The Cochrane Collaborative Review Group on HIV Infection and AIDS

1. George W. Rutherford, MD, AMCoordinating Editor, Cochrane HIV/AIDS GroupSalvatore Pablo Lucia Professor of Epidemiology, Preventive Medicine and PediatricsDirector, Prevention and Public Health Group, Global Health SciencesUniversity of California, San Francisco, USA The Cochrane Collaborative Review Group on HIV Infection and AIDS

2. Cochrane Collaboration • International non-profit organization, based in UK, that prepares, maintains, and disseminates systematic up-to-date reviews of health care interventions • Named for Scottish physician and evidence-based medicine pioneer Archibald (“Archie”) Cochrane (1909-1988) • In 1987, the year before Cochrane died, he referred to a systematic review of randomised controlled trials of care during pregnancy and childbirth as "a real milestone in the history of randomised trials and in the evaluation of care.” Suggested that other specialties should copy the methods used. • His encouragement led to the opening of the first Cochrane centre (Oxford, UK) in 1992 and the founding of The Cochrane Collaboration in 1993.

3. Cochrane Collaborative Review Groups • 54 Review Groups, each focused around an area of health care, e.g. HIV/AIDS, Acute Respiratory Infections, Wounds, Breast Cancer, Occupational Health, STIs, Infectious Diseases etc. etc. • Most based in the UK and Canada; others are in Australia, Denmark, Germany, New Zealand and a couple of other countries (including Bolivia and USA) • Some groups cross-cutting, e.g. Effective Practice & Organization of Care, Consumers & Communication etc. • Produce systematic reviews of interventions; recently also of diagnostic test accuracy • Editorial bases facilitate review process with volunteer authors from around the world • International and multidisciplinary focus

4. Cochrane Collaborative Review Group on HIV Infection and AIDS • Established in 1997 • One of two Cochrane review groups based in the USA • Editorial base at University of California, San Francisco • Satellite editorial base at South African Cochrane Centre • Conducts reviews in four general areas: • Behavioral, social and policy prevention interventions • Biomedical prevention interventions • Treatment, diagnosis and prognosis • Health services and care

6. Cochrane HIV/AIDS GroupProductivity • 99 published reviews, 43 more in progress (May 2013) • Mentoring program at SACC for first-time authors from the region • >400 authors in >30 countries • >40% authors from LMIC, highest proportion among all Cochrane Review Groups

7. Cochrane HIV/AIDS GroupImpact • Unique feature of group is close relationship with the World Health Organization (WHO) • Prepare systematic reviews and evidence quality analyses for many HIV/AIDS guidelines documents over the past decade • Viewed as THE technical experts on systematic review and guidelines development by WHO’s Department of HIV/AIDS • Probably the most experienced Cochrane Review Group in practical use of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for assessing evidence quality

8. Assessing evidence quality with GRADE methodology • The quality of evidence reflects the extent to which confidence in an estimate of the effect is adequate to support recommendations. • GRADE rates the quality of evidence for each outcome separately, across studies (pooling data for each outcome, if multiple studies) • GRADE ranks the quality of evidence on four levels: "high," "moderate," "low" and "very low." • Evidence from randomised controlled trials starts at "high," but can be downgraded based on study limitations, inconsistency of results, indirectness of evidence, imprecision or for reporting bias. • Evidence from observational studies starts at "low," but can be upgraded if the magnitude of treatment effect is very large, if there is a significant dose-response relation, or if all possible confounders would decrease the magnitude of an apparent treatment effect. Evidence from observational studies can also be downgraded. • Transparency: Explicit footnotes to provide rationale for judgments Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6.

9. Outcome #1 Quality: High Outcome #2 Quality: Moderate Outcome #3 Quality: Low I B II V III GRADE Quality of evidence across studies Other systems GRADE Working Group (gradeworkinggroup.org)

10. WHO guidelines development • Historically (1951-2003), recommendations mainly developed with expert opinion: not evidence-based • 2003: WHO guideline-development handbook recommends use of Cochrane and other high-quality systematic review methods and the emerging GRADE methodology • 2007: Scathing article in Lancet shows how seldom this was actually being done* • 2008: WHO guideline-development handbook reiterates (and more strongly emphasizes) that WHO departments are required to use Cochrane review and GRADE methodology in developing recommendations *Oxman AD, Lavis JN, Fretheim A. Use of evidence in WHO recommendations. Lancet. 2007 Jun 2;369(9576):1883-9.

11. Cochrane HIV/AIDS GroupWork for WHO and other agencies • 2001: Four reviews on HIV prevention among minority populations in the United States for the US Office of Minority Health • 2002: Seven reviews on antiretroviral therapy (ART) to inform WHO Model List of Essential Medicines • 2003: Evidence assessment for IOM and State Department report on scaling up global ART provision • 2006: Many reviews for WHO guidelines on essential care and prevention interventions for people with HIV • 2007-2008: Three reviews on health services integration (e.g. HIV and MCH) for WHO, UNFPA and IPPF • 2009: Numerous (>20) reviews for WHO to inform new guidelines on care for children with HIV infection, on adult and adolescent antiretroviral therapy, and on prevention of mother-to-child HIV infection (PMTCT)

12. Cochrane HIV/AIDS GroupWork for WHO and other agencies • 2010: Three reviews for WHO to inform new guidelines on preventing HIV in MSM and transgender people • 2011: Many (>10) reviews for WHO to inform new guidelines on diagnosis, prevention and treatment of cryptococcal infection • 2011: Seven reviews for WHO to inform new guidelines on preventing HIV in serodiscordant couples • 2012: Four reviews to inform new WHO adolescent health guidelines on optimizing care for adolescents with HIV • 2012: Three reviews for WHO nutrition guidelines on micronutrient supplementation for people with HIV • 2012: Numerous (>60) reviews for WHO to inform new consolidated guidelines on antiretroviral therapy, PMTCT, and health services integration and delivery for people with HIV

13. Broader topics of WHO guidelines work in 2012 (many sub-topics not shown) HIV/AIDS consolidated guidelines: • What ART regimen to start (once daily NNRTI regimens) • What ART regimen to switch to • What ART regimen to start in HIV-2 infection • What ART regimen to start in children >3 years • What ARV prophylaxis should be given to HIV+ pregnant women who do not receive lifelong ART • What recommendation should be made on duration of breastfeeding in BF populations for HIV+ women? • When to start: TasP >350 HIV+ individuals, community, pregnant women • When to start: HBV and HCV co-infections • When to start: HIV+ adults >50 years • When to start: HIV-2 infection • Performance characteristics of 2010 WHO immunological and clinical criteria for predicting virological failure • Using liver fibrosis markers instead of CD4 count to guide ART initiation in patients with HIV-HBV or HIV-HCV co-infection

14. Broader topics of WHO guidelines work in 2012 (many sub-topics not shown) HIV/AIDS consolidated guidelines: • Decentralization of initial HIV treatment delivery in low- and middle-income countries • Decentralization of maintenance HIV treatment delivery in low- and middle-income countries • Community-based provision of maintenance HIV treatment and care • Provision of HIV treatment and care at tuberculosis clinics • Provision of tuberculosis treatment and care at HIV clinics • Provision of HIV treatment and care at antenatal or maternal & child health clinics • Provision of tuberculosis diagnosis and treatment at antenatal or maternal & child health clinics • Provision of HIV treatment and care in drug dependency treatment settings • Provision of tuberculosis diagnosis and treatment in drug dependency treatment settings • Task shifting from physicians to non-physicians for initiation of HIV treatment • Task shifting from physicians to non-physicians for maintenance of HIV/AIDS treatment • mHealth for promoting adherence to ART in patients with HIV infection • Social support for people with HIV infection in generalised and concentrated epidemic settings

15. Broader topics of WHO guidelines work in 2012 (many sub-topics not shown) Nutrition guidelines: • Micronutrient supplementation for children with HIV infection • Micronutrient supplementation for pregnant women with HIV infgection • Micronutrient supplementation for non-pregnant adults with HIV infection Adolescent guidelines: • HIV testing & counseling for linkage to care and promoting adherence & retention in adolescents with HIV • Training of health workers in adolescent health issues to improve retention and adherence among adolescents living with HIV • Disclosure of HIV status for reducing sexual risk behavior and improving retention and adherence in adolescents with HIV • Community-based approaches for improve adherence to treatment and retention to care in adolescents with HIV

16. Example presentation (partial) from recent WHO work PICO 5a: Treatment as prevention (individual-level outcomes) PICO 5b: Treatment as prevention(community-level outcomes) George W. Rutherford, MD, AM Coordinating Editor, Cochrane Review Group on HIV/AIDSSalvatore Pablo Lucia Professor of Epidemiology, Preventive Medicine and PediatricsUniversity of California, San Francisco, USA

17. PICO 5a and 5b framework • Treatment as prevention (individual-level and community-level outcomes)

18. Searches (Treatment as prevention: individuals, community) Databases (01 Jan 1996–24 Aug 2012) • PubMed • EMBASE • CENTRAL • Web of Science • WHO Global Health Library Virtual Platform (AIM, LILACS, IMEMR, IMSEAR, WPRIM, WHOLIS) • WHO International Clinical Trials Registry Platform (ICTRP) Core PubMed strategy, modified as needed for use in the other databases. Also: CROI, IAS, IAC conference abstracts, conference inception to 2012 Standard Cochrane methods were used throughout the review process. Combined search/screening process for the T as P reviews, the When to start: pregnant women review and the When to start: age >50 review

19. Results of searches: Individual outcomes • 24 studies (3 RCTs, 21 observational) • Multiple countries throughout Europe, North America, Central and South America, sub-Saharan Africa, and Asia-Pacific • Though mostly Europe and North America • Outcomes reported: • Mortality, progression to AIDS, progression to Cat. B or C disease, CD4 increase, progression to AIDS or death, viral suppression, viral failure, viral rebound, non-AIDS defining cancer, serious non-AIDS events and non-opportunistic diagnoses, SAEs, and Grade 3 or 4 lab abnormalities

20. RCTs included in GRADE analyses: * ACTG 5202 randomized patients by VL strata to receive ABC+3TC or TDF+FTC in combination with either ATZ/r or EFV; 27% had CD4 >350 cells/µL and 35% 200-350 cells/µL.

21. GRADE: PICO 1 When to start

22. Quality of evidence: RCTs • Low quality evidence from one RCT that there is no significant difference in mortality between early and deferred treatment cohorts. Evidence quality was graded down for very serious imprecision. • Low quality evidence from two RCTs that patients on early treatment are at lower risk of progression to AIDS or death. Evidence quality was graded down for serious indirectness and serious imprecision. • Low quality evidence from one RCT that patients on early treatment are at lower risk of progression to AIDS. Evidence quality was graded down for serious indirectness and very serious imprecision. • Very low quality evidence from one RCT that patients on early treatment are at lower risk of developing a non-AIDS-defining illness or dying of non-OI-related disease. Evidence quality was graded down for serious indirectness and very serious imprecision. • High quality evidence from one RCT that there is no significant difference in SAEs between early and deferred treatment cohorts

23. Observational studies

24. Observational studies

25. GRADE: Observational studies

26. GRADE: Observational studies

27. GRADE: Observational studies

28. Summary of observational literature • 21 cohort studies from North America and Europe with many different endpoints reported • All outcomes of very low quality; no studies report data separately for pregnant women • Significant findings (N studies): • Improved survival at 2 and 4 years for those who began ART at ≥350 cells/µL (1) • Improved AIDS-free survival at 2 but not 4 years (1) • Decreased risk of death for those who began ART at ≥350 cells/µL (13) • Decreased risk of death or progression to AIDS (9) • Decreased risk of progression to CDC state B/C disease (1) • Decreased risk of non-AIDS-defining cancer (1) • Higher proportion with immune restoration for those who began ART at ≥350 cells/µL (1) • Higher proportion with prolonged viral suppression (2)

29. GRADE evidence profile

30. Conclusions: Individual-level outcomes • Early ART initiation (with baseline CD4 ≥350) can reduce the risk of progression to AIDS or death, can increase the likelihood of immunologic recovery (CD4 reaching ≥ 800 after ART), and can reduce the risk of being diagnosed with a non-AIDS defining illness. • Grade 3 or 4 lab abnormalities are more commonly found among patients treated early. • However: Little confidence in the effect measures for nearly all of the outcomes. • Low or very low quality evidence for nearly all outcomes • Mostly problems with imprecision or indirectness; sometimes both • High quality evidence for SAE and Grade 3 or 4 lab abnormalities • Most participants came from high-income countries

31. Conclusions: Community-level outcomes • 16 studies identified: evidence too indirect to perform GRADE analyses • To estimate the impact of early ART initiation at the community level, communities would need to be compared. One community would start ART ≥ 350 cells/µL, and the other at <350 cells/µL • Alternatively, a pre-post intervention in one community could provide direct evidence, if it were conducted deliberately. • When practice changes gradually and is not the result of a particular intervention, studies reporting these results could suffer from ecologic fallacy.

32. What evidence is there for TasP for key populations? • Transmission category data from HPTN 052 • Individual observational studies • Community-wide and ecological studies

33. HPTN 052 • 37 (2%) discordant couples were male-male • Couples in which either partner had injected drugs in the past 5 years were excluded • In 872 (51%) of the 1725 heterosexual couples studied, the woman was the infected partner • Inclusion criterion “Plans to maintain a sexual relationship with the person who is enrolled in the study with them” might or might not have been met by FSW • No separately published data on outcomes in MSM

34. Key populations participating in TasP observational studies

36. When to start • Low quality evidence for lower risk of progression to AIDS or death associated with early ART from two RCTs • Supportive but very low quality evidence for lower risk of death or progression to AIDS associated with early ART from large observational literature • High and moderate quality evidence that treatment prevents sexual transmission of HIV (both RCT and observational) • Ecological evidence that associates decreased HIV incidence (or proxy measures for incidence) and community-level viral load with expansion of ART treatment criteria

37. Evidence quality for WHO guidelines: Often not very high Relative paucity of high-quality or moderate-quality evidence to inform World Health Organization guidelines on antiretroviral therapy George W. Rutherford, Tara Horvath, Gail E. Kennedy. 21st Cochrane Colloquium, Quebec City, Canada, September 2013 [submitted]  BACKGROUND: Guidelines development hinges on identifying evidence for specific interventions. When the World Health Organization (WHO) updates its guidelines, the process requires narrowly constructed PICO questions, which are designed to update specific recommendations. Because randomized controlled trials (RCTs) are generally designed and conducted without reference to WHO’s specific concerns, it is often not possible to obtain high-quality evidence directly addressing WHO’s questions of interest. OBJECTIVES: To inform the 2013 update of WHO’s antiretroviral therapy (ART) guidelines, we were asked to conduct systematic reviews with 44 PICO questions specifying 306 outcomes. METHODS: We searched the Cochrane Central Register, EMBASE, PubMed, Web of Science, and WHO’s Global Index Medicus, as well as abstracts from key scientific conferences. We used standard Cochrane methods for the reviews. In addition to RCTs, observational studies with comparators were eligible for inclusion. We used GRADE methodology to classify evidence quality for each outcome. RESULTS: We identified 145 publications, 68 (49%) of which were reports of RCTs. Of the 306 outcomes for which we gathered evidence (including assessments at different time-points), 37 (12.1%) were addressed by high-quality RCT data, 50 (16.3%) by moderate-quality RCT data, 87 (28.4%) by low-quality RCT data and 72 (23.5%) by very low quality RCT data. Observational studies provided low and very low-quality evidence for 60 (19.6%) outcomes. Indirectness and imprecision were particular problems, which resulted in downgrading of evidence quality for 244 (79.7%) outcomes. CONCLUSIONS: There was relatively little high-quality or even moderate-quality evidence to inform the new ART guidelines. In the absence of large RCTs that specifically inform PICO questions, we suggest that analyzing unpublished cohort data from large registries (such as that of the International Epidemiological Databases to Evaluate AIDS) may be an important adjunct to reviewing data from published RCTs and individual observational studies.

38. hiv.cochrane.org