ART Regimen Selection and Treatment Initiation for PMTCT Programs Lara Stabinski, MD, MPH Medical Officer Clinical Services S/GAC June 18, 2012

Technical Overview 1. PMTCT Options and ART Regimens Recognized in WHO PMTCT Programmatic Update Who needs ART? 3. Benefits of ART 4. New WHO Guidance on ART in Pregnancy

WHO PMTCT Update 2012

Women Eligible for ART Are At Highest Risk for Mother to Child HIV Transmission and Mortality  Cohort 1,025 pregnant women in Zambia prior to HAART availability  Analyzed MTCT/mortality by eligibility for ART with current WHO criteria (CD4 <350 or WHO Stage 3 or 4) Kuhn L et al. AIDS 2010;24: Who needs ART?

WHO Options A & B Who needs ART?

Transforming PMTCT: Option B+ “Recent developments suggest that substantial clinical and programmatic advantages can come from adopting a single, universal regimen both to treat HIV-infected pregnant women and to prevent mother-to-child transmission of HIV.” -April 2012 WHO Programmatic Update on the use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants 10 PEPFAR countries are currently implementing, transitioning to, or considering Option B+ Who needs ART? Option B+ provides full antiretroviral treatment for life for all HIV-positive pregnant women, regardless of CD4

Connecting PMTCT and Treatment Pregnant Women represent an increasing proportion of all patients initiating combination antiretroviral therapy at PEPFAR sites. A recent study of PEPFAR programs in Kenya, Uganda, and Tanzania found that between 2002 and 2008 the prevalence of pregnancy at cART start increased from 2.6% to 16.0% Year of ART initiation Estimated proportionObserved proportion Proportion pregnant at ART start Who needs ART? Holmes, et al, CROI 2012

National ARV Coverage for PMTCT, 2010 Source: Universal Access Report, 2011 % National ARV Coverage for PMTCT Who needs ART?

Linking Eligible Women with ART Who needs ART?

WHO 2010 Treatment Recommendations CD4<350 & for TB, ART initiation regardless of CD4 count Starting Treatment Earlier in Resource Limited Settings Reduces Morbidity and Mortality (CD4 350 vs 200) Severe, P et al. NEJM, % reduction in the rate of death 50% decrease in the incidence of tuberculosis CIPRA HT-001 Benefits of ART

CD4 <500 (Mostly Cohort Studies, sub-analysis of RCCT) – NA-ACCORD 6,278 patients* Delayed Treatment 70% increase progression to AIDS or Mortality – ART-CC 45,691 patients, 18 cohort studies# Delayed Treatment 30% increased progression to AIDS or Mortality – HIV-CAUSAL 8,392 patients# Delayed Treatment 38% increase progression to AIDS or Mortality – CASCADE 5,527 patients Early treatment decreased mortality by half – SMART 249 patient subgroup Deferred therapy were 4.6 times more likely to die or have an AIDS related event – HPTN 052 1,763 patients Approximately 40% reduction in events/mortality, benefits driven by extrapulmonary TB *Also showed mortality benefit >500 # Did not show morbidity or mortality benefit >500 Decreasing Morbidity & Mortality With Earlier Treatment Benefits of ART

ART Potential Benefits to Maternal Health Maternal Mortality 24 months post-partum – Zambia study 2010 (n=14,110;ref group= HIV-) HIV+ Mortality higher all CD4 Counts Cause specific mortality higher TB, pneumonia, meningitis, puerperal sepsis, hemorrhage, PID Benefits of ART Hargrove JW et al. AIDS.Hargrove JW et al. AIDS Jan 28;24(3):F11-4. < K >1K

HPTN 052:Treatment Prevents HIV Transmission Benefits of ART

HPTN052: Linked HIV-1 Transmissions: 27 vs 1 Cohen et al, NEJM 2011 Treatment as Prevention Benefits of ART “A real game changer …” “People can say with a good deal more confidence that treatment is prevention.” - Dr. Tony Fauci, US National Institute of Allergy and Infectious Diseases

Validation: HIV Incidence and ART Coverage Tanser, CROI 2012 Benefits of ART Every percentage point increase in ART coverage among all HIV + adults in a community was associated with a 1.7% decline in the hazard of HIV acquisition (p <0.001) faced by an HIV – adult living in the same community

ART and Maternal Health Services Investigators assessed the effect of HIV programs on the utilization of maternal health services by HIV negative women over time: 257 PEPFAR-funded facilities in 9 countries (1907 quarters) There was a 1.3% increase in facility deliveries for a 10% increase in HIV patients in care per quarter. The number of facility deliveries was positively associated with the total number of ART patients in care in the past quarter, availability of HIV support groups, onsite CD4+ testing, and electronic HIV data systems. Evidence that building systems to deliver ART and other services can have beneficial effects. Kruk et al, CROI 2012 Benefits of ART

WHO 2010 Guidance on ART Regimens for Pregnant Women These guidelines also suggested that: Efavirenz (EFV) should not be used in the first trimester. Nevirapine (NVP) should not be used at CD4 counts >350

WHO Updated Guidance June 2012 Supports the use of EFV to Optimize and Simplify Treatment EFV superior efficacy and tolerability compared to NVP Substantial reduction in the price of EFV Increasing availability as part of a once-daily FDC Reassuring data on the risk of birth defects in pregnancy Programmatic experience highlighting complications and misconceptions about switching EFV to NVP in pregnancy

Price Evolution of NVP and EFV

TDF In Pregnancy Concern in pregnancy for fetal growth based on animal data at high doses PHACS Study (2012) – N=2,000 births women TDF in Pregnancy – No greater risk of low birth weight, small head circumference or reduced weight for gestational age – Found very small but significant difference in length for age at 1 year in infants Should be viewed in the context of potential increased mitochondrial toxicity seen with infant AZT exposure and maternal anemia on AZT May be especially useful where prevalence of HIV-HBV co- infection is high Can be used in once daily FDC

Acknowledgements S/GAC Clinical Team PEPFAR Technical Working Groups (Adult Treatment, PMTCT)