Is the time for an AIDS-free new generation different in resource-limited and industrialized countries?
Russo, Gianluca; Lichtner, Miriam; Traditi, Fiore; Vullo, Vincenzo
Department of Tropical and Infectious Diseases, ‘Sapienza’ University of Rome, Rome, Italy.
Received 11 April, 2008
Revised 15 September, 2008
Accepted 29 September, 2008
Correspondence to Gianluca Russo, MD, PhD, Viale del Policlinico 155, 00161 Rome, Italy. Tel: +39 06 49970313; fax: +39 06 49972625; e-mail: firstname.lastname@example.org
In recent years, much progress has been reported about the availability of access to three-drug combination antiretroviral therapy (cART) in resource-limited countries, but many goals still remain to be achieved. WHO's public health recommendations for the scaling up of cART in adults and adolescents in resource-limited countries  define similar criteria for starting therapy as those in use in industrialized countries . Unfortunately, however, the same is not true for WHO's recommendations concerning prevention of mother-to-child transmission of HIV (PMTCT) [3,4]. In resource-rich settings, the use of three-drug cART in all HIV-infected pregnant women during the antepartum period, regardless of their immune status, has been the cornerstone of a multi-tiered PMTCT strategy that has reduced the perinatal transmission rate to less than 2% [4,5]. The same strategy has been adopted by some low-income/middle-income countries, for example, Brazil, with similar excellent results . In industrialized countries, pregnancy is a major criterion for starting a three-drug cART in HIV-infected women . These women, who may not require treatment for their own health, should receive three-drug cART throughout pregnancy for prevention of perinatal transmission . In these settings, an antiretroviral prophylaxis with one or two drugs is considered exclusively for those HIV-infected pregnant women with near term HIV RNA less than 1000 copies or for those arriving late in pregnancy or in labour to the attention of the health services. Consequently, in the daily clinical practice of the industrialized countries, the use of three-drug cART in the antepartum period is applied to all HIV-infected pregnant women, except for those that arrive late in labour or refuse the three-drug cART because not in need for their own health. By this approach, the majority of HIV-pregnant women in those countries have access to the strongest preventive antiretroviral protocol for HIV-1 vertical transmission. On the contrary, the last WHO guidelines for PMTCT of HIV-1 in resource-limited countries recommend in general a short-course of antiretroviral drugs, and three-drug cART only for HIV-pregnant women with immunological deficit (CD4 <200 cells/μl) or WHO clinical stage III and CD4 less than 350 cells/μl, without viral load measurement  that is normally not largely available in these settings (Table 1).
The latest joint report of UNAIDS, WHO and UNICEF (April 2007) towards the universal access to HIV care  affirms that in resource-limited countries, 2 million people are currently on treatment and receive cART, representing 28% coverage of those needing cART and two-thirds are in sub-Saharan Africa. Fifteen countries (11 in sub-Saharan Africa) account for the majority of people receiving cART (75%) and needing cART (70%). Concerning the PMTCT of HIV in resource-limited countries, the same report  affirms that in 2005 only about 220 000 of the more than 2 million HIV-infected pregnant women in need received an antiretroviral prophylaxis [mostly a nevirapine single dose (NVPsd)-based regimen] with an estimated coverage of 11%. Eighty-five percent of HIV-infected pregnant women live in sub-Saharan Africa where the PMTCT coverage is around 11% (ranging from 1 to 54%). Nine out of 10 of the countries with almost 75% of the burden related to HIV-infected pregnant women are sub-Saharan countries: among these countries, only South Africa has PMTCT coverage of 30% (Fig. 1) . In these nine sub-Saharan countries, there is also an important gap between antenatal consultation coverage, PMTCT coverage and cART coverage for adults (Fig. 1) . HIV testing and counselling is a critical entry point to PMTCT, but an inadequate access and uptake of these services (especially in sub-Saharan Africa for social-related stigma) (Fig. 2) continues to jeopardize efforts to expand PMTCT and ensure timely access to treatment and care. The low uptake of antenatal HIV care of these countries can be improved significantly through a structural reinforcement of their health systems by facing firstly the general lack of infrastructures and the shortages of healthcare workers. Waiting for an appropriate health system reinforcement, the most efficacious preventive approach must be routinely available for those pregnant women who have access to antenatal HIV care services. During the year 2006, 420 000 newly infected children in the world with 330 000 paediatric AIDS-related deaths were registered, and 90% of the paediatric HIV/AIDS burden is localized in sub-Saharan Africa . Comparing the latest UNAIDS AIDS epidemic update  with the homologous of the year 2003 , we observe an important reduction of newly infected children per year in the world. Unfortunately, this decreasing trend is not the consequence of a real improvement of coverage and effectiveness of PMTCT services in resource-limited countries (firstly sub-Saharan Africa), but instead depends on the advances in the methodology of estimation of HIV epidemics applied to an expanded range of countries .
Considering this picture of the PMTCT and paediatric HIV infection in resource-limited countries and considering the public health approach shown by the WHO in the scaling up of the treatment for adults in this kind of settings, we were therefore surprised to read from the 2006 WHO's guidelines for PMTCT in resource-limited settings that similar criteria were set for starting three-drug cART for pregnant women, adults and adolescents, independently of their pregnant status . By this approach also, the majority of HIV-pregnant women who have access to PMTCT services in those countries (only 11% of those needing) will not receive three-drug cART during pregnancy for PMTCT that is considered standard in industrialized countries . Considering that nearly all these HIV-pregnant women are naive for cART, in this way the effectiveness of PMTCT will be dramatically reduced in these countries where the efficiency of the prevention must be maximal for giving a hope for an AIDS-free new generation. Why is the preventive value of three-drug cART in the antepartum, which we consider to be pivotal in a public health approach to prevention and cure of HIV/AIDS in industrialized countries not being taken sufficiently into consideration for resource-limited counties by the WHO? The reasons for such a conservative approach in the WHO's document needs further discussion. The WHO affirms that mono-therapy and bi-therapy have also shown a high rate of efficacy in the PMTCT: this evidence is given only from some clinical trials, but generally the ‘real life’ is completely different in resource-limited countries [10,11]. A comparison of the best result available in literature concerning African trials on PMTCT of HIV using short-course antiretroviral regimen (DITRAME Plus AZT + 3TC + NVPsd mother group)  or HAART [13,23] shows a 4% difference in terms of HIV-MTCT rate (about 80 000 new infection per year avertable). The WHO also refers to the risk of toxicity of nevirapine (NVP)-based three-drug cART during pregnancy, but we would like to highlight that this regimen (as the other first-line antiretroviral drugs) is routinely used in HIV-pregnant women also in industrialized countries. However, the available evidence on NVP toxicity in pregnancy are controversial [14–16], but are convergent on the consideration that this risk can be prevented or detected by regular clinical visits supported by serum transaminases analysis. We consider the management of NVP toxicity feasible also in many contexts of resource-limited countries.
Strengthening the PMTCT is also convenient from a strictly economical point of view. For example, the average cost of a first-line three-drug cART per year per adult is around US$ 220 in resource-limited settings; this is less than the monthly cost for the cART per HIV-infected child. The economic cost–benefit value of strengthening the PMTCT is evident and unquestionable, as well as the social value for the present and future of resource-limited countries.
We believe that three-drug cART for HIV-infected pregnant women, regardless of individual CD4+ cell count, may have a significant public health impact in resource-limited countries by
1. dramatically reducing the number of HIV-infected infants born in sub-Saharan Africa, which would in turn reduce the HIV-related morbidity and mortality in these countries where there is limited access to and uptake of paediatric HIV care (global coverage 15%) ;
2. reducing the risk of resistance to antiretroviral drugs related to mono-therapy or bi-therapy regimens [17,18] and, consequently, the risk of virological failure of three-drug cART for HIV-positive children  and for women who met the criteria for starting treatment after delivery [19–21], especially in a context in which second-line regimens for cART may not be easily available;
3. probably (if the ongoing trials – BAN study in Malawi and the multicountries Kesho Bora Study  – will confirm the evidence of other studies [23–26]) reducing the risk of postnatal transmission by continuing three-drug cART during lactation when breast-feeding is the only feasible feeding option.
As health operators in general, heavily involved in the ‘real-life’ fight against HIV/AIDS in resource-limited settings, we believe that the time has come for the best standard of care to be internationally recommended even in resource-limited countries and, wherever possible, to discuss alternative options in which conditions are not favourable. We would like to ask WHO to reconsider, at least for the next guidelines for resource-limited settings, the possibility of recommending the use of three-drug cART in antepartum for all HIV-pregnant women (starting from 25th week); and eventually, with the support of the data from ongoing specific trials, also during the breast-feeding period for lactating HIV mothers (in context in which there is no other practical options for infant feeding), regardless of their country of residence and CD4+ cell count, wherever the local situation allows. We are convinced that a more efficient standard of PMTCT will also be feasible in resource-limited countries, at least in the sites where the three-drug cART is available for adults – thanks to the support offered by international governmental and nongovernmental aid organizations. PMTCT is an essential part of a comprehensive approach that includes prevention and treatment together as pillars of the fight against HIV/AIDS. Scaling up and improving the effectiveness of the PMTCT is not only a humanitarian and ethical imperative challenge, but it is also the only way for giving a hope for socioeconomic development for the new generation of resource-limited countries, especially in sub-Saharan Africa.
All the authors participated in the ideation and elaboration of the study. We would like to thank Prof. Francesco Castelli (University of Brescia, Department of Mother-Infant and Biomedical Technology) for his support and for sharing this experience.
1. WHO. Antiretroviral Therapy for HIV infection in adults and adolescents: toward universal access. Recommendations for a public health approach
. Geneva: WHO; 2006.
3. WHO. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants in resource-limited countries: towards universal access. Recommendations for a public health approach
. Geneva: WHO; 2006.
4. Public Health Service Task Force. Perinatal HIV Guidelines Working Group. Recommendations for use of antiretroviral drugs in pregnant HIV1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States
; 2 November 2007.
5. European Collaborative Study. Mother-to-child transmission of HIV infection in the era of highly active antiretroviral therapy. CID
6. Recomendações para Profilaxia da Transmissão Vertical do HIV e Terapia Antiretroviral em Gestantes [Recommendations for prophylaxis for vertical transmission of HIV and antiretroviral therapy in pregnant women]. Brazil: Ministry of Health; 2003.
10. Manzi M, Zachariah R, Teck R, et al
. High acceptability of voluntary counselling and HIV-testing but unacceptable loss to follow-up in a prevention of mother-to-child transmission programme in rural Malawi: scaling up requires a different way of acting. Trop Med Int Health 2005; 12:1242–1250.
11. Reithinger R, Megazzini K, Durako SJ, Harris DR, Vermund SH. Monitoring and evaluation of programmes to prevent mother-to-child transmission of HIV in Africa. BMJ 2007; 334:1143–1146.
12. Leroy V, Ekouevi DK, Becquet R, et al. 18-month effectiveness of short-course antiretroviral regimens combined with alternatives to breast-feeding to prevent HIV mother-to-child transmission. PLoS ONE
:e1645. doi: 10.1371/journal.pone.0001645.
13. Ekouevi DK, Coffie PA, Becquet R, et al
. Antiretroiviral therapy in pregnant women with advanced HIV disease and pregnancy outcomes in Abidjan, Cote d'Ivoire. AIDS 2008; 22:1815–1820.
14. Hitti J, Frenkel LM, Stek AM, et al
. Maternal toxicity with continuous nevirapine in pregnancy [results from PACTG 1022]. J Acquir Immune Defic Syndr 2004; 36:772–776.
15. João EC, Calvet GA, Menezes JA, et al
. Nevirapine toxicity in a cohort of HIV-1 infected pregnant women. Am J Obstetr Gynaecol 2006; 194:199–202.
16. Marazzi MC, Germano P, Liotta, 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
17. Arrivé E, Newell ML, Ekouevi DK, et al
, for Ghent Group on HIV in Women and Children. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol 2007; 36:1009–1021.
18. Turriziani O, Russo G, Lichtner M, et al
. Study of the genotypic resistant pattern in HIV-infected women and children from rural west Cameroon. AIDS Res Hum Retroviruses 2008; 24:781–785.
19. Lockman S, Shapiro RL, Smeaton LM, et al
. Response to antiretroviral therapy after a single peripartum dose of nevirapine. N Engl J Med 2007; 356:135–147.
20. Jourdain G, Ngo-Giang-Huong N, Le Coeur S. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004; 351:229–240.
21. Wind-Rotolo M, Durand C, Cranmer L, et al. Identification of nevirapine-resistant HIV-1 in the latent reservoir following single-dose nevirapine. CROI
2008. Session 106 [Resistance associated with ART for PMTCT]. Abstract 634.
22. Mofenson LM. Antiretroviral prophylaxis to reduce breast milk transmission of HIV type 1: new data but still questions. J Acquir Immune Defic Syndr 2008; 3:237–240.
23. Palombi L, Marazzi MC, Voetberg A, Magid NA. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS 2007; 21(Suppl 4):S65–S71.
24. Thomas T, Masaba R, Ndivo R, et al. Prevention of mother-to-child transmission of hiv-1 among breastfeeding mothers using HAART: the Kisumu Breastfeeding Study, Kisumu, Kenya, 2003–2007. CROI
2008. Session 14 [Prevention Mother-to-Child Transmission]. Abstract 45aLB.
25. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers prophylactically with triple antiretroviral therapy in Dar es Salaam, Tanzania – the MITRA plus study.
In: 4th International AIDS Society Conference on HIV Pathogenesis
; Treatment and Prevention: Sydney, Australia, 22–25 July 2007. Abstract TuAX101.
26. Arendt V, Ndimubanzi P, Vyankandonera J, et al.
AMATA study: effectiveness of antiretroviral therapy in breastfeeding mothers to prevent postnatal vertical transmission in Rwanda.
In: 4th International AIDS Society Conference on HIV Pathogenesis
; Treatment and Prevention: Sydney, Australia, 22–25 July 2007. Abstract TuAX102.
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Bulletin of the World Health OrganizationIntegrating antiretroviral therapy into antenatal care and maternal and child health settings: a systematic review and meta-analysisBulletin of the World Health Organization
antiretroviral therapy; HIV; pregnancy; prevention of mother-to-child transmission; resource-limited countries
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