Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HIV Treatment for Adults and Adolescents Stefano Vella MD Istituto Superiore di Sanità - Rome - Italy

WHO 2013 Guidelines contribution to fill the treatment gap Operational / Programmatic Guidance –Improve testing coverage, address late presentation –Optimize care delivery models: offer something meaningful in the pre-art period, task sharing, decentralization and integration of care, address attrition community involvement procurement Clinical Guidance –Improve the quality of drugs –Simplify and harmonize 1 st line regimens –Perfect monitoring –Streamline subsequent treatment lines –Consider co-infections and co-morbidities

WHO’s 2013 Guidelines: the challenge To find the right balance between : the “individualized” approach to ART….. and the “public health” approach needed to start and maintain on ART over 20 million persons….… …. considering the different HIV epidemics …. while keeping the same - evidence-based - standard of care!

Strong evidence of the impact of ART on HIV transmission: o HPTN 052 study Emerging data on the impact of ART on HIV incidence at the population level Increasing evidence on clinical benefits of early ART initiation: o Observational studies showing impact on HIV mortality and morbidity o Scientific insights on HIV immunopathogenesis and on the effects of chronic inflammation associated with HIV infection Better regimens: o Better tolerable drugs o Better formulations o New classes When to start ART: what is new since 2010 ?

When to start ART 2013 WHO consolidated Guidelines Evaluating Risks & Benefits of earlier ART initiation Potential benefits ↓ risk of HIV transmission (sexual and vertical) ↓ risk of TB disease ↓ risk of serious non-AIDS conditions (HBV disease, cardiovascular disease, renal disease, liver disease, cancers)  linkage to care  chance to achieve higher CD4 values (immune recovery) ↓ long term costs (infections and co morbidities averted) Potential risks long-term adverse effects / toxicities limitation of future treatment options (with drug resistance concerns)  stigma & discrimination ↓ long term adherence ?  burden on healthcare infrastructure / feasibility  immediate cost

When to start in adults: what is new in the 2013 Guidelines Considering both the individual and the Public Health benefit…. Threshold moved to < 500 CD4 Priority for reaching all HIV+ symptomatic persons and those with CD4 ≤ 350 More CD4-independent situations for ART initiation (in addition to HIV/TB coinfection and HBV advanced liver disease): – HIV serodiscordant couples, – Pregnancy – Children less than 5 years of age GL are a “tool” for countries to produce their own guidelines: they will adapt the new threshold(s) with operational / programmatic local context

Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count < 200/mm 3 CD4+ Cell Count /mm 3 CD4+ Cell Count /mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2013 Yes Yes 1 Yes 2 International AIDS Society-USA, 2012 Yes Yes 1 Yes 2 British HIV Association, 2012 Yes Consider 3 Defer 3 European AIDS Clinical Society, 2012 Yes Consider 3 Defer 3 World Health Organization, 2013 Yes Yes 4 Defer 5 (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers and serodiscordant couples (4) Individuals with CD4 < 350 as a priority. (5) But treat all HIV+ pregnant women,TB co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls Major Guidelines for Initiation of Antiretroviral Therapy

2013 WHO consolidated Guidelines What ARV regimens to be used in adults O ne-pill-a-day FDC as preferred 1 st line(s) Reducing the number of preferred regimens Defining substitution regimens Harmonizing regimens across different target populations (TB, Hepatitis B, Pregnant Women)

1st Line ART Adults and Adolescents (including pregnant women, TB co- infection and HBV co-infection) Preferred (FDC) Regimen(s) TDF+3TC (or FTC) + EFV Alternative Regimens AZT+ 3TC + EFV (or NVP) TDF+ 3TC (or FTC)+ NVP Special situations ABC +3TC +EFV (or NVP) AZT (or ABC)+ 3TC + LPV/r or ATV/r One regimen cannot fit all: alternative, special situations 2013 WHO consolidated Guidelines

Major parameters TDFABCAZTd4T Major toxicities Renal and bone toxicity ABC hypersensitivity syndrome Anemia and neutropenia Lipodystrophy and neuropathy Major drug Interactions Boosted PIsNot significant IFN RBV INH ddI Convenience (once vs twice daily regimen) once daily once or twice daily twice daily Safety in pregnancy Yes yes Availability as triple FDCs YesNoYes GI intolerance Not common FrequentNot common Consistency with pediatric regimens (all ages) No (only for 3 years and older) Yes Cost (generic, annual, per patient) US$ 57US$ 169US$ 75US$ 19 Challenges ahead (i): current NRTIs

Phasing out d4T: trends of d4T, AZT and TDF use in adults first line ART (2006 – 2012 ) N= 12 countries 44% 27.9% 70% 27.9% HIV/AIDS Department

Challenges ahead (ii): second-line regimens

Comparative Analysis of ATV/r, LPV/r and DRV/r

Additional 1 st line options Better 2 nd / 3 rd lines New strategies (if proven effective) Additional 1 st line options Better 2 nd / 3 rd lines New strategies (if proven effective) NucleosidesIntegrase InhibitorsNon-nucleosidesProtease Inhibitors Available agents / combinations RaltegravirRilpivirine (FDC)Darunavir (boosted FDC) Elvitegravir (FDC) Investigational agents / combinations TAF (TDF prodrug)Dolutegravir (FDC)MK-1439TMC New drugs and new combinations shall be made available, globally, at affordable price, when possible as FDCs New drugs and new combinations shall be made available, globally, at affordable price, when possible as FDCs Need to move forward: towards the 2015 guidelines…..

17 April WHO ART Guidelines in Adults: a summary Topic When to start CD4 ≤200 - Consider CD4 ≤ 350 for TB CD4 ≤ 350 -Irrespective CD4 for TB and HBV CD4 ≤ 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 ≤ 350 as priority 1 st Line 8 options - AZT preferred 4 options - AZT preferred 8 options - AZT or TDFpreferred - d4T dose reduction 6 options &FDCs - AZT or TDF preferred - d4T phase out 2 options & FDCs -TDF and EFV preferred across all populations 2 nd Line Boosted and non-boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r Boosted PI - Heat stable FDC: ATV/r, LPV/r Boosted PIs -Heat stable FDC: ATV/r, LPV/r 3 rd Line None DRV/r, RAL, ETV Viral Load Testing No (Desirable) Yes (Tertiary centers) Yes (Phase in approach) Yes (VL preferred for monitoring) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

17 April WHO ART Guidelines in Adults: a summary Topic When to start CD4 ≤200 - Consider CD4 ≤ 350 for TB CD4 ≤ 350 -Irrespective CD4 for TB and HBV CD4 ≤ 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 ≤ 350 as priority 1 st Line 8 options - AZT preferred 4 options - AZT preferred 8 options - AZT or TDFpreferred - d4T dose reduction 6 options &FDCs - AZT or TDF preferred - d4T phase out 2 options & FDCs -TDF and EFV preferred across all populations 2 nd Line Boosted and non-boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r Boosted PI - Heat stable FDC: ATV/r, LPV/r Boosted PIs -Heat stable FDC: ATV/r, LPV/r 3 rd Line None DRV/r, RAL, ETV Viral Load Testing No (Desirable) Yes (Tertiary centers) Yes (Phase in approach) Yes (VL preferred for monitoring) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department Evidence-based, but intentionally aspirational…

MONITORING ART RESPONSE Targeted viral load monitoring (suspected clinical or immunological failure) Routine viral load monitoring (early detection of virological failure) Switch to second-line therapy Maintain first-line therapy Viral load ≤1000 copies/ml Viral load >1000 copies/ml Repeat viral load testing after 3–6 months Evaluate for adherence concerns Viral load >1000 copies/ml Test viral load 70% greater resuppression rate after adherence intervention Viral load as a tool to reinforce adherence and discriminate between treatment failure and non-adherence: need to expand the availabity of point-of care diagnostics

A “game changer” document, and an important step towards the global alignment of the HIV standard of care 2013 WHO consolidated Guidelines

Acknowledgements Guideline Development Group Co-chairs: Anthony Harries, Gottfried Hirnschall Elaine Abrams (International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, Columbia University, USA) Tsitsi Apollo (Ministry of Health and Child Welfare, Zimbabwe) Kevin De Cock (United States Centers for Disease Control and Prevention, USA) Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d’Ivoire) Adeeba Kamarulzaman (University of Malaya, Malaysia) Yogan Pillay (National Department of Health, South Africa) Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda) Stefano Vella (Istituto Superiore di Sanità, Italy) Special thanks to all members of the Guideline Development Groups, the Peer Review panel and to those who contributed to the GRADE systematic reviews and supporting evidence which informed the guidelines process. WHO Department of HIV Andrew Ball Philippa Easterbrook Meg Doherty Eyerusalem Kebede Negussie Nathan Shaffer Lulu Muhe Nathan Ford Marco Vitoria Joseph Perriëns Guideline Development Group Pedro Cahn (Fundación Huesped, Argentina), Alexandra Calmy (University of Geneva, Switzerland), Frank Chimbwandira (Ministry of Health, Malawi), David Cooper (University of New South Wales and St Vincent’s Hospital, Australia), Judith Currier (UCLA Clinical AIDS Research & Education Center, USA), François Dabis (School of Public Health (ISPED) of the University Bordeaux Segalen, France), Charles Flexner (Johns Hopkins University, USA), Tendani Gaolathe (Princess Marina Hospital, Botswana), Beatriz Grinsztejn (Fundação Oswaldo Cruz – FIOCRUZ, Brazil), Diane Havlir (University of California at San Francisco, USA), Charles Holmes (Centre for Infectious Disease Research in Zambia, Zambia), John Idoko (National Agency for the Control of AIDS, Nigeria), Kebba Jobarteh (Centers for Disease Control and Prevention, Mozambique), Elly Katabira (Makarere University, Uganda), Nagalingeswaran Kumarasamy (Y.R. Gaitonde Centre for AIDS Research and Education, India), Volodymyr Kurpita (All-Ukrainian Network of People Living with HIV, Ukraine), Karine Lacombe (Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), France), Albert Mwango (Ministry of Health, Zambia), Leonardo Palombi (DREAM Program, Community of Sant’Egidio, Rome, Italy), Anton Pozniak (Chelsea and Westminster Hospital, United Kingdom), Luis Adrián Quiroz (Derechohabientes Viviendo con VIH del IMSS, Mexico), Kiat Ruxrungtham (Chulalongkorn University, Chula Vaccine Research Center, King Chulalongkorn Memorial Hospital, Thailand), Michael Saag (University of Alabama at Birmingham, USA), Gisela Schneider (German Institute for Medical Mission, Germany), Yanri Subronto (Universitas Gadjah Mada, Indonesia) and Francois Venter (University of the Witwatersrand, South Africa)