International Health Policy Program -Thailand Should Thailand adopt early initiation of ART as recommended by WHO 2010? Viroj Tangcharoensathien, Walaiporn Patcharanarumol, Nakorn Premsri, Chawetsan Namwat, Peeramon Ningsanon, Waraporn Puangkantha, And Sudarat Tantiwat Presented to HIV/AIDS subcommittee of NHSO 28 March 2011

International Health Policy Program -Thailand 2 Objectives 1. Review of scientific evidence – Siegfried et al. Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults. Cochrane Database of Systematic Reviews 2010, Issue 3 2. Review current ART program performance 3. How do we go—what policy strategies? 2

International Health Policy Program -Thailand 3 I. Review evidences

International Health Policy Program -Thailand 4

5 Optimal time for initiation 1 Objectives – To assess the evidence for the optimal time to initiate ART in treatment- naive, asymptomatic, HIV-infected adults Search strategy – Identify all relevant studies regardless of language or publication status from electronic journal and trial databases: MEDLINE, EMBASE, CENTRAL. – Electronic conference database of NLM Gateway, conference proceedings and prospective trials registers. – Contacted researchers and relevant organizations and checked reference lists of all included studies. Selection criteria – Randomized controlled trials that compared the effect of ART consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial. Early initiation could be at levels of , , or >500 cells/μL, with the comparison group initiating ART at CD4 counts below 200 x 10 6 cells/μL or as defined by the trial. 5

International Health Policy Program -Thailand 6 Optimal time for initiation 2 Included studies: only two trials included – The CIPRAHT trial, Does starting ART at CD4 counts cells/μL significantly improve mortality and morbidity compared with starting at 200 cells/μL or below? Conducted in one centre in a resource-poor country (Haiti), enrolled August 2005 and stopped early in May – The SMART 2008 trial, Covered 318 sites in 33 countries, enrollment commenced in January 2002 and was stopped early on 10 January 2006 by the study’s Data Safety and Monitoring Board. The trial compared a viral suppression strategy, with an experimental drug conservation strategy. The results for a sub-set of those participants within the larger trial who were treatment naive are included in this review. This analysis was reported as post-hoc and included a group of participants who were either ART naive orwho had received ART and ceased to take it 6 months prior to enrollment. For This review we report the results only for those ART-naive participants.

International Health Policy Program -Thailand 7 Optimal time for initiation 3 Primary outcomes Death Responses to ART measured by Clinical occurrence of new HIV-related events (Tuberculosis) Disease progression measured by opportunistic infections: Secondary outcomes Proportion of patients discontinuing or switching ART due to virologic failure, as defined by the trial Development of ART resistance Proportion of participants remaining on therapy as originally assigned at the end of the trial Quality of life indicators as reported in the studies None of the anticipated secondary outcomes identified in our protocol were reported in the two trials

International Health Policy Program -Thailand 8 Optimal time for initiation 4 Main results 1 – One completed trial (N = 816 CIPRAHT trial) and one sub-group (N = 249 SMART 2008 trial) of a larger trial met inclusion criteria. – Mortality data for both trials were combined, comparing early initiation (350 cells/μL or between 200 and 350 cells/μL) with deferring initiation of ART (CD4 levels of 250 cells/μL or 200 cells/μL). – There was a statistically significant reduction in death when starting ART at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). – Risk of tuberculosis was reduced by 50% in the groups starting ART early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI: 0.26, 1.12; P = 0.01). – Starting ART at enrollment when participants had CD4 counts of 350 cells/μL rather than deferring to starting at a CD4 count of 250 cells/μL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).

International Health Policy Program -Thailand 9 Optimal time for initiation 5 Main results 2 – One RCT found no statistically significant difference in the number of independent Grade 3 or 4 adverse events occurring in the early and standard ART groups when we conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = 0.06). – However, when analyzing only participants who actually commenced ART in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02).

International Health Policy Program -Thailand 10 Optimal time for initiation 6 Authors’ conclusions – There is evidence of moderate quality that initiating ART at CD4 levels higher than 200 or 250 cells/μL reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. Practitioners and policy-makers may consider initiating ART at levels ≤ 350 cells/μL for patients who present to health services and are diagnosed with HIV early in the infection High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

International Health Policy Program -Thailand 11 Optimal time for initiation 7 Discussion – Ideally additional trials would be needed to improve precision. The important outcomes of sexual, immunological and virologic response, adherence, tolerance and retention, and HIV drug resistance were not measured in either of the trials. – No data is available on follow-up beyond the median of 21 months, on development of possible resistance to ART. Given there are two RCT in the field, future research should focus on long-term cohort studies to assess the incidence and nature of adverse effects, and the development of viral resistance, in those initiating ART at higher CD4 levels than previous standard practice. In resource poor setting, huge challenges remain To identify patients early in the course of the infection to benefit from early treatment. Research e.g. clinical trials, to devise interventions to promote VCT, to reduce the stigma of testing and to encourage people to present for testing. Cost effectiveness remains an area requiring ongoing investigation.

International Health Policy Program -Thailand 12 II. ART program performance

International Health Policy Program -Thailand 13 ART program: poor performed + inequitable outcome CD4 at enrolment – 38% symptomatic AIDS, 43% CD<100 cells Total 81% of ART enrolee came late at CD<100 cells Poor survival outcome among this group – Early initiation was implicitly adopted, 5% CD , 4% >350 ART program functions in a serious constrained health systems – As result of UC, high level of service utilization, annual per capita use rate reached 3 OP visits and 0.1 admissions – Supply side limitations: VCT, high turnover of counsellors – Demand side poor awareness and use of VCT

International Health Policy Program -Thailand 14 Poor survival outcome: Majority enrolees came late phase of infection, N38,880 between Oct 2007 to June 2009

International Health Policy Program -Thailand 15 III. Policy strategies?

International Health Policy Program -Thailand 16 Guiding principles of ART program 1.Do no harm – When introducing changes, preserve access for the sickest and most in need 2.Ensure access and equity – All clinically eligible people should be able to enter treatment services, including ART, with fair and equitable distribution of treatment services 3.Promote quality and efficiency – Ensure delivery of the highest standards of care within a public health approach so as to achieve the greatest health impact with the optimal use of available human and financial resources 4.Be sustainable – Understand the long-term consequences of change with the vision of providing continued, life-long access to ART for those in need

International Health Policy Program -Thailand 17 Policy messages Given the current ART situation, no matter early initiation is adopted or rejected, the immediate actions are required – Improve program performance Early recruitment through demand side campaign and scaling up VCT services Consider targeted PICT among high HIV prevalent areas Effective pre-ART counselling, close follow up to prevent defaults Ensure adherence to ART These result in minimizing inequity gap and improved survival outcome Awaiting for better evidence

Policy strategies Strategy 1 Improve VCT performance, setting target between on CD4 at entry, – <100 cells, not more than 10% of total enrolees – cells should be the majority 75-85% of total enrolees – will naturally increase from 5-15% of total enrolees Strategy 2 Give the highest priority to increase number of enrolees from 200 to 400 thousand by 2015, As a result CD4 will shift to the right gradually, and naturally, will increase its proportion Major policy review in 2013 on the achievements of these policy strategies, when more evidence on outcome of early enrolment are available

International Health Policy Program -Thailand 19 Thank you for your attention 19