Mothers, orphans, and prevention of paediatric AIDS
Karen Palmore Beckerman, MD
In the Lancet (6 April 2002), investigators from the Petra trial of the prevention of transmission of HIV from mother to child report that short-term prophylaxis with a two-drug antiretroviral combination significantly reduces vertical transmission rates more than two-fold in early infancy.
At 6 weeks of age, 15% of infants in the placebo group were infected, compared with 6% in the group that received antepartum, intrapartum, and neonatal prophylaxis with zidovudine plus lamivudine. However, when measured as HIV-free survival at 18 months of age, this benefit was not sustained.
This study was planned many years ago and used a two-drug combination that, in developed countries at least, is no longer administered without a third antiretroviral agent. While the risks and benefits of such an intervention were acceptable when this study was planned, progress in HIV treatment and geometric expansion of the HIV pandemic have altered such considerations significantly.
Benefits of prophylaxis for perinatal transmission include protection of babies from HIV infection and an opportunity to introduce communities to AIDS education, testing, and drugs. Considerable infrastructure is required for the distribution of even the simplest antiretroviral prophylactic regimens—a good start when looking forward to expansion of AIDS therapies in the developing world. Indeed declines in cost of AIDS therapies, availability of generic and proprietary formulations of double and triple antiretroviral combinations, and changing global commitment against the pandemic have made arguments discounting the feasibility of treatment access in poorer nations largely irrelevant. Successful AIDS treatment protocols among the marginally housed, the urban poor in Brazil, and the displaced rural poor in Haiti have been published.
The risks of Petra and other perinatal prophylaxis interventions, such as HIVNET 012, which use single-dose nevirapine intrapartum and neonatally as prophylaxis, have increased in proportion to the increasing probability of access to AIDS treatment in resource-poor settings. Treatment success in such regions will hinge on the use of low-pill-burden non-protease-inhibitor combinations, relying on the very classes of drugs used in such studies. Nevirapine prophylaxis used in HIVNET 012 resulted in selection of single-point mutations strongly associated with high resistance to non-nucleoside reverse transcriptase inhibitors that were detectable in 19% of mothers and 46% of the 16% of infants infected despite nevirapine prophylaxis. Given the 6-week absence of nevirapine exposure (and therefore of selective pressure favouring replication of resistant virus), the reported resistance underestimates the true rates. That these mutations may fade from detection after a year provides little comfort. The K103N and Y181C mutations produce virus that is resistant and fit (ie, will continue to replicate and compete with wild-type virus, even in the absence of nevirapine to produce selective pressure against wild-type virus), and current assays fail to detect minority populations and mutations archived in lymphocytes. By contrast with HIVNET 012, where intrapartum and neonatal exposure to nevirapine or zidovudine was limited, the Petra interventions led to ongoing maternal exposure to zidovudine plus lamivudine from 36 weeks’ gestation (arm A) or from delivery (arm B) to 7 days’ postpartum. Induction of significant single-mutation (M184V ) lamivudine resistance in one or both of these arms is certain.
Is it justifiable to visit the antiretroviral mistakes of the industrialised world on regions that have been devastated by the HIV epidemic but are at least antiretrovirally naive? Active deployment of Petra A or B or the HIVNET 012 protocols for millions of pregnancies (as both teams and many others advocate) may prevent hundreds of thousands of paediatric infections per year. However, these same women and their infected children exposed to short-course zidovudine plus lamivudine or single-dose nevirapine will be at substantial risk of treatment failure when antiretroviral therapy becomes available.
Instead of inducing resistance to AIDS therapies, prophylaxis against mother-to-child transmission must be linked to preventing the creation of orphans. We know that 3-4% of HIV-infected sub-Saharan mothers die within a year of delivery. Within 2 years, 11% of HIV-infected breast-feeding mothers die. Their babies are unlikely to survive infancy. An older child who survives the death of mother will join the rapidly growing global ranks of orphans less than 15 years of age predicted to reach 44 million by 2010. With or without antiretroviral prophylaxis, most of these children will be HIV-uninfected. They will face extraordinary risk of inadequate nutrition, housing, and health care, in addition to servitude, harshness, abuse, and acquisition of HIV infection themselves. Sub-Saharan teenagers will outnumber adults by 2020, rendering already politically unstable regions potentially explosive. However, although support for home care, community programmes, and government services are routinely mentioned as effective responses to the global orphan tragedy, strategies to prevent the creation of orphans – that is, saving the lives of parents – are rarely discussed. This lack is particularly disturbing in view of the developed world’s experience that treatment of maternal HIV disease results in transmission rates far lower than transmission prophylaxis alone.
The silence surrounding HIV disease and maternal health has been long-standing. Typical of perinatal prophylaxis trials, the Petra report mentions no maternal-health endpoints and no maternal mortality data later than 6 weeks after birth. 10-15 years into the pandemic when these trials were conceived, treatment access and success had not been widely demonstrated or acknowledged anywhere in the world. Now, in the third decade of AIDS, HIV prevention and AIDS treatment can and must be integral parts of the global response to the AIDS catastrophe. What better place to start than with mothers and children?
Beckerman KP. Mothers, orphans, and prevention of paediatric AIDS. Lancet 2002 Apr 6;359(9313):1168-9.
Correspondence: Karen Palmore Beckerman, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco/San Francisco General Hospital, San Francisco, CA 94110, USA (e-mail:firstname.lastname@example.org).