MTCT Agenda:

Although perinatal transmission has dropped to less than 2% in the U.S., in developing countries approximately 640,000 MTCT infections occur each year. Shorter ARV regimens have proven to be efficacious [57-59], but overall effectiveness is suboptimal due to later transmission via breastfeeding, the limited efficacy of shorter regimens in the antenatal period, and the difficulty of implementing programs for VCT and PMTCT regimens. In addition, even short regimens of nevirapine or 3TC can rapidly select for drug resistance that may potentially limit future treatment options in HIV+ women and children. The perinatal agenda will evaluate new ARV regimens to prevent MTCT during the perinatal period with special emphasis on low resource areas, evaluate MTCT prevention strategies to minimize development of ARV resistance in mothers and infants, focus on interventions such as use of ARVs and vaccines to prevent breastfeeding transmission, evaluate strategies to increase population-based coverage of MTCT prevention, and assess ARV PK and toxicities in pregnant women. Substudies to evaluate the role of HIV subtype, host genetics, drug resistance, pharmacodynamics, HIV-specific immunity, and HIV viral load in compartments in PMTCT are also planned.

Specific Aim 1: To develop and improve simple, safe, and effective ARV regimens to prevent mother-to-child HIV transmission in the perinatal period with special emphasis on low-resource areas.

Specific Aim 2: To optimize MTCT-related ARV treatment strategies to improve maternal and infant health through the reduction of ARV resistance and improved safety.

Specific Aim 3. To evaluate simple, safe, and effective interventions to prevent HIV transmission through breastfeeding.

Specific Aim 4. To evaluate population-based strategies for prevention of mother-to-child HIV transmission among childbearing populations receiving PMTCT care in limited-resource settings or with limited access to structured antenatal PMTCT programs.

Specific Aim 5. To determine the pharmacokinetics, safety, tolerability, and toxicity of ARVs used for PMTCT HIV transmission and maternal health management

Translational Agenda:

In this priority area IMPAACT plans to conduct translational research in three areas:

1. Primary antiretroviral therapy for treatment of HIV infection
2. Prevention and treatment of the complications of HIV infection and ARV drug toxicities.
3. Therapeutic HIV vaccines

Specific Aim 1: To evaluate the pharmacokinetics and safety of new ARVs and formulations leading to optimal labeling and licensing for infected infants, children, and adolescents.

Specific Aim 2: To evaluate safety and/or immunogenicity of approaches for the prevention and treatment of co-infections, ARV toxicities and associated metabolic complications, and developmental complications of HIV infection.

Specific Aim 3. Determine safety, immunogenicity, and affect on viral replication of candidate vaccines in infected infants, children, and adolescents.

Optimization of Clinical Management, Including Co-Morbidities Agenda:

IMPAACT has identified the following strategic areas of primary therapy, immune based therapies, and treatment of co-infections/toxicities, where carefully constructed clinical studies can yield data that will improve the outcomes of HIV-infected infants, children and adolescents worldwide.

Specific Aim 1. Evaluate ARV treatment strategies in infants, children, adolescents that have the potential to result in greater and more prolonged suppression of viral load, enhanced immune response, decrease mortality, toxicity, and drug resistance, produce more affordable regimens, and less expensive assay monitoring.

When to Start – A number of infants and children mount an effective immune response to HIV and do not qualify for treatment under WHO guidelines. Two studies are proposed to evaluate whether early vs deferred treatment makes a significant difference in disease outcome:

Treatment Interruption Strategies – A proportion of HIV infected children who stop ARV treatment indicate that some children do not virologically or immunologically progress [68-70]. Studies examining various strategies to maximize immune function, while minimizing ARV toxicities and expense, are needed. Within these studies parameters that predict success with intermittent ART and need for continuous ART will be identified.

Strategies to deal with ARV Resistance – Three trials will compare specific multi-drug regimens or cycling of different HAART regimens for suppression of HIV replication. In addition, protocols will examine the efficacy of NNRTI-ART regimens in nevirapine exposed vs unexposed infants

Second-Line Therapy for Children Failing NNRTI-based first line treatment is a priority area within Africa and Asia, as to which second-line regimen is most efficacious and least toxic.

Specific Aim 2: To conduct studies leading to the optimal use of vaccines, prophylactic regimens and therapies for prevention and treatment of co-infections in HIV infected and exposed infants, children, adolescents, and pregnant women.

Specific Aim 3: To conduct studies to evaluate, prevent, and treat the complications of pediatric HIV infection and antiretroviral drugs, including but not limited to metabolic disorders, neurologic and psychiatric co-morbidity, and other complications.

VACCINES FOR PREVENTION OF SEXUAL HIV TRANSMISSION:

Specific Aim 1. To evaluate and implement an effective vaccine regimen to prevent sexual transmission of HIV-1 in adolescent and pre-adolescent populations.