The strategic use of ARVs Global evidence and experience to date Professor Charles Gilks UNAIDS India National Consultation on the Strategic Use of ARVs Bangkok 9 – 10 th August 2012

Strategic use of ARVs Background Evolution of the concept Evidence it may work Implications for Thailand Global implications

ARVs for therapy Cumulative Life-Years Gained from Antiretroviral Therapy, 1996–2011 — Global total High-income countries Low- and middle income countries 25 Cumulative life-years gained (in millions) Source: Joint United Nations Programme on HIV/AIDS,

ARVs for prevention Biological plausibility – HIV is an infectious disease – Clear gradation of viral load on infectivity – PACTG 076 (1994): AZT prevents MTCT – TB control based on treatment Global ART scale-up since 2001 – Massive achievements in starting ART ARV prophylaxis for HIV prevention – Pregnant women in PMTCT programmes – Health-care workers access to PEP So why so long for strategic use for Prevention?

False dichotomy Treatment or Prevention Initial focus in many countries on prevention ART unaffordable and too complex ART scale-up will squeeze prevention funding – Insufficient new funding will come in for ART – Over-medicalise the response to HIV/AIDS Cannot treat our way out of the epidemic – Condoms work; behaviour change; NSP – Prevention revolution: vaccines, microbicides, MC No evidence of impact as ART scaled up

Scale-up of ART, number of AIDS deaths and new HIV infections in LMIC, 2001–2011

Low-income Lower middle- income High-income come Upper middle- income Year of starting ART Mean CD4 count (cells/µl ) (ccells/µells/µL) Estimates from random-effects model adjusted for age, sex and year of starting ART, Mean CD4 count at ART initiation is below 200 in Low and Middle-income Countries Source: Egger M. CROI

Evolution of the concept: Strategic use of ARVs for prevention Limited ecological data showing ART had an impact at population level: Taiwan; BC, Canada; KZN S. Africa PMTCT worked – goal of elimination by 2015 PEP (Post-exposure Prophylaxis) works Why such limited impact with ART scale-up: – was ART started too late ? – was coverage too limited? Need for evidence: – Randomised controlled trials –PrEP and ART – Modelling while RCTs underway Motivation: this would generate new impetus for HIV prevention and generate new resources for ART scale-up & HIV prevention as global funding was flat-lining and/or reversing and declining

The Test and Treat Model

A framework to understand the epidemiological impact of cART to onward HIV transmission The HIV Modelling Consortium TasP Editorial Writing Group PLoS Medicine 2012 vol 9 e

Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death HPTN 052 Study Design Immediate ART CD Delayed ART CD4 <250 Randomization Immediate Arm 886 Couples Delayed Arm 877 Couples

Total HIV-1 Transmission Events: 39 HPTN 052: HIV-1 Transmission Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 p < Immediate Arm: 1 Delayed Arm: 27 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm 3, and VL >50,000 copies/ml at transmission 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners

HIV Prevention Technologies Shown to Be Effective in Reducing HIV Incidence in Randomized Clinical Trials

Mode of TransmissionGeographic Focus 94% of new infections 41% 11% 32% 10% 6% 27 provinces (1/3 rd of provinces) cover 70% of new HIV infections Know your epidemic: who is getting infected? Strategic use of ARVs : implications for Thailand Note also infants born with HIV/year (< 350: <3% )

Build on success Enhance PMTCT programme to eliminate new HIV infections among Thai children by 2015 and keeping their mothers alive PMTCT

Oral Pre-Exposure Prophylaxis: PrEP

End 2011: 500,000 adults and children HIV+ 10,450 new cases of HIV nationally in 2011 ART Threshold (2010) is CD4 < 350 cells/mm % ART coverage (225,272 / 348,671) Late entry into ART: median CD4 77 cells/mm 3 Revise CD4 threshold: immediate or < 500 Improve coverage to 80% + Intense focus on test-treat-retain cascade Special focus on couple counselling Early ART as Prevention : implications for Thailand

TasP: implications for Thailand Improve ART coverage to 80% – Current CD4 threshold <350: extra 55,000 patients – Test and treat (80% of 150,000): extra 120,000 patients Median time to CD4 threshold for ART Test and treatimmediate / no delay CD4 < 500within 2 years CD4 < 350within 4 – 5 years CD4 < 200within 8 – 10 years Source: CASCADE data: Sara Lodi et al CID 2011;

TasP: implications for Thailand From Controlling the HIV epidemic with ARVs consensus statement IAPAC July 2012

TasP global issues: elimination of new HIV infections among children by 2015 and keeping their mothers alive

TasP global issues : ART eligibility policy Recommended Since 2003 CD4 ≤ 200 Recommended since 2010 Recommended since 2010 CD4 ≤ 350 Incremental approach 2012 CD4 ≤ TasP Ongoing systematic review of evidence (GRADE review) Ongoing systematic review of evidence (GRADE review) CD4 ≤ 500 “Test and treat” All HIV+ ART regardless of CD4 count for: - Serodiscordant couples - Pregnant women - Key populations (SW, IDU, MSM) ART regardless of CD4 count for: - Serodiscordant couples - Pregnant women - Key populations (SW, IDU, MSM) Estimated millions of people eligible for ART in LMIC in Estimated millions of people eligible for ART in LMIC in

TasP global issues : treatment gap to 2015

Potential future areas for ART Optimization Simplification of tenofovir route synthesis Use of 3TC instead of FTC Reduced dosage of 3TC and EFV Substitution of EFV for Rilpivirine or NVPxr or Lersivirine TDF-FTC-EFV AZT-3TC + LPVr Reduced dose of AZT, 3TC and LPVr Substitution of 3TC for Apricitabine or Racivir or Elvucitabine Substitution of LPVr for ATVr or DRVr Substitution of AZT/3TC for integrase inhibitors (Raltegravir, Elvitegravir or GSK 572) Maintenance with PI monotherapy Substitution of RTV for cobicistat or SPI st Line 2 nd Line Use of co-blister packs

Fear of HIV DR is not a reason to hold back on TasP and further rapid treatment scale-up; Nor does it mandate intensive and routine laboratory monitoring; HIV drug resistance

Illustration by Peter Schrank From The Economist Nov 27th 2008 Illustration by Peter Schrank The ideal and the good Deploying the drugs used to treat AIDS may be the way to limit its spread