In this issue of the journal, Leroy et al1 present one of the largest and most complete analyses to date describing mortality and loss to follow-up (LTFU) outcomes in HIV-infected children undergoing antiretroviral treatment (ART). Their analysis of 13,611 children, comprising the International Epidemiological Databases to Evaluate AIDS cohort, documents 18-months or 20,471 child-years of outcomes in Asia, East Africa, Southern Africa, and West Africa. The results of the International Epidemiological Databases to Evaluate AIDS cohort show cumulative mortality and LTFU rates of 5.7% and 12.3%, respectively, with noteworthy geographical variations.1
A major factor associated with both increased mortality and LTFU in this study was patient age, with a younger patient age correlating with a higher risk of mortality and LTFU.1 Specifically, children younger than 12 months of age had a mortality hazards ratio of 2.7 [95% confidence interval (CI): 2.1 to 3.5] and a LTFU hazards ratio of 1.6 (95% CI: 1.3 to 2.0) when compared with children aged 10–15 years.1 Although there are various reasons why children younger than 12 months of age might be at an increased risk of death (immature immune system, unique nutritional requirements, and other such reasons), it is reasonable to assume that being LTFU would also correlate with an increased mortality risk. These results advocate for starting children on ART as early as possible and launching new initiatives aimed at decreasing LTFU and improving adherence to medication among the very young. One of the most important approaches toward this will also be revisiting how we think of preventing maternal-to-child-transmission (PMTCT) of HIV.
It is estimated that 3.4 million children are living with HIV globally.2 Because the vast majority of new pediatric HIV infections are transmitted during labor or breastfeeding, PMTCT is the cornerstone intervention toward ending the pediatric HIV epidemic.3 This has been noted as a global political priority, with the US Secretary of State Hillary Rodham Clinton declaring the United States government's intent to create an “AIDS-free generation” by 2015 by focusing on strengthening PMTCT initiatives.
In 2010, the World Health Organization revised their guidelines for how to manage HIV-positive women during pregnancy.4 They recommended choosing one of two prophylactic regimens, termed “option A” and “option B” (women with CD4 counts <350 are still recommended to be placed on full treatment regimens). The 2 options are different in the antiretroviral agents used, but they are similar in that both are started during pregnancy and neither regimen goes beyond the breastfeeding period.4 Perhaps this abbreviated maternal treatment period, inherent to both option A and B, contributes to the high rates of LTFU in younger children and consequently higher risks for pediatric mortality. This thesis is an argument for scaling up a third option of PMTCT, known as option B+.
Option B+, initially introduced by Shouten et al in 2011 as a mechanism for Malawi to sidestep the necessity for CD4 testing of all pregnant women, involves placing all HIV-positive pregnant women on ART for life, regardless of CD4 count.5 There are various benefits to this proposed strategy, the most obvious being that women on life-long therapy will be healthier with less risk of contracting opportunistic infections, leading to lower overall mortality. But equally important, Option B+ could also result in less HIV maternal-to-child-transmission, especially in subsequent pregnancies, leading to the potential end of pediatric HIV (as opposed to stop–start methods proposed with option A and B).5
If the message to a mother is that she herself does not need treatment after the cessation of breastfeeding, as in option A or B, it is not unreasonable to assume that she might think the same about her HIV-positive children. The mixed message that we are giving to caregivers, that it is okay to stop treatment but that children should remain on it, might be contributing to the higher rates of LTFU in the younger-than-12-month age group, as reported by Leroy et al.
One of the major factors associated with pediatric adherence to ART is the caregiver's beliefs and attitudes toward medication.2,6–8 Previous studies from McCord Hospital's Sinikithemba HIV/AIDS pediatric clinic in South Africa demonstrated that HIV-positive primary caregivers showed a protective effect against mortality in HIV-infected children when compared with primary caregivers who were untested or HIV-negative.2,6–8 We hypothesize that HIV-positive mothers on ART at the same treatment site with option B+ may be able to provide more informed treatment support for their children, resulting in better pediatric clinical outcomes, including lower rates of LTFU and mortality. Further research is necessary to investigate these possibilities, but the importance of supporting all caregiver/dependent relationships is clear.7
At the 2012 International AIDS Conference, there was much attention given to option B+ and many discussions about a rapid scale-up of this program. However, studies on clinical and economic feasibility have yet to be done. Additional studies investigating postpartum adherence and resistance to ART are also needed before a global scale-up of option B+ is implemented.
This impactful study by Leroy et al points out many interesting findings related to mortality and LTFU in pediatric HIV patients, and the scope of the problem is clear. Ultimately, to improve pediatric LTFU and mortality, our efforts should also be focused on improving PMTCT initiatives toward ending the pediatric HIV/AIDS epidemic. A programmatic shift could be the targeted scale-up of option B+ for PMTCT in the countries with the highest rates of LTFU and mortality as reported by Leroy et al. We believe family-centered ART treatment models, emphasizing PMTCT option B+ and adult and pediatric ART treatment concurrently, are needed to protect the integrity of care giving structures and prevent the negative pediatric outcomes associated with the decline in health or death of primary caregivers.2,6–8
Note added in proof: Since the initial submission of our commentary, Adjorlolo-Johnson et al9 document outcomes from the Elizabeth Glazer Pediatric AIDS Foundation cohort comprising more than 33,000 children from Cote d'Ivoire, Mozambique, South Africa, Tanzania, and Zambia. The authors report increased pediatric enrollment in treatment programs that have specific linkages with people living with HIV (adjusted odds ratio = 4.2; CI: 1.8 to 9.5) and onsite PMTCT services (adjusted odds ratio = 3.1; CI: 1.0 to 11.1). Interestingly, linkages with people living with HIV and PMTCT are associated with an increase in children younger than 2 years of age on ART. These data affirm our recommendations of linking PMTCT with family centered treatment models.
A. Thyssen would like to acknowledge Simon Agolory and Andrew Abutu at the Centers for Disease Control and Prevention for their mentorship on PMTCT and global HIV/AIDS. A. Reddi acknowledges the inspirational mentorship extended to him by his former mentors at McCord Hospital's Sinikithemba HIV/AIDS clinic and at the Nelson R. Mandela School of Medicine, University of KwaZulu-Natal. The authors also acknowledge valuable discussions with Sarah Leeper in conceptualizing the family centered antiretroviral treatment model.
1. Leroy. J Acquir Immune Defic Syndr. 2012. In this issue.
2. Leeper SC, Reddi A. United States global health policy: HIV/AIDS, maternal and child health, and the President's Emergency Plan for AIDS Relief (PEPFAR). AIDS. 2010;24:2145–2149.
3. De Cock KM, Fowler MG, Mercier E, et al.. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA. 2000;253:1175–1182.
4. WHO. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach (2010 Version). Geneva, Switzerland: World Health Organization; 2010.
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. Reddi A, Leeper SC, Grobler AC, et al.. Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZulu-Natal, South Africa. BMC Pediatr. 2007;7:13.
7. Reddi A, Leeper SC. Antiretroviral therapy adherence in children: outcomes from Africa. AIDS. 2008;22:906–907.
8. Leeper SC, Montague BT, Friedman JF, et al.. Lessons learned from family-centered models of treatment for children living with HIV: current approaches and future directions. J Int AIDS Soc. 2010;13(suppl 2):S3.
9. Adjorlolo-Johnson G, Wahl A, Ramachandran S, et al.. Scaling up pediatric HIV care and treatment in Africa: clinical site characteristics associated with favorable service utilization. J Acquir Immune Defic Syndr. [published online ahead of print September 5, 2012]. doi: 10.1097/QAI.0b013e3182706401.