Antiretroviral regimens included NVP for 2012 (90%) patients, with lamivudine (3TC) and either ZDV or stavudine (d4T). An additional 189 (9%) patients, including two pregnant women in their third trimester, started efavirenz with 3TC and either ZDV or d4T. Initial ART regimens were similar for men, pregnant women, and nonpregnant women.
Predicted CD4 cell count response did not vary by WHO stage at baseline, but did vary by country. Participants from sites in Cote d'Ivoire had the greatest increase in CD4 cell count at 6 months and at every time point thereafter.
As of January 2007, 1902 (85%) of the 2229 patients who initiated ART were alive and in active follow-up. Over 4193 person-years of follow-up, 77 (3.5%) patients were known to have died (1.8 per 100 person-years) and 192 (8.6%) patients were LTF (4.6 per 100 person-years). An additional 58 patients (2.6%) voluntarily withdrew from the program (1.4 per 100 person-years) due to change in place of residence (n = 17), seeking care elsewhere (n = 24), refusal of further participation (n = 8), inability to adhere to ART or the visit schedule (n = 6), or other reasons (n = 3). The mortality rates for pregnant women (17 deaths, 1.5 per 100 person-years), nonpregnant women (34 deaths, 1.7 per 100 person-years), and men (26 deaths, 2.4 per 100 person-years) were similar (P = 0.18). Mortality was associated with lower baseline CD4+ cell count (P < 0.001), higher baseline WHO stage (P < 0.001), and country of enrollment (P < 0.001), but not sex or pregnancy status.
Kaplan–Meier probability of program retention (death, LTF and withdrawal) was 0.85 overall, and was similar across sex and pregnancy groups: 0.82 for pregnant women, 0.87 for nonpregnant women, and 0.86 for males (log rank P = 0.10). Poorer program retention was associated with higher WHO stage (III or IV) at baseline (P < 0.001), but not CD4+ cell count.
This study is one of the first to report on immunologic outcomes, mortality, and program retention for ART-eligible women starting ART during pregnancy. We demonstrate a robust CD4+ cell count response during the first 2.5 years of treatment comparable to, if not better than, nonpregnant adults. Furthermore, we report low mortality and high retention for all patients initiating ART. These findings are particularly important as national PMTCT programs evolve to prioritize the identification and treatment of eligible pregnant women with therapeutic ART . The MTCT-Plus Initiative has previously documented the benefit of ART use during pregnancy in reducing the risk of MTCT .
We noted lower mortality rates in our population of adults initiating ART as compared with other studies in the literature. Most programs have reported higher mortality rates, 5.5–9.7 per 100 person-years of follow-up, during the first few months of treatment attributed to the highly advanced disease status of many of the patients [16,55,56]. In comparison, there were only 17 documented deaths among women initiating ART during pregnancy (1.5 per 100 person-years), 34 deaths among nonpregnant women (1.7 per 100 person-years) and 26 deaths among men (2.4 per 100 person-years) in this cohort. Overall retention in care was high: 82% for pregnant women, 86% for men, and 87% of nonpregnant women at 30 months of follow-up. The healthier status of MTCT-Plus patients likely contributed to lower mortality risk and high retention rates, as it has been noted that a significant percentage of patients LTF in most cohort studies [30–32] have died. In addition, the MTCT-Plus model of care emphasized psychosocial support and adherence to care and treatment as critical components of the program. Sites supported through the MTCT-Plus Initiative were relatively well resourced with high provider–patient ratios and access to a wider range of supportive services.
This study has several strengths. Sites followed standardized MTCT-Plus protocols, received standardized MTCT-Plus training prior to start-up, and used standardized data collection forms. Furthermore, most patients initiated NNRTI-based ART, primarily with NVP, resulting in a relatively homogenous treatment population.
However, the study had several limitations. The data were derived from a clinical care program rather than a research study. Thus, there may have been variability across the program CD4+ cell counts, as measurements were done in local laboratories.
In summary, we have demonstrated that pregnant women as well as nonpregnant women and male partners who initiated first-line ART had excellent CD4+ cell count response and high retention in care during the first 2.5 years of follow-up. These findings lend support to the WHO recommendations for RLCs, which suggest initiation of ART in pregnant women if they are eligible for treatment .
Funding for the MTCT-Plus Initiative was provided by the Bill and Melinda Gates Foundation, the William and Flora Hewlett Foundation, the Robert Wood Johnson Foundation, the Henry J. Kaiser Family Foundation, the John D. and Catherine T. MacArthur Foundation, the David and Lucille Packard Foundation, the Rockefeller Foundation, and the Starr Foundation.
MTCT Plus Initiative: ACONDA FSU and Abobo clinics, Cote d'Ivoire (Dr Siaka Toure); Moi University College of Health Sciences Clinics, Kenya (Drs Robert Eintez and Joseph Mamlin); Nyanza Provincial General Hospital Clinic, Kenya (Dr Juliana Otieno); Treatment and Research AIDS Center, Rwanda (Dr Anita Assimwe); Cato Manor Clinic of UKZN, South Africa (Dr Anna Coutsoudous); Langa Health Clinic of Western Cape, South Africa (Dr Ivan Toms); Perinatal HIV Research Unit of University of Witswatersrand, South Africa (Dr James McIntyre); Thai Red Cross Clinic, Thailand (Dr Praphan Phanuphak); MU-JHU Cares Clinic, Uganda (Dr Philippa Musoke); St. Francis Hospital Clinic, Uganda (Dr Pius Okong); and Mtendere and Chelstone Health Clinics, Zambia (Dr Elizabeth Stringer).
P.T. was the primary writer of the manuscript and led the analysis. M.K. was the analyst/statistician. She reviewed and edited the manuscript. R.C. revised drafts and gave input throughout the analytic phase. W.E.-S. edited the manuscript and gave input throughout the writing process. L.M. edited the manuscript and gave specific input into issues of HIV treatment during pregnancy. D.N. advised during analysis. E.A. gave extensive editorial support and advised throughout the analysis.
1. WHO. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector
. Geneva, Switzerland: WHO; 2008.
2. DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa
3. Coetzee D, Hildebrand K, Boulle A, Maartens G, Louis F, Labatala V, et al
. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18:887–895.
4. Dabis F, Balestre E, Braitstein P, Miotti P, Brinkhof WG, Schneider M, et al
. Cohort profile: Antiretroviral Therapy
in Lower Income Countries (ART-LINC): international collaboration of treatment cohorts. Int J Epidemiol 2005; 34:979–986.
5. Djomand G, Roels T, Ellerbrock T, Hanson D, Diomande F, Monga B, et al
. Virologic and immunologic outcomes and programmatic challenges of an antiretroviral treatment pilot project in Abidjan, Cote d'Ivoire. AIDS 2003; 17(Suppl 3):S5–S15.
6. Fischer A, Karasi JC, KiRi D, Omes C, Lambert C, Uwayitu A, et al
. Antiviral efficacy and resistance in patients on antiretroviral therapy
in Kigali, Rwanda: the real-life situation in 2002. HIV Med 2006; 7:64–66.
7. Frater AJ, Dunn DT, Beardall AJ, Ariyoshi K, Clarke JR, McClure MO, Weber JN. Comparative response of African HIV-1-infected individuals to highly active antiretroviral therapy
. AIDS 2002; 16:1139–1146.
8. Kebba A, Atwine D, Mwebaze R, Kityo C, Nakityo R, Peter M. Therapeutic responses to AZT + 3TC + EFV in advanced antiretroviral naive HIV type 1-infected Ugandan patients. AIDS Res Hum Retroviruses 2002; 18:1181–1187.
9. Landman R, Schiemann R, Thiam S, Vray M, Canestri A, Mboup S, et al
. Once-a-day highly active antiretroviral therapy
in treatment-naive HIV-1-infected adults in Senegal. AIDS 2003; 17:1017–1022.
10. Laurent C, Diakhate N, Gueye NF, Toure MA, Sow PS, Faye MA, et al
. The Senegalese government's highly active antiretroviral therapy
initiative: an 18-month follow-up study. AIDS 2002; 16:1363–1370.
11. Spacek LA, Shihab HM, Kamya MR, Mwesigire D, Ronald A, Mayanja H, et al
. Response to antiretroviral therapy
in HIV-infected patients attending a public, urban clinic in Kampala, Uganda. Clin Infect Dis 2006; 42:252–259.
12. Tassie JM, Szumilin E, Calmy A, Goemaere E. Highly active antiretroviral therapy
in resource-poor settings: the experience of Medecins Sans Frontieres. AIDS 2003; 17:1995–1997.
13. Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al
. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002; 360:34–40.
14. Calmy A, Pinoges L, Szumilin E, Zachariah R, Ford N, Ferradini L. Generic fixed-dose combination antiretroviral treatment in resource-poor settings: multicentric observational cohort. AIDS 2006; 20:1163–1169.
15. 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.
16. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al
. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy
: comparison between low-income and high-income countries. Lancet 2006; 367:817–824.
17. Rosen S, Fox MP, Gill CJ. Patient retention in antiretroviral therapy
programs in sub-Saharan Africa: a systematic review. PLoS Med 2007; 4:e298.
18. Dalal RP, Macphail C, Mqhayi M, Wing J, Feldman C, Chersich MF, Venter WD. Characteristics and outcomes of adult patients lost to follow-up at an antiretroviral treatment clinic in Johannesburg, South Africa. J Acquir Immune Defic Syndr 2008; 47:101–107.
19. Brinkhof MW, Dabis F, Myer L, Bangsberg DR, Boulle A, Nash D, et al
. Early loss of HIV-infected patients on potent antiretroviral therapy
programmes in lower-income countries. Bull World Health Organ 2008; 86:559–567.
20. Ginsburg A, Hoblitzelle C, Sripipatana T, Wilfert C. Provision of care following prevention of mother-to-child HIV transmission services in resource-limited settings. AIDS 2007; 21:2529–2532.
21. Gray R, Li X, Kigozi G, Serwadda D, Brahmbhatt H, Wabwire-Mangen F, et al
. Increased risk of incident HIV during pregnancy
in Rakai, Uganda: a prospective study. Lancet 2005; 366:1182–1188.
22. Mataka E. Maternal health and HIV: bridging the gap. Lancet 2007; 370:1290–1291.
23. Abrams EJ, Myer L, Rosenfield A, El-Sadr WM. 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. Am J Obstet Gynecol 2007; 197:S101–106.
24. Whelan D. Gender and HIV/AIDS: taking stock of research and programmes [POPLINE Document Number 165705]
. Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS; 1999. 40 p.
25. WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access
. Recommendations for a public health approach; 2006.
26. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Vwalika C, et al
. Prolonged breast-feeding and mortality up to two years postpartum among HIV-positive women in Zambia. AIDS 2005; 19:1677–1681.
27. Garcia F, de Lazzari E, Plana M, Castro P, Mestre G, Nomdedeu M, et al
. Long-term CD4+
T-cell response to highly active antiretroviral therapy
according to baseline CD4+
T-cell count. J Acquir Immune Defic Syndr 2004; 36:702–713.
28. van der Merwe K, Chersich MF, Technau K, Umurungi Y, Conradie F, Coovadia A. Integration of antiretroviral treatment within antenatal care in Gauteng Province, South Africa. J Acquir Immune Defic Syndr 2006; 43:577–581.
29. Martin F, Navaratne L, Khan W, Sarner L, Mercey D, Anderson J, et al
. Pregnant women with HIV infection can expect healthy survival: three-year follow-up. J Acquir Immune Defic Syndr 2006; 43:186–192.
30. Black V, Hoffman RM, Sugar CA, Menon P, Venter F, Currier JS, Rees H. Safety and efficacy of initiating highly active antiretroviral therapy
in an integrated antenatal and HIV clinic in Johannesburg, South Africa. J Acquir Immune Defic Syndr 2008; 49:276–281.
31. Kaplan R, Orrell C, Zwane E, Bekker LG, Wood R. Loss to follow-up and mortality among pregnant women referred to a community clinic for antiretroviral treatment. AIDS 2008; 22:1679–1681.
32. Wang B, Losina E, Stark R, Munro A, Walensky R, Wilke M, et al
. Loss to follow-up in community clinics in South Africa: role of CD4 count, gender and pregnancy [poster #841]
. In: 15th Conference on Retrovirus and Opportunistic Infections
; 3–6 February 2008; Boston, Massachusetts, USA; 2008.
33. Rabkin M, El-Sadr WM. Saving mothers, saving families: the MTCT-Plus Initiative [case study].
Geneva, Switzerland: WHO; 2004.
34. Myer L, Rabkin M, Abrams EJ, Rosenfield A, El-Sadr WM. Focus on women: linking HIV care and treatment with reproductive health services in the MTCT-Plus Initiative. Reprod Health Matters 2005; 13:136–146.
35. WHO. Antiretroviral therapy in HIV infection in adults and adolescents: recommendations for a public health approach
. Geneva, Switzerland: WHO; 2006. pp. 1–128.
36. WHO. WHO list of prequalified medicinal products
. Geneva, Switzerland: WHO; 2007.
37. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982; 38:963–974.
38. Tonwe-Gold B, Ekouevi DK, Viho I, Amani-Bosse C, Toure S, Coffie PA, et al
. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. PLoS Med 2007; 4:e257.
39. Collini P, Schwab U, Sarfo S, Obeng-Baah J, Norman B, Chadwick D, et al
. Sustained immunological responses to highly active antiretroviral therapy at 36 months in a Ghanaian HIV cohort
. Clin Infect Dis
40. Bekker LG, Myer L, Orrell C, Lawn S, Wood R. Rapid scale-up of a community-based HIV treatment service: programme performance over 3 consecutive years in Guguletu, South Africa. S Afr Med J 2006; 96:315–320.
41. Nash D, Katyal M, Brinkhof MW, Tuboi S, Braitstein P, Balestre E, et al
. Long-term CD4 response to potent ART among ART-naive patients in several low-income countries
. In: 15th Conference on Retroviruses and Opportunistic Infections
; 3–6 February 2008; Boston, Massachusetts, USA; 2008.
42. Nash D, Katyal M, Brinkhof MW, Keiser O, May M, Hughes R, et al
. Long-term immunologic response to antiretroviral therapy
in low-income countries: a collaborative analysis of prospective studies. AIDS 2008; 22:2291–2302.
43. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al
. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy
: a collaborative analysis of prospective studies. Lancet 2002; 360:119–129.
44. Egger M. Antiretroviral therapy
in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America. Trop Med Int Health 2008; 13:870–879.
45. Ross A, Van der Paal L, Lubega R, Mayanja BN, Shafer LA, Whitworth J. HIV-1 disease progression and fertility: the incidence of recognized pregnancy
outcome in Uganda. AIDS 2004; 18:799–804.
46. Tuomala RE, Kalish LA, Zorilla C, Fox H, Shearer W, Landay A, et al
. Changes in total, CD4+
, and CD8+
lymphocytes during pregnancy
and 1 year postpartum in human immunodeficiency virus-infected women. The Women and Infants Transmission Study. Obstet Gynecol 1997; 89:967–974.
47. Ekouevi DK, Inwoley A, Tonwe-Gold B, Danel C, Becquet R, Viho I, et al
. Variation of CD4 count and percentage during pregnancy
and after delivery: implications for HAART initiation in resource-limited settings. AIDS Res Hum Retroviruses 2007; 23:1469–1474.
48. Lebon A, Bland RM, Rollins NC, Coutsoudis A, Coovadia H, Newell ML. Short communication: CD4 counts of HIV-infected pregnant women and their infected children – implications for PMTCT and treatment programmes. Trop Med Int Health 2007; 12:1472–1474.
49. Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, et al
. Response to antiretroviral therapy
after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356:135–147.
50. Westreich D, Eron J, Behets F, Horst C, Van Rie A. Survival in women exposed to single-dose nevirapine for prevention of mother-to-child transmission
of HIV: a stochastic model. J Infect Dis 2007; 195:837–846.
51. Chi BH, Sinkala M, Stringer EM, Cantrell RA, Mtonga V, Bulterys M, et al
. Early clinical and immune response to NNRTI-based antiretroviral therapy
among women with prior exposure to single-dose nevirapine. AIDS 2007; 21:957–964.
52. Coovadia A, Hunt G, Abrams EJ, Sherman G, Meyers T, Barry G, et al
. Persistent minority K103N mutations among women exposed to single-dose nevirapine and virologic response to nonnucleoside reverse-transcriptase inhibitor-based therapy. Clin Infect Dis 2009; 48:462–472.
53. Nicastri E, Leone S, Angeletti C, Palmisano L, Sarmati L, Chiesi A, et al
. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy
: a systematic review. J Antimicrob Chemother 2007; 60:724–732.
54. Moore AL, Mocroft A, Madge S, Devereux H, Wilson D, Phillips AN, Johnson M. Gender differences in virologic response to treatment in an HIV-positive population: a cohort study. J Acquir Immune Defic Syndr 2001; 26:159–163.
55. Boulle A, Bock P, Osler M, Cohen K, Channing L, Hilderbrand K, et al
. Antiretroviral therapy
and early mortality in South Africa. Bull World Health Organ 2008; 86:678–687.
56. Marazzi MC, Liotta G, Germano P, Guidotti G, Altan AD, Ceffa S, et al
. Excessive early mortality in the first year of treatment in HIV type 1-infected patients initiating antiretroviral therapy
in resource-limited settings. AIDS Res Hum Retroviruses 2008; 24:555–560.