Critical issues for Adults with HIV: Presentation of Systematic reviews and Main recommendations WHO 2013 ARV Guidelines Launch Dr. Meg Doherty, WHO, Geneva Coordinator Treatment and Care

Objectives of Presentation Overview of Evidence Base and Rationale for Recommendations for Adults: When to Start ART What ART to Start (First-Line) What ART to Switch to (Second-Line) How to Monitor ART

When to Start ART

Summary of Changes in Recommendations When to Start in Adults

Evidence Summary: When to Start in Adults Systematic Review of 24 studies (3 RCTs, 21 observational ) Multiple countries throughout Europe, North America, Central & South America, sub-Saharan Africa and Asia-Pacific 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

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

Evidence Summary: Risk of HIV Sexual Transmission RCT on efficacy of ART to prevent HIV transmission between discordant couples HIV+ partner with CD4 ≥ cells/µL randomized to early vs. delayed ART Significant HIV prevention benefit – a 96% reduction in transmission. 1 genetically linked infection in early ART arm versus 29 infections in delayed arm. RCT on efficacy of ART to prevent HIV transmission between discordant couples HIV+ partner with CD4 ≥ cells/µL randomized to early vs. delayed ART Significant HIV prevention benefit – a 96% reduction in transmission. 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 High to moderate quality evidence that treatment prevents sexual transmission of HIV (1 RCT and observational data) RCT and Observational data High to moderate quality evidence that treatment prevents sexual transmission of HIV (1 RCT and observational data)

Recommendations: CD4 Independent Conditions

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

WHAT ART REGIMEN TO START

Summary of Changes in Recommendations: What to Start in Adults

Rationale: One Regimen For All 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 Harmonizes regimens across range of populations (Adults, Pregnant Women (1 st trimester), Children >3 years, TB and Hepatitis B) Simplifies drug procurement and supply chain by reducing number of preferred regimens (phasing out d4T) Safety in pregnancy Efficacy against HBV 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) Affordability (cost declined significantly since 2010) Preferred 1 st line regimen: TDF + 3TC (or FTC) + EFV

Evidence Summary: What to Start 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) 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) 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

WHAT ART TO SWITCH TO

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 NRTI backbone 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

Rationale: 2 nd Line Regimens in Adults Simplifying second-line ART Limiting number of preferred options, and harmonisation across populations Availability of more convenient heat stable bPI formulations Daily dosing, FDC with reduced pill burden Management of co-morbidities in the context of 2 nd line ART TB (use of rifampicin and PIs) HBV (use of ARV with anti-HBV activity) Evidence summary – systematic review (6 RCTs) - comparison of major PIs used for second-line ART (ATV/r, LPV/r and DRV/r) ATV/r comparable to LPV/r in ART-experienced individuals but better virological response and better retention in care among ART-naive DRV/r better virological response and retention in care than LPV/r, both in treatment-naive and experienced people No good quality evidence to support changing the recommendation established in the 2010 guidelines

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

HOW TO MONITOR AND WHEN TO SWITCH

Recommendations: Monitoring for ART Response 6 studies (4 RCTs and 2 observational studies) 1.Clinical+Immunological versus Clinical+Immunological+Virological: (1 RCT + 1 obs study ): no difference in terms of mortality and new AIDS-defining 2.Clinical+Immunological versus Clinical+Virological: (1 RCT): no difference in clinical failure, switch to second line regimens, and resistance mutations. Children (Arrow 2013): mortality and disease progression are comparable between clinical and laboratory monitoring

Evidence Summary: Virological vs. CD4 + Clinical Monitoring 6 studies (4 RCTs and 2 observational studies) 1.Clinical+Immunological versus Clinical+Immunological+Virological: (1 RCT + 1 obs study ): no difference in terms of mortality (moderate-quality evidence) and new AIDS-defining illness (moderate-quality evidence). 2.Clinical+Immunological versus Clinical+Virological: (1 RCT): no difference in clinical failure (low), switch to second line regimens (low), and resistance mutations (low). Children (Arrow 2013): mortality and disease progression are comparable between clinical and laboratory monitoring Viral load threshold: Children: 1 RCT: No difference in clinical or virological outcomes, but less drug resistance if ART switched at a viral threshold of 1000 copies/mL compared to 30,000 copies/mL (medium quality of evidence). (PENPACT1) Viral blips (50–1000 copies/ml) during effective treatment not associated with risk of treatment failure unless low-level viraemia is sustained

Rationale: for VL Earlier capture of treatment failure & reducing HIVDR Help discriminate between treatment failure & non- adherence Lack of viral load or CD4 capacity should not prevent starting ART If VL availability limited, phase in use of targeted approach (or CD4/clinical monitoring) Same for adults & children 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

Predictive value of WHO immunological and clinical criteria PopulationViral load Number of studies Number of patients SensitivitySpecificity Positive predictive value Negative predictive value Adults >5000 copies/mL %92.1%27.0%98.6% Adults copies/mL %74.5%29.8%89.6% Adults >10000 copies/mL %95.5%15.0%96.0% Children >5000 copies/mL %99.3%54.9%85.5% Children >400 copies/mL %97.7%20.0%91.8%

Summary of Adult Guidelines 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 1 preferred option & 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 (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring

Acknowledgements Adult Guideline Development Group Co-Chairs Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d’Ivoire) Stefano Vella (Istituto Superiore di Sanità, Italy) Members of the Adult Guideline Development Group Other Guideline Development Groups Special thanks to all the external experts who contributed as 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 Marco Vitoria Nathan Ford Andrew Ball Philippa Easterbrook Eyerusalem Kebede Negussie Nathan Shaffer Lulu Muhe Joseph Perriëns Lisa Nelson