan Africa, antenatal care clinics (ANC) are among the most frequently utilized services of the public sector health system.⁷ Primary care antenatal and obstetric services are usually run by nurse-midwives with minimal access to specialists, and high patient-to-provider ratios are the norm. The simplicity of SD-NVP has allowed widespread coverage of PMTCT in this context, but delivering more complex multidrug PMTCT interventions may be less straightforward. Enhanced linkages between HIV treatment programs and PMTCT services can facilitate the introduction of more complex antiretroviral regimens, including HAART for women with advanced HIV disease who require treatment for their own health, as well as 2- and 3-drug combinations for pregnant women who do not yet need chronic therapy.

Women with advanced HIV disease, as defined by high viral load, low CD4 count, and AIDS, are at the greatest risk of transmitting the virus during pregnancy and delivery as well as postpartum through breastfeeding.⁸, ⁹, ¹⁰, ¹¹ Maternal viral load was the strongest predictor of vertical transmission of HIV in a study of PMTCT in Thai women.⁹ Similarly, in an analysis of late postnatal transmission, lower maternal CD4 count was associated with a significantly higher risk of transmission through breastfeeding.¹⁰ It is in this subset of pregnant women with advanced HIV disease in which HAART, beyond simpler 1- or 2-drug strategies, can have the greatest impact on reducing MTCT.

There are also significant advantages to the use of more complex regimens for women with less advanced disease. In settings in which HAART is used during pregnancy for almost all HIV-infected women, such as the United States and Western Europe, MTCT rates have dropped dramatically.¹², ¹³ However, several simpler and less costly PMTCT regimens, such as SD-NVP with either short-course zidovudine or zidovudine and lamivudine, have demonstrated efficacy greater than SD-NVP alone and are highly effective for preventing transmission, particularly in women with less advanced disease.¹⁴, ¹⁵

If PMTCT programs in developing countries are to achieve successes in preventing pediatric infections similar to those seen in well-resourced countries, PMTCT services need to be able to deliver more complex antiretroviral regimens. In addition to access to the appropriate antiretroviral drugs, this will require the ability to assess HIV disease state, rapidly identify the subset of pregnant women with advanced HIV disease who require HAART, expedite the initiation of treatment, and closely monitor drug toxicity. While short-course regimens are less demanding than HAART therapy, they will also require a level of monitoring and support not routinely needed for the administration of SD-NVP. Given the limited capacity of most ANC and PMTCT services, it is unlikely that these activities will be integrated successfully into PMTCT programs without significant support. For this reason, it will be critical to link HIV care and treatment services, in which the expertise to administer multidrug regimens is well established, with PMTCT services, thereby enhancing the capacity of PMTCT programs to offer more complex regimens and more comprehensive services.

One example of the potential interface between PMTCT and HIV care and treatment services in a low-resource setting comes from the Western Cape Province of South Africa. All HIV-infected pregnant women identified through PMTCT services undergo immunologic testing. Pregnant women with CD4-positive counts greater than 200 cells/μL receive a 2-drug regimen of short-course zidovudine and SD-NVP for PMTCT, whereas those with CD4-positive counts of 200 or fewer cells/μL are immediately referred to separate HIV treatment facilities for a “fast-track” evaluation and HAART initiation.¹⁶ Instituted in 2004, this dual strategy has now been implemented on a wide scale and has contributed to the Province’s overall low rate of vertical transmission of HIV, estimated at approximately 6% to 8%.¹⁷ In addition to the enhanced PMTCT benefits, this dual strategy facilitates the entry of women into chronic HIV treatment.

Despite the success of this approach, there have been concerns that the need to refer women requiring HAART from PMTCT services to separate HIV treatment centers may lead to delays in HAART initiation because of administrative complexities and the difficulties that women face in seeking care at another facility. For example, at many sites in the Western Cape, the separate location of PMTCT and HIV treatment services means that HIV-infected women with CD4 counts below 200 cells/μL are referred to initiate HAART at facilities that are several kilometers away from the ANC/PMTCT service and are expected to regularly attend separate follow-up visits at both ANC/PMTCT and HIV treatment services.

Anecdotal evidence suggests that there is substantial loss to follow-up of pregnant women with advanced HIV disease in this referral system (with women not completing distant referrals and failing to initiate HAART during the antenatal period as a result). In response to this, public sector PMTCT services in the community of Khayelitsha in Cape Town, which are managed with support from Médecins Sans Frontières, have instituted a different approach to linking services. Pregnant HIV-infected women with advanced HIV disease initiate HAART and clinical follow-up entirely within PMTCT clinics, through “outreach” or satellite clinics operated within PMTCT programs by the local HIV treatment service. This approach streamlines the rapid initiation of HAART during pregnancy and reduces the likelihood that women will be lost or treatment will be delayed. This approach also requires more intensive involvement of providers from HIV treatment services and active coordination between the 2 services.

Other models to link PMTCT and HIV care and treatment services have been explored within the Columbia University Mailman School of Public Health MTCT-Plus Initiative, a multicenter program in sub-Saharan Africa and Thailand that uses PMTCT as a platform to provide comprehensive HIV care to women and their families.¹⁸ In several sites, peer workers trained to provide support and education to newly diagnosed HIV infected women, also play the role of patient navigator, assisting and accompanying pregnant women as they make and attend appointments in HIV care clinics.

In some programs, HIV clinics have identified a weekly session during which pregnant women are seen so that their enrollment and treatment initiation can be expedited. At most sites, multidisciplinary teams of HIV providers, including staff from PMTCT as well as HIV treatment clinics, meet weekly to review and discuss new patients, creating a venue to discuss, track, and assure that eligible pregnant women are successfully initiating treatment. Although the advantages and limitations of different models for the provision of HAART to pregnant women require further investigation and will need to be tailored to a variety of settings, these experiences suggest the types of linkages that are possible between PMTCT and HIV care and treatment programs.

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PMTCT services as a gateway to family-based HIV care and treatment 

The rationale for linking these services also extends beyond enhancing PMTCT interventions. Antenatal services are a critical venue for the identification of HIV-infected women for long-term HIV care and treatment. For example, 1 recent analysis from Lusaka, Zambia suggests that more than 10,000 HIV-infected women could be identified annually through the city’s PMTCT services.¹⁹ PMTCT services provide one of the few opportunities to identify women across the spectrum of HIV disease, including asymptomatic patients and those with advanced disease. In addition to HAART and prophylaxis against opportunistic infections, there are important interventions that can promote the long-term health of HIV-infected women with earlier stages of HIV disease by reducing morbidity and delaying HIV disease progression.²⁰ These include case finding and treatment for tuberculosis, malaria prevention interventions, nutritional supplementation, and family planning.

To date, most HIV care and treatment services in resource-limited countries have approached HIV-infected adults and children as individual patients, with little recognition of the effect of HIV on entire families. In many health systems, pediatric and adult HIV services are often in different locations, provided by distinct groups of providers, with little effort to coordinate care for mothers, children, and families. Such an approach overlooks the potential benefits of directing services toward families. By recognizing the mother–child dyad as a principal unit of care, PMTCT services can help to change this view of HIV care and treatment to increase the emphasis on family-centered services.

A family-centered approach offers the ability to reach and retain a greater number of HIV-infected family members. Throughout the world, women are at the center of families and households. By identifying HIV-infected women through PMTCT programs and enrolling them into family-based care, health services are more likely to access other HIV-infected household members. A family-centered approach may be particularly important for pediatric care because children frequently receive less attention in HIV care and treatment services than adults. With postnatal follow-up, PMTCT programs afford the opportunity to identify and follow up both HIV-exposed and infected children; with appropriate links to care and treatment, these children can receive routine health interventions such as co-trimoxazole and isoniazid prophylaxis.

For HIV-infected children, a family-based approach may help ensure better access to services and retention in care than if parents’ and children’s services are provided separately and in different locations. Also, engaging families affords an opportunity to identify family and household members at earlier stages of HIV disease and to provide interventions aimed at slowing disease progression. Late entry into care for adults has been associated with poor outcomes in response to HAART.⁶, ²¹ More generally, the retention of patients in long-term primary care services is a ubiquitous concern for HIV treatment programs, and having families receiving care at the same facility facilitates patient follow-up over time. For example, among patients on antiretroviral therapy (ART), the support provided by family members is likely to be an important determinant of treatment adherence.²²

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The MTCT-Plus Initiative 

Despite the potential benefits of using PMTCT services as an entry point to long-term HIV care and treatment, few programs in resource-limited settings have recognized this unique potential of PMTCT programs. The MTCT-Plus Initiative provides a leading example of the feasibility and benefits of such integration.¹⁸ The concept of MTCT-Plus builds on existing PMTCT programs, which often offer little medical care to HIV-infected women and their families.²³ MTCT-Plus programs enroll HIV-infected women identified through antenatal or postnatal PMTCT services. Women receive a comprehensive package of care adapted to their stage of HIV disease, and they serve as the index patient for family-centered HIV care and treatment services. Women enroll their newborn infants; other HIV-infected family and/or household members, including male partners, are also enrolled into the same program of long-term HIV care.

The interventions that are included in the MTCT-Plus Initiative are delivered as part of a comprehensive package of HIV primary care (Figure). This approach to comprehensive care is necessary to address the different needs of HIV-infected family members, which are likely to change through time with the progression of HIV disease and improvements in health that come with initiating ART.²³ To deliver this kind of comprehensive HIV primary care and address the complex needs of families with HIV, the MTCT-Plus Initiative emphasizes multidisciplinary teams to provide care, incorporating nurses, counselors, doctors, community health workers, social workers, pharmacists, and peers. Coordinating the efforts of these different types of service providers is a significant challenge, and regular team meetings are an important tool for addressing the needs of patients and families.

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• FIGURE. 

  Enrollment into and services provided by the MTCT-Plus Initiative

• Abrams. PMTCT: a gateway to family-focused HIV care and treatment. AJOG 2007.

Currently, there are 13 programs in sub-Saharan Africa and Southeast Asia participating in the MTCT-Plus Initiative. As of September 2006, more than 12,000 individuals have been enrolled into care. Approximately half of the patients are index women identified through PMTCT services; of these, 45% initiated care during the antenatal period, whereas the remainder enrolled postpartum. More than two-thirds of index women have enrolled another family member, usually an HIV-infected or HIV-exposed child. Across MTCT-Plus sites, 69% of women enrolled into the program received SD-NVP for PMTCT, but a substantial proportion received multidrug PMTCT combinations (12%) or HAART (7%).

At sites that have developed the capacity to initiate HAART during pregnancy, up to 30% of pregnant women are eligible and receive triple-drug therapy and low MTCT rates at several sites suggest the effectiveness of this approach for both prevention of MTCT as well as enhancement of maternal health.²⁴ Early virologic testing of all HIV-exposed infants is supported within MTCT-Plus to identify infected infants within the first months of life, and there is an emphasis on retaining exposed babies in care throughout the first years of life until a final infection status is determined. More than 2000 infants, 90% of those who have reached 18 months of age, have been determined to be uninfected. Of 761 infected children enrolled in MTCT-Plus, including children of the index pregnancy as well as older siblings, 65% are currently receiving HAART. Thirty-seven percent of infected children are less than 12 months of age. This is an unusually high proportion of young babies, reflecting the success of the attention to follow-up of exposed babies and early identification and diagnosis of those who are infected. Overall, retention of patients and adults as well as children in MTCT-Plus programs is excellent, with fewer than 600 adults leaving the program, including 190 reported deaths.

The MTCT-Plus Initiative has provided several valuable lessons regarding the provision of woman-centered, family-based HIV care and treatment services linked to PMTCT programs (Table). The rapid expansion of MTCT-Plus services at participating sites and the high levels of patient retention in services demonstrate that PMTCT programs are valuable settings to engage women and families in long-term HIV care and treatment services. For women with advanced HIV disease who require HAART, several sites have made rapid evaluation and initiation of treatment available, with promising results.²⁴ For other sites, the links between PMTCT programs and HIV treatment services allows the delivery of multidrug PMTCT regimens that would not otherwise be possible through standard antenatal care services. And across all MTCT-Plus sites, women, their children, and their families from across the spectrum of HIV disease receive comprehensive HIV care and treatment services.²⁵ With growing evidence that providing health care services to HIV-infected individuals before they require HAART can yield important benefits, the use of PMTCT services as a gateway to family-based HIV care and treatment is likely to gain increasing attention in many resource-limited countries.

TABLE. Key lessons learned from the MTCT-Plus Initiative

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Conclusion 

There is a strong rationale for linking PMTCT and HIV care and treatment services. Enormous benefits can be garnered that will result in markedly decreased morbidity and mortality for women, their children, and their families. PMTCT programs identify large numbers of HIV-infected women and, ultimately, HIV-exposed and infected children and provide the ideal opportunity to engage women, their partners, and their children in long-term care. HIV care and treatment services, when linked with PMTCT programs, can facilitate the use of highly potent ART regimens during pregnancy, further diminishing the risks of vertical transmission and can engage families in long-term preventive and therapeutic care. Perinatal HIV prevention efforts will not be able to attain the successes seen in more resourced settings without comprehensive integration with care and treatment services. HIV care and treatment programs will miss the opportunity to provide critical, lifesaving services to large numbers of women and children unless they are effectively linked to PMTCT services.

In light of the clear benefits of linked systems, there is a pressing need for greater insight into how such integration may take place. There are few well-documented public sector experiences that can be used as a basis for scaling-up programs. There are important outstanding questions regarding how resource constraints, human capacity, national agendas, and community preferences influence the feasibility of linkages between services. With countless lives of women, children, and families at stake, addressing these questions and developing reproducible models for using PMTCT programs as a gateway to HIV care and treatment services may represent 1 of the most significant interventions to improve the lives of HIV-infected individuals around the globe.

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Acknowledgments 

MTCT-Plus has supported the following sites: Cote d’Ivoire: Formation Sanitaire Urbaine de Yopougon-Attie, Abidjan; Cameroon: Mbingo and Banso Baptist Hospitals, Bamenda; Kenya: Moi Hospital and Mosoriot Rural Health Center, Eldoret, Nyanza Provincial General Hospital, Kisumu; Mozambique: Beira and Chimoio Day Hospitals; Rwanda: Treatment and Research AIDS Center, Kicukiro Health Center, Kigali; South Africa: Ekuphileni Clinic, Cato Manor, Durban, Langa Clinic, City of Cape Town Health Department, Cape Town, Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto; Thailand: Thai Red Cross Research Center, Bangkok; Uganda: Mulago Hospital, Kampala, St. Francis Nsambya Hospital, Kampala; Zambia: Chelstone and Mtendere District Health Clinics, Lusaka.

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References 

1. Joint United Nations Programme on HIV/AIDS/World Health Organization. AIDS epidemic update, May 2006. Geneva (Switzerland): Joint United Nations Programme on HIV/AIDS; 2006;
   • View In Article
2. United Nations Children’s Fund. PMTCT report card 2005: monitoring progress on the implementation of programs to prevent mother-to-child transmission of HIV. New York: United Nations Children’s Fund; 2005;December
   • View In Article
3. World Health Organization. Antenatal care in developing countries: promises, achievements and missed opportunities, an analysis of trends, levels and differentials, 1990-2001. Geneva: World Health Organisation; 2003;
   • View In Article
4. Stringer JS, Sinkala M, Maclean CC, et al. Effectiveness of a city-wide program to prevent mother-to-child HIV transmission in Lusaka, Zambia. AIDS. 2005;19:1309–1315
   • View In Article
   • MEDLINE
5. Coetzee D, Hildebrand K, Boulle A, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS. 2004;18:887–895
   • View In Article
   • MEDLINE
   • CrossRef
6. Braitstein P, Brinkhof MW, Dabis F, et al. Mortality of HIV-1 infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet. 2005;367:817–824
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (122 KB)
   • CrossRef
7. In:  Tsui AO,  Wasserheit JN,  Haaga JG editor. Reproductive health in developing countries: expanding dimensions, building solutions. Washington (DC): National Academy Press; 1997;
   • View In Article
8. Garcia R, Kalish L, Pitt J, et al. Maternal levels of plasma HIV type 1 RNA and the risk of perinatal transmission. N Engl J Med. 1999;341:394–402
   • View In Article
   • MEDLINE
   • CrossRef
9. Shaffer N, Roongpisuthipong A, Siriwasin W, et al. Maternal virus load and perinatal human immunodeficiency virus type 1 subtype E transmission, Thailand (Bangkok Collaborative Perinatal HIV Transmission Study Group). J Infect Dis. 1999;179:590–599
   • View In Article
   • MEDLINE
   • CrossRef
10. Mofenson L, Lambert J, Stiehm E, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine (Pediatric AIDS Clinical Trials Group Study 185 Team). N Engl J Med. 1999;341:385–393
    • View In Article
    • MEDLINE
    • CrossRef
11. Breastfeeding and HIV International Transmission Study Group. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis. 2004;189:2154–2166
    • View In Article
    • MEDLINE
    • CrossRef
12. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002;29:484–494
    • View In Article
    • MEDLINE
    • CrossRef
13. European Collaborative Study. Mother-to-child transmission in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005;40:458–465
    • View In Article
    • CrossRef
14. Lallemant M, Jourdain G, Le Coeur S, et al. Single dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med. 2004;351:217–228
    • View In Article
    • CrossRef
15. Dabis F, Bequet L, Ekouevi DK, et al. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS. 2005;19:309-1
    • View In Article
16. Western Cape Provincial Government. Revised protocol for PMTCT services in the Western Cape. Cape Town: Western Cape Provincial Government; 2004;
    • View In Article
17. Coetzee D, Hilderbrand K, Boulle A, Draper B, Abdullah F, Goemaere E. Effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of HIV in South Africa. Bull World Health Organ. 2005;83:489–494
    • View In Article
    • MEDLINE
18. Rabkin M, El-Sadr WM. Saving Mothers, Saving Families: The MTCT-Plus Initiative. Geneva: World Health Organization; 2003;
    • View In Article
19. Chi BH, Fusco H, Sinkala M, Goldenberg RL, Stringer JS. Cost and enrolment implications of targeting different source population for an HIV treatment program. J Acquir Immune Defic Syndr. 2005;40:350–355
    • View In Article
    • MEDLINE
    • CrossRef
20. McIntyre J. Maternal health and HIV. Reprod Health Matters. 2005;13:129–135
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (825 KB)
    • CrossRef
21. Lawn SD, Myer L, Orrell C, Bekker LG, Wood R. Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS. 2005;19:2141–2148
    • View In Article
    • MEDLINE
22. Lyon ME, Trexler C, Akpan-Townsend C, et al. A family group approach to increasing adherence to therapy in HIV-infected youths: results of a pilot project. AIDS Patient Care STDS. 2003;17:299–308
    • View In Article
    • MEDLINE
    • CrossRef
23. Rosenfield A, Figdor E. Where is the M in MTCT? (The broader issues in mother-to-child transmission of HIV). Am J Public Health. 2001;91:703–704
    • View In Article
    • MEDLINE
    • CrossRef
24. Toure H, Tonwe-Gold B, Becquet R, et al. Adverse pregnancy outcomes in HIV-infected women treated with HAART in Abidjan, Cote d’Ivoire (3rd IAS Conference on HIV Pathogenesis and Treatment). 2005;Abstract TuFo0202, Rio de Janeiro, Brazil, July.
    • View In Article
25. Myer L, Rabkin M, Abrams EJ, Rosenfield A, El-Sadr WM. Columbia University MTCT-Plus Initiative (Focus on women: linking HIV care and treatment with reproductive health services in the MTCT-Plus Initiative). Reprod Health Matters. 2005;13:136–146
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1805 KB)
    • CrossRef