1. ICASA IAS Scaling up Treatment Delivery Programmes: Issues, Challenges & Best Practices Siobhan Crowley HIV Department WHO Geneva

3. % Pregnant women with HIV who received ARVs to reduce MTCT increased 2004-2007 - but 49% still received only single dose nevirapine Distribution of ARV regimens, 2007Percentage of pregnant women with HIV receiving ARVs for PMTCT in low- and middle-income countries Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

4. More children are receiving ART Increased from 75,000 in 2005 to almost 200,000 in 2007 19 of 20 countries with highest PMTCT burden are in sub-Saharan Africa 90% of burden is in 20 countries East,S and SE Asia increase coverage from 18% to 25% in 2008 Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008 Progress has been made

5. WHO - A Public Health Approach Goal Maximize survival with improved quality of life Principles:  Population-based approach  Evidence-based standards of care  Simplified standardised treatment regimens & patient monitoring  Decentralised and integrated service delivery

6. Core elements of the a Public Health Approach  Comprehensive approach to HIV prevention, care and ART  Provider-initiated Testing and Counselling  Prevention for those who test negative  Positive prevention for those who test positive  Pre-ART care for those who do not need ART immediately  Continuum of care  Decentralised and integrated service delivery  Treatment literacy, adherence and chronic care  Simplified clinical monitoring & basic laboratory

7. Harmonised ART Policy Guidance IMAI/IMCI Implementation tools

8. Audience for WHO guidelines  Primarily national planners and policy makers engaged in public sector ART and in target-setting  Which ARVs to make available in public sector for first and second-line regimens  How to use: the four Ss of clinical management: when to start, substitute, switch and stop  Care implementers - basic knowledge to use ARVs effectively according to national policy recommendations  Trainers, M&E experts – to design appropriate tools and materials to support national policy recommendations

9. When to start ART

10. Recommendations for initiating antiretroviral treatment in adults WHO Clinical Staging CD4 testing not available CD4 testing available 1Do not treat Treat if CD4 cell count < 200/mm 3 2Do not treat 3Treat Consider ART if CD4 < 350/mm3, start before it drops to < 200 /mm3 Recommend for all HIV+ pregnant women if CD4 < 350 /mm 4TreatTreat irrespective of CD4 cell count

11. Issues for -when to start Earlier initiation of adult ART with CD4 350 – 500 Reduced non AIDS events from cohort data not RCTs, and in industrialised settings May further reduce HIV transmission ? Feasibility of CD4 dependent strategy No's - estimates for disease burden rise > 30% Associated costs Health systems demands – increase # providers/sites Caution with NVP in women + CD4 > 250, men >400

12. Areas for 2008 review in criteria to start ART adults CD4 Stage < 200200-349350-499>500 1Treat ? TreatDo not treat 2Treat ? Treat Do not treat 3Treat ? Treat 4Treat

13. When to start in pregnant women Currently WHO recommends  ART in all symptomatic women with CD4 < 350,  Consider ART for all pregnant women with CD4 < 350  Prophylaxis (AZT + 3TC tail + Sd NVP ) for non ART eligible Being evaluated:  ? combination prophylaxis for all pregnant women <350 or < 500 +/- combination prophylaxis for all women who are breast-feeding  ? Treat all pregnant women irrespective of CD4  Extended infant prophylaxis if breastfeeding

14. Key issues ART & pregnancy  ? Safety of stopping post-partum: SMART data  Access to CD4 in ANC  Feasibility in universal ART antenatal / MCH clinic settings  ? What to use – NVP contraindicated CD4 > 250, Efavirenz – teratogenic, concerns re TDF, PIs and metabolic complications not  Complexity and health systems demands  Equity: very different ART access for pregnant  ? Adherence in well women  ? adverse pregnancy outcomes

15. Children

16. Starting ART when severely immunodeficient increases mortality Months from ART startProbability of Death After Starting ART Immune Deficient at Start ART Not Immune Deficient at Start ART 6 months 7.8%1.8% 12 months 8.2%2.2% 6% excess mortality 73% median age > 5 years of age, > 50% start with severe immune deficiency, most deaths within 6 months of starting ART Risk factors for death: low CD4 < 18 months age WHO stage 3/4 viral load greater than 6·0 log severe malnutrition Arrive E et al. 14th CROI, Los Angeles, CA, 2007 Abs. 727 Sutcliffe et al. Lancet Infect Dis 2008;8: 477–89

17. CD4% Increase in Children on cART in SSA Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89

18. 0.00 0.20 0.40 0.60 0.80 1.00 036912 Time to Death (months) Failure Probability DeferredImmediate CHER STUDY : 76% Reduction in the Risk of Death with Immediate Compared to Deferred ART Patients at risk 5299145213 252Immediate 224472104 125Deferred Month 12Month 9Month 6Month 3 Month 0 P = 0.0002 Most deaths occurred within first 6 months (i.e., before age 10 months) immediate deferred 16% 4%

19. Revised WHO Guidelines 2008 : When to Start Antiretroviral Therapy in HIV-Infected Children < 12 months HIV Confirmed < 12 months Presumptive Severe HIV* 1- 4 yrs> 5yrs All regardless of CD4/clinical Clinical or immune criteria Clinical or immune criteria <20% or 12-35 mos: <750/uL 36-59 mos: <350/uL <15% or <200/uL ( or as adults) *If Viral test is not possible, use presumptive diagnosis of severe HIV (thrush, severe pneumonia or sepsis) in infants with +ve HIV antibody test and with clinical symptoms of severe HIV – confirm infection status as soon as possible.

20. What to use

21. Adults & children (1 year or over) Clinical and/or immunological criteria to start ART Standard first line regimen NNRTI + 2NRTI < 3 years NVP + AZT + 3TC > 3 years EFV + AZT + 3TC Standard second line regimen PI + 2 new NRTI

22. What ART to Start in infants – 2008 revision No infant or maternal ARV exposure MTCT ARV Exposure Sd NVP or NNRTI containing ART No NNRTI exposure Unknown infant maternal MTCT Exposure NVP triple ART PI triple ART # NVP triple ART # If no PI is available use NVP triple ART Mum 34% Baby 18%

23. Revised simplified dosing infants & children

24. 1 ADULT FDC AM & PM 1 BABY FDC AM & 1 PM 1 ADULT FDC AM & 0.5 PM 2 BABY FDC AM & PM 2 BABY FDC AM & 1 PM 0.5 ADULT FDC AM + PM WHO FDC ARV tablet regimen superimposed Same dosing irrespective of FDC, or same dosing for all three single ARV agents Most dose adjustments done in 1 st year Adapted from T. NUNN

25. Percentage of adults and children on 1st and 2 nd line regimens (2007)

26. Median transaction prices for one years treatment Transaction prices for ARVs Summary Report form GPRM Oct 2008

27. First line failure – when to switch

28. WHO Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen Clinical failure a Occurrence of new or recurrent WHO stage 4 condition CD4 cell failure  Fall of CD4 count to pre-therapy baseline (or below) or  50% fall from the on-treatment peak value (if known) or  Persistent CD4 levels < 100 cells/mm 3 Virological failure Plasma viral load >10,000 copies/ml a.Any clinical event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)

29. VirologicClinicalImmunologic Viral load CD4 count "Early Switch" "Late Switch" Failure / When to Switch Clinical criteria

30. WHO ART Failure Meeting: Major Conclusions Time on ART : Clinical: WHO Stage 3 or 4 after at least 1 year on ART CD4: confirmed CD4 < 100-200 after at least 1 year on ART (check/reinforce adherence before switching decision) HIV RNA threshold : Maintain 10,000 as a switch point (little immediate immune damage). Action when VL> 1,000 (adherence, toxicity, drug interaction assessment) and start to consider switching More efficient use of VL (targeted strategy) Confirm immunologic/clinical failure (?discordance) Pregnant women Adherence monitoring

32. What to switch to……..second line

33. Patient group Preferred first line regimen Preferred second line regimen Infant not exposed to NVPNVP + AZT # + 3TCBoosted PI + 2 new NRTI Infant exposed to NVPLop/r + AZT # + 3TCNNRTI + 2 new NRTI Infant Unknown NVP exposure NVP + AZT # + 3TC Boosted PI + 2 new NRTI Children 3 or overEFV + AZT # + 3TCBoosted PI + 2 new NRTI # if anaemia use alternative ABC or d4T

34. Summary of Regimen options - adults

35. Options for adult second-line ART 1 st Line NRTI Second line NRTI ComponentPI Component If AZT or d4T is used in 1 st line ABC + ddI or TDF+3TC (FTC) ATV/r or LPV/r If TDF is used in 1 st line AZT+3TC If ABC is used in 1 st line AZT+3TC or TDF+3TC (FTC)

36. Managing co-infection with TB

37. Geographical distribution of estimated HIV-positive TB cases, 2006

38. Opportunistic Illnesses

39. 0.96% 12% 0.08% Number of people receiving the intervention as % of estimated PLHIV in reporting Countries (Number of Countries reporting; % of total estimated HIV+ TB patients accounted for by those Countries) Intensified TB case finding and IPT provision among people living with HIV, 2006

40. WHO the 3 'Is' Intensified case finding Infection control for TB Isoniazid preventive therapy

41. Steering Committee Time-Limited Subject Matter Working Groups WG WHO HIVResNet Laboratory Network Surveillance and Monitoring Network WHO Secretariat Modeling of The emergence and transmission of resistance HIVDR database development and support Public Health Assessment Tool For evaluation of country HIVDR data Global Laboratory Network: Criteria, Protocols, Training, QA The WHO HIVResNet is a global group of experts, laboratories, and organizations constituted to support HIVDR prevention, surveillance, and monitoring as antiretroviral treatment (ART) is rolled out worldwide. Country HIVDR Committees HIVDR monitoring & surveys WG Operational Research WG Mutation lists for Surveillance and monitoring

42. Transmitted HIV drug resistance Articles reporting results from HIVDR transmission surveys in 7 countries all showed <5% DR in incident cases

43. Interface between prevention and care Lancet, November 26, 2008 POSITIVE PREVENTION Pre ART care – condoms safer sex Disclosure & partner testing MTCT prevention OI & STI prevention ART CARE Reduce Viral load Likely reduction transmission PRIMARY PREVENTION Prep and PEP

44. HIV ART No ART Current ART Proposed Universal ART

45. Acknowledgments: Paediatric and adult Guideline groups HIV DR team HIV- dept staff Paediatric ARV dosing working group Charlie Gilks. Marco Vitoria, Lynne Mofenson, Ying-ru Lo, HIV -AMD & GPRM HIV- SIR Yves Soutyrandy Thank you