1. Country Experience Informing Feasibility Option B+ (Malawi) Tenofovir phase in 1 st line( Zambia) d4T phase out in HIV programmes Raising CD4 threshold to 350 cells (Ethiopia) Viral Load roll out (MSF and Kenya) Accelerated global phasing out of d4T Implementing Option B+: Malawi The ART programme in Ethiopia No of ART sites (2006-2012) The ART programme in Ethiopia No of ART sites (2006-2012) MSF UNITAID Funded Viral Load Project (2013-2015)

2. 2013 ARV Guidelines: Highlights ADDITIONAL SUMMARY BRIEFS (15 PAGES) ICONS FOR TARGET POPULATIONS ICONS FOR NEW RECOMMENDATIONS 6 CHAPTERS: ALONG THE CONTINUUM OF CARE OVER 50 NEW RECOMMENDATIONS Clinical Operational and Service Delivery HIV testing & counselling OVER 50 NEW RECOMMENDATIONS Clinical Operational and Service Delivery HIV testing & counselling TABLES, CHECKLISTS & ALGORITHMS

3. Clinically relevant Earlier initiation of ART (CD4 ≤ 500) Immediate ART for children below 5 years ART initiation for all pregnant and breastfeeding women (Option B/B+) and lifelong ART (Option B+) Harmonization of ART across populations (e.g., adults and pregnant women, Option B/B+) and age groups Simplified, fewer, and less toxic 1 st -line regimens (TDF/XTC/EFV) Clinically relevant Earlier initiation of ART (CD4 ≤ 500) Immediate ART for children below 5 years ART initiation for all pregnant and breastfeeding women (Option B/B+) and lifelong ART (Option B+) Harmonization of ART across populations (e.g., adults and pregnant women, Option B/B+) and age groups Simplified, fewer, and less toxic 1 st -line regimens (TDF/XTC/EFV) Key Themes of New Recommendations Operationally relevant Use of Fixed Dose Combinations as a preferred approach Improved patient monitoring to support better adherence and detect earlier treatment failure (increased use of VL) Recommend task shifting, decentralization, and integration Community based testing to complement broader HTC Operationally relevant Use of Fixed Dose Combinations as a preferred approach Improved patient monitoring to support better adherence and detect earlier treatment failure (increased use of VL) Recommend task shifting, decentralization, and integration Community based testing to complement broader HTC

4. 1. What are the components of Guidance for Programme Managers? Review tools for costing and planning Discuss key data needed for evidence- based decisions Discuss implementation considerations Examine key parameters for decision making Design an inclusive and transparent process

5. When to Start ART

6. Summary of Changes in Recommendations: When to Start in Adults

7. Evidence Summary: When to Start in Adults o Systematic Review of 24 studies (3 RCTs, 21 observational ) o Multiple countries throughout Europe, North America, Central & South America, sub-Saharan Africa and Asia-Pacific o Outcomes reported: mortality progression to AIDS progression to AIDS or death non-AIDS defining cancer serious non-AIDS events C D4 increase viral suppression, failure, rebound SAE and grade 3 or 4 lab abnormalities

8. Evidence Summary: Risk of Death and/or Progression to AIDS Observational data RCTs – SMART / HPTN 052 Risk of Death or Progression to AIDS Risk of Death Risk of Progression to AIDS

9. Evidence Summary: Risk of HIV Sexual Transmission o RCT to examine efficacy of ART in preventing HIV transmission between discordant couples o HIV+ partner had CD4 ≥ 350-550 cells/µL and was randomized to early vs. delayed ART o Significant HIV prevention benefit – a 96% reduction in transmission. o 1 genetically linked infection in early ART arm versus 29 infections in delayed arm. o RCT to examine efficacy of ART in preventing HIV transmission between discordant couples o HIV+ partner had CD4 ≥ 350-550 cells/µL and was randomized to early vs. delayed ART o Significant HIV prevention benefit – a 96% reduction in transmission. o 1 genetically linked infection in early ART arm versus 29 infections in delayed arm. Observational data Clinical Trial - HPTN 052 Early ART Late ART RCT and Observational data o High to moderate quality evidence that treatment prevents sexual transmission of HIV (1 RCT and observational data) RCT and Observational data o High to moderate quality evidence that treatment prevents sexual transmission of HIV (1 RCT and observational data)

10. Recommendations: CD4 Independent Conditions

11. Populations With No Specific Recommendations Insufficient evidence and/or favorable risk-benefit profile for ART initiation at CD4 > 500 cells/mm 3 (or regardless of CD4 count) in the following situations: Individuals with HIV who are 50 years of age and older Individuals co-infected with HIV and HCV Individuals with HIV-2 Key populations with a high risk of HIV transmission (e.g.: MSM, sex workers, IDU) These populations should follow the same principles and recommendations as for other adults with HIV

12. WHAT ART REGIMEN TO START

13. Summary of Changes in Recommendations: What to Start in Adults

14. Rationale: One Regimen For All o Simplicity: regimen is very effective, well tolerated and available as a single, once- daily FDC and therefore easy to prescribe and easy to take for patients – facilitates adherence o Harmonizes regimens across range of populations (Adults, Pregnant Women (1 st trimester), Children >3 years, TB and Hepatitis B,) o Simplifies drug procurement and supply chain by reducing number of preferred regimens (phasing out d4T) o Safety in pregnancy o Efficacy against HBV o EFV is preferred NNRTI for people with HIV and TB (pharmacological compatibility with TB drugs) and HIV and HBV coinfection (less risk of hepatic toxicity) o Affordability (cost declined significantly since 2010) Preferred 1 st line regimen: TDF + 3TC (or FTC) + EFV

15. Evidence Summary: What to Start o Systematic review (10 RCTs): TDF+3TC (or FTC)+EFV superior vs. other EFV containing regimens and vs. TDF/3TC+ PI/r on major outcomes - occurrence of SAEs, virologic and immunologic response (high to moderate quality of evidence) o Systematic review (7 RCTs, 27 observational): NVP > 2 fold more likely to be discontinued due any adverse effect compared to EFV (moderate to low quality of evidence) o Systematic review of preclinical data (5 studies): support pharmacological equivalence interchangeability of 3TC and FTC (low quality evidence) Immunologic Response (48 weeks) Virological response (48 weeks) Severe adverse events (48 weeks) Comparative efficacy 3TC and FTC Discontinuation NVP vs. EFV

16. No increased risk of birth defects with EFV when compared with other ARVs Evidence Summary: Safety of EFV and TDF in Pregnancy o Systematic review (including Antiretroviral Pregnancy Registry), reported outcomes for 1502 live births to women receiving EFV in the first trimester and found no increase in overall birth defects o Excludes > 3 fold increased risk in overall birth defects o Systematic review (including Antiretroviral Pregnancy Registry), reported outcomes for 1502 live births to women receiving EFV in the first trimester and found no increase in overall birth defects o Excludes > 3 fold increased risk in overall birth defects Source: Ford N et al. AIDS, 2011. Ford N et al. AIDS, 2013. Ekouevi DK et al.J AIDS, 2011. WHO, Geneva Use of EFV during pregnancy. 2012. http://www.who.int/hiv/pub/treatment2/efavirenz/en Nightingale SL. JAMA, 1998. British HIV Association. Guidelines for the management of HIV infection in pregnant women. HIV Medicine. 2012. De Santis M et al. Arch of Int Medicine, 2002. Source: Antiretroviral Pregnancy Registry Steering Committee http://www.APRegistry.com Siberry GK et al. AIDS, 2012 EFV o Potential concerns include renal toxicity, adverse birth outcomes and effects on bone density o Systematic review assessed the toxicity of fetal exposure to TDF in pregnancy In Antiretroviral Pregnancy Registry, prevalence of all birth defects with TDF exposure in 1 st trimester was 2.4% (same as background) o Limited studies showed no difference in fetal growth between exposed/unexposed o No studies of TDF among lactating women, who normally have bone loss during breastfeeding o Current data reassuring o More extensive studies ongoing o Potential concerns include renal toxicity, adverse birth outcomes and effects on bone density o Systematic review assessed the toxicity of fetal exposure to TDF in pregnancy In Antiretroviral Pregnancy Registry, prevalence of all birth defects with TDF exposure in 1 st trimester was 2.4% (same as background) o Limited studies showed no difference in fetal growth between exposed/unexposed o No studies of TDF among lactating women, who normally have bone loss during breastfeeding o Current data reassuring o More extensive studies ongoing TDF

17. HIV/AIDS DEPARTMENT 2013 Consolidated ARV Guidelines Treatment Recommendations for Pregnant and Breastfeeding Women: Critical Issues

18. Evolution of WHO PMTCT ARV Recommendations 20012006 2010 2004 Launch July 2013 PMTCT 4 weeks AZT; AZT+ 3TC, or SD NVP AZT from 28 wks + SD NVP AZT from 28wks + sdNVP +AZT/3TC 7days Option A (AZT +infant NVP) Option B (triple ARVs) Option B or B+ Moving to ART for all PW/BF ART No recommendation CD4 <200 CD4 <350CD4 <500 Move towards: more effective ARV drugs, extending coverage throughout MTCT risk period, and ART for the mother’s health

19. Rationale o Limited coverage and implementation of PMTCT and ART for pregnant women in many high burden countries ~ 1.4 million HIV+ pregnant women 65% PMTCT ARV coverage Limited ART in those eligible for treatment High loss to follow-up along PMTCT cascade Low ARV coverage during breastfeeding o Complexity of Option A Different treatment and prophylaxis regimens through pregnancy and breastfeeding Difficulty of long-term NVP dosing for infants Requirement for CD4 to determine eligibility Follow up along the PMTCT cascade is very low o Current approach needs to be optimized to achieve universal access and elimination 0 100 200 300 400 500 600 2009: ~430,000 infant infections 2012: ~290,000 infant infections 2015: Global Plan target <40,000 Steady progress reducing infant infections

20. “Option B+” “Option B” “Option B+” “Option B” For programmatic and operational reasons, particularly in generalized epidemics, all pregnant and breastfeeding women infected with HIV should initiate ART as lifelong treatment. (conditional recommendation, low- quality evidence) For programmatic and operational reasons, particularly in generalized epidemics, all pregnant and breastfeeding women infected with HIV should initiate ART as lifelong treatment. (conditional recommendation, low- quality evidence) All pregnant and breastfeeding women infected with HIV should initiate triple ARVs (ART), which should be maintained at least for the duration of mother-to-child transmission risk. Women meeting treatment eligibility criteria should continue lifelong ART. (strong recommendation, moderate-quality evidence) In some countries, for women who are not eligible for ART for their own health, consideration can be given to stopping the ARV regimen after the period of mother-to-child transmission risk has ceased. (conditional recommendation, low- quality evidence) In some countries, for women who are not eligible for ART for their own health, consideration can be given to stopping the ARV regimen after the period of mother-to-child transmission risk has ceased. (conditional recommendation, low- quality evidence) Recommendations

21. Rationale: Shift from Option A to B+ or B Major issue now is not “when to start” or “what to start” but “whether to stop”

22. Programmatic considerations for B+ Initiate all HIV+ pregnant and breastfeeding women on ART Operational and programmatic advantages to lifelong ART for pregnant and breastfeeding women (“B+”), particularly in settings with: – Generalized epidemics – High fertility (though need to strengthen FP) – Long duration of breastfeeding – Limited access to CD4 to determine ART eligibility – High partner serodiscordance rates National programmes need to decide B or B+

23. ARVs and breastfeeding

24. Implementation Issues Adequate planning for changes in guidelines Expansion and integration of ART into PMTCT sites —Supply chain for ARVs (avoidance of stock-outs) —Task-shifting for ART initiation —Adherence, retention, follow up, linkages with chronic ART —All MNCH sites become ART sites Access to ART monitoring Major challenge for PMTCT and MNCH settings: How to expand access to VL monitoring? How to utilize CD4 data, especially for women with high baseline CD4? Major challenge for PMTCT and MNCH settings: How to expand access to VL monitoring? How to utilize CD4 data, especially for women with high baseline CD4?

25. WHAT ART TO SWITCH TO

26. TARGET POPULATION WHAT TO SWITCH IN ADULTS (PREFERRED REGIMENS) 2010 ART GUIDELINES 2013 ART GUIDELINES STRENGTH & QUALITY OF EVIDENCE HIV+ ADULTS AND ADOLESCENTS If d4T or AZT used in first-line TDF + 3TC (or FTC) + ATV/r or LPV/r No change strong, moderate- quality evidence If TDF used in first-line AZT + 3TC + ATV/r or LPV/r No change strong, moderate- quality evidence HIV+ PREGNANT WOMEN Same regimens recommended for adults No change strong, moderate- quality evidence HIV/TB CO-INFECTION If rifabutin available Same regimens as recommended for adults No change strong, moderate- quality evidence If rifabutin not available Same NRTI backbones recommended for adults plus LPV/r or SQV/r with adjusted dose of RTV (i.e., LPV/r 400mg/400mg BID or SQV/r 400mg/400mg BID) No change strong, moderate- quality evidence HIV/HBV CO-INFECTION AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r) No change strong, moderate- quality evidence Summary of changes to recommendations: What ART to Switch to