Prevention of maternal-to-infant HIV transmission has been one of the major success stories in the fight against this relatively new infection. New Jersey Medical School (NJMS) investigators and associated clinical trials programs have made major contributions to this effort, beginning with the landmark PACTG 076 trial in 1994, which demonstrated that the sequential use of AZT during pregnancy, labor, and in the newborn reduced transmission by two-thirds. The ‘076’ prevention strategy has become a public health standard in the developed world and is a key component in the dramatic reduction of new pediatric HIV infections. The remarkable success of 076, combined with the inability to implement such a complex regimen in resource-poor countries, where most of the infection burden resides, led to a search for simpler, more feasible strategies, culminating in the HIVNET 012 trial. This study, conducted in Uganda, demonstrated in 1999 that a single dose of the drug nevirapine, administered to an HIV-infected mother in labor, and a single dose to her newborn, can reduce transmission risk by about half. Both trials were conducted in NIH-funded HIV Clinical Trials Networks in which our local group of NJMS investigators participates, and like 076, HIVNET 012 has resulted in sweeping public health policy changes in the global setting.
The euphoria following the announcement of the 012 results was tempered modestly one to two years later by the realization that a large percentage of women developed viral resistance to nevirapine after just the single dose. In addition, the subset of infants exposed to single dose nevirapine who became HIV-infected also demonstrated a high rate of viral resistance to the drug. While the viral resistance generally wanes to a non-detectable level over a six- to 12-month time period (using standard, relatively insensitive assays), this phenomenon raised serious concerns about the effectiveness of subsequent treatment strategies should a mother and/or her baby qualify for and have access to treatment. Although multiple antiretroviral (ARV) agents and drug classes are available in the developed world, limited treatment options are available in resource poor settings. In particular, first line treatment regimens feature the non-nucleoside reverse transcriptase inhibitors — nevirapine and efavirenz — both of which will be hypothetically compromised by prior single dose nevirapine exposure. Preliminary studies of a cohort of Thai mothers who began treatment after prior receipt of single dose nevirapine suggested that treatment responses were modestly inferior compared with control mothers, but rigorous follow-up studies are clearly warranted. There are additional hypothetical concerns for infected babies in this situation, given that their
initial infection is established with mutated, resistant viruses as the majority
Many research groups were quick to take up the challenge posed by this very effective, but potentially seriously flawed prevention modality. One such group was organized by the NIH Division of AIDS, which convened a think tank meeting in 2003. It resulted in four interrelated trial concepts — two to probe innovative approaches to prevent the emergence of resistant virus in mothers and neonates in the prevention setting and two to study the consequences of single dose nevirapine exposure on subsequent treatment efforts in women and children.
I have been fortunate to lead the formation of a trial team charged with investigating treatment consequences in HIV-infected children with prior single dose nevirapine exposure. Together with my associate chair — Avye Violari, MD, from Johannesburg, South Africa — we have assembled a group of domestic and international experts, including pharmacologists, biostatisticians, and community representatives, and developed a clinical trial entitled: PACTG 1060 — Parallel Randomized Clinical Trials Comparing the Responses to Initiation of NNRTI-based versus PI-based Antiretroviral Therapy in HIV-Infected Infants Who Have and Have Not Previously Received Single Dose Nevirapine for Prevention of Mother to Child Transmission. This trial will be conducted at international sites within the Pediatric AIDS Clinical Trials Network (PACTG) funded by NIH. It has two major goals: 1) to compare treatment responses of single dose nevirapine-exposed and unexposed infants who qualify for HIV treatment by World Health Organization criteria and who are between six months and three years of age; and 2) to compare the relative efficacy of NNRTI-based versus PI-based ARV regimens for initial therapy in this age group, for which there is plenty of investigator bias but a lack of data. The trial plans to enroll 480 children, is rigorously designed biostatistically, and is currently targeted for implementation in three South African sites (Johannesburg, Cape Town and Durban) and possibly in Uganda, Zimbabwe and Botswana.
Serial challenges have presented themselves, not the least of which has been negotiating with three individual pharmaceutical companies to serve as collaborators for trial design and provision of trial drugs. Special issues, such as breast versus formula infant feeding, maintenance of a local cold chain for drug storage, and trial indemnification, have had to be addressed. In addition, multiple trial approvals have to be received from the Division of AIDS at NIH, from local Institutional Review Boards and from Ministries of Health of each country involved. PACTG 1060 is projected to begin enrollment in the fall of 2005 and to require two years to complete enrollment and an additional half year for cohort follow-up. A new, independent International Data Safety Monitoring Board (iDSMB) has been convened by the Division of AIDS to oversee the progress, safety and outcome of the trial. The iDSMB has recently reviewed the protocol and plans serial, closed reviews during the course of the trial. Rigorous rules have been established for early study termination should safety or outcome issues warrant. The outcome of this trial is eagerly anticipated by the international community and it is hoped that substantial contributions to pediatric HIV treatment will be forthcoming.
Paul Palumbo, MD, is a professor of pediatrics, biochemistry and molecular biology at UMDNJ-New Jersey Medical School. He has been a long-standing participant in maternal and pediatric HIV clinical trials and in laboratory-based studies of pathogenesis. Dr. Palumbo participates in the leadership of multiple HIV clinical trials groups, including the Pediatric AIDS Clinical Trials Group (PACTG; NIAID-funded) in which he serves as the group vice-chair, the Adolescent Trials Group (ATN; NICHD-funded), and the newly formed IMPAACT Network, which is a collaboration of the PACTG and the Perinatal Working Group of the HIV Prevention Trials Network (HPTN; NIAID-funded).§