THE NEVEREST STUDY AT RAHIMA MOOSA MCH Ashraf Coovadia Adjunct Professor Enhancing Childhood HIV Outcomes (Wits Paediatric HIV Clinics) Rahima Moosa Mother and Child Hospital University of the Witwatersrand

Rahima Moosa Mother and Child Hospital HIV Research Unit

Research PCR testing of infants 2001/2002 (Prof Gayle Sherman) Earlier Infant Diagnosis Study underway (Prof Gayle Sherman) 2008 COPE Pregnant Women on HAART IeDEA

NEVEREST Rationale PMTCT programmes globally using sdNVP Simple, effective and cheap Downside is the issue of NVP resistance ? Impact on future treatment efficacy with an NNRTI-containing regimen Research required to answer the question for both women and children

NEVEREST 1 Objective Whether there are long-lasting effects of exposure to sdNVP treatment on virologic response to NNRTI–based therapy among HIV–infected women.

NEVEREST 1 EXPOSED Group - 94 HIV-infected women who had received sdNVP (18– 36 months earlier) UNEXPOSED Group - 60 unexposed, HIV-infected women who had been pregnant (12–36 months earlier)

NEVEREST 1 VL measured at regular intervals Time to viral Suppression (VL 400 cpm) were compared. Drug resistance was assessed using K103N allele–specific real-time PCR assay and population sequencing.

NEVEREST % of Exposed women and 91.3% of Unexposed women achieved viral suppression by week 24 (P=0.21) 19.4% of Exposed women and 15.1% of Unexposed women experienced viral rebound within 78 weeks (P=.57) after treatment

NEVEREST % of women for whom K103N was detected did not experience viral suppression or experienced viral rebound, compared with 15.1% of women for whom K103N was not detected (P<.001)

CONCLUSION Exposure to sdNVP in the prior 18–36 months was not associated with a reduced likelihood of achieving and sustaining viral suppression while receiving NNRTI-based therapy. However, women with minority K103N mutations before treatment had a reduced durability of virologic suppression.

PUBLICATIONS ° CID 2009:48 (15 February) ° HIV/AIDS

NEVEREST 2 Treatment options for HIV-infected children are limited Many children in resource-limited settings have been exposed to sdNVP Guidelines recommend starting PI-based regimens in infants No data on whether or not we need to sustain PI regimen indefinitely Investigation of a switch strategy is warranted given concerns around cost and long-term toxicity of PI-based regimens

NEVEREST 2 Objective To examine the efficacy of switching from a PI-based regimen to an NNRTI-based regimen in children previously exposed to sdNVP

Study design sdNVP-exposed children Meet criteria for ARVs 6 weeks – 24 months of age Start RTV or LPV/r, 3TC, d4T Suppressed <400 cpm > 3 months by 52 weeks Eligible for randomization Stay on LPV/rSwitch to NVP By 52 weeks post-random <50 cpm By 52 weeks post-random <50 cpm

PUBLICATIONS AIDS 2009, 23:

TRANSLATION The impact this has made Allowed us to impact on PMTCT guidelines locally (and hopefully internationally) How has this work has developed into other research or practice and what you expect to accomplish in the years to come Plan to continue work on children exposed to sdNVP and investigate switch strategies at a later age. Optimal regimens for children who are co-treated for TB Optimal PMTCT regimens Adherence strategies

ACKNOWLEDGEMENTS Co-Investigators Louise Kuhn, Tammy Meyers, Gayle Sherman Sub-Investigator – Renate Strehlau, Leigh Martens The Principal Funders – STF, NIH (Archie Smuts, Sebastian Wanless, Prof Lynne Mofenson) The Gauteng Department of Health The staff and patients on the NEVEREST study The collaborators