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How can ART observational cohorts and randomized clinical trials inform policy and practice


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Title: How can ART observational cohorts and randomized clinical trials inform policy and practice

How can ART observational cohorts and randomized
clinical trials inform policy and practice?
  • Praphan Phanuphak, M.D., Ph.D.
  • Thai Red Cross AIDS Research Centre, Bangkok
    IAS 2005

Strengths of randomized controlled trials (RCT)
  • Random allocation minimizes selection bias
    confounding. All confounders are evenly
    distributed between the groups being compared.
  • Thus, RCT is the gold standard since the results
    are most reliable especially if the results can
    be duplicated by another RCT.

Rating scheme for clinical practice
  • Category Definition
  • Strength of recommendation
  • A Strong should always be offered
  • B Moderate should usually be offered
  • C Optional
  • D Should usually not be offered
  • E Should never be offered
  • Quality of evidence for recommendation
  • I At least one randomized trial with
    clinical results
  • II Clinical trials with laboratory results
  • III Expert opinion
  • Dybul M et al, Guidelines for using ARVMMWR

Strengths of RCT (II)
  • Results can be obtained relatively short.
  • HIV diseases are relatively urgent. It is a
    dead or live situation such as AZT monotherapy
    could double the life span of AIDS patients in
    1990 or an infected vs. uninfected situation such
    as the use of AZT in preventing mother-to-child
    transmission (ACTG 076)

HIV observational cohorts
  • Multicenter AIDS Cohort Study (MACS)
  • French Hospital Database on HIV (FHDH)
  • Swiss Cohort
  • EuroSIDA
  • Australian HIV Observational Database (AHOD)
  • TREAT Asia HIV Observational Database (TAHOD),
    etc, etc.

How the HIV observational cohorts being used?
  • Predict disease progression
  • Monitor trends in HIV disease outcomes
  • - Too sad a story, we are treating physician,
    not horoscopist!
  • Monitor trends in HIV treatment
  • -Do we try to be in the norms?
  • Assess association between HIV treatment and
    disease outcomes
  • -Dont we all know?

How the HIV observational cohorts being used (2)?
  • Compare different populations
  • -Can Asians be compared to Caucasians?
  • Monitor long-term efficacy long-term
  • -Can also be learned by clinical experience
    post-marketing surveillance
  • See whether knowledge from clinical trials can be
    applied in clinical practice
  • -It depends on how convincing the results are and
    its feasibility

How the HIV observational cohorts being used (3)?
  • Assess effectiveness of particular ARV
    combinations some agreement such as
  • -ZDV monotherapy could have a short-term
  • -Graham et al, Lancet 1991338265
  • -Moore et al, NEJM 19913241412
  • -Vella et al, JAMA 19922671232
  • -Lundgren et al, JAMA 19942711088
  • - Double nucleosides was better than
  • -Graham et al, Ann Intern Med
  • -Phillips et al, JAIDS 199717239
  • Do we really need these information?
  • And sometimes it can be misleading!!

Results from some observational cohorts can be
  • Phillips et al, AIDS 1999 132075-82.
  • Compared progression to AIDS death between RCT
    (Delta, ACTG175, CPCRA 007, ACTG320) and 3
    cohorts (EuroSIDA, FHDH, Swiss) all agree except
    FHDH which showed higher risk of progression on
    triple therapy as compared to double nucleosides
    (RR 1.20, 95CI 1.01-1.44) while ACTG320 results
    showed a RR of 0.50, 95CI 0.33-0.76. The reason
    was due to those who received triple therapy in
    FHDH were more advanced patients.

Weakness of observational cohorts
  • Selection bias
  • Information (observation, classification,
    measurement) bias
  • Confounding bias known unknown
  • By chance? what p value? adequate power?
  • Causal association?
  • At the end, critical clinicians will always ask
    about the experimental evidence, i.e., randomized
    control trials

Statisticians magic
  • Observational cohorts open the door for
    experienced statisticians to use various magic
    statistical methods to prove or disprove their
    hypotheses such as Weibull proportional hazards
    model, parametric survival model, log-logistic,
    lognormal, generalized gamma and gompertz
    distributions, etc.
  • Do any practitioners or policy makers really
    understand these techniques?
    Thus, should one believe or not believe?

Translation of RCT results into practice policy
  • Practice of experts or general internist Who is
    more difficult to convince?
  • Practice in resource-limited settings not very
    many options!!
  • Policy guidelines IAS/USA, DHHS, WHO
  • Government policy how committed?
  • Policy of funding agencies always thinking
    about the best buy for their money, example
    Mwanza trial

For practicing physician
  • Results from reliable (investigators,
    institutions, journals, carefully planned
    methodology analysis, p value lt0.00..) and
    sizable (Ngt100) RCT, particularly double-blinded
    and confirmed by at least another group of
  • Recommended in treatment guidelines by
    professional or reliable organizations, not
    necessarily government
  • Observational cohorts are nice to learn but will
    believe only if can be confirmed by RCT, e.g.,
    D/C cotrimoxazole prophylaxis after CD4 rise.

For policy makers (government funding agencies)
  • For a good government policy on treatment
    guidelines should be based on the best reliable
    data, i.e., RCT results because public money will
    be used
  • For a bad government wait for long term efficacy
    safety data, i.e., data from long term
    observational cohorts so that they dont have to
    spend money early

For policy guidelines makers
  • IAS/USA, DHHS other developed country
    guidelines based on the most solid evidence (AI,
    AII, BII)
  • Developing country guidelines the minimum
    standards, adjusted on affordability and
    willingness to pay (by the government)
  • WHO guidelines minimum standards and applicable
    to all resource-limited countries, no distinction
    between low vs. medium income developing

Examples of translating RCT results into practice
  • HAART is better than double NUCs
  • (ZDV/3TC vs. ZDV/3TC/IDV Hammer et al, NEJM
    1997 337725,

  • Gulick et al, NEJM 1997 337734)
  • Half-dose d4T is as good as full-dose d4T (ddI)
  • (Ruxrungtham et al, AIDS 2000 14 1375)
  • NNRTI is as good as or better than PI
  • (EFV vs. IDV Staszewski et al, NEJM 1999
  • (EFV vs. ATV Squires et al, JAIDS 2004 361011)
  • LPV/r is better than 1st generation PI
  • (LPV vs. NLV Walmsley et al, NEJM 2002
  • ATV does not cause dyslipidemia as compared to
    other PIs
  • (ATV vs. NLV Murphy et al, AIDS 2003 172603,
    Wood et al, JAIDS 2004 36684)
  • PMTCT regimens (ACTG 076, HIVNET 012)

Moving clinical trials to the South
  • Plenty of examples of good clinical trials from
    the South HIV-NAT (Bangkok), Chennai (India),
    South Africa, Argentina, Brazil
  • Knowledge, skill, patient population, need and
    willingness are there.
  • Infrastructure local funding may not be optimal
    but can be strengthened, not starting from
  • But not many trials from the South. Why how can
    we improve it?

Rationales of doing clinical trials in the South
  • Enormous number of naïve patients HIV-infected
    pregnant women for PMTCT pediatric trials
  • Recruitment is rapid, adherence, tolerance
    retention are much better than the trials in the
  • Personnel laboratory costs are lower.
  • A way to sensitize academicians, government NGO
    in the country in the region for research ARV
  • Opportunity for research on top of the ongoing
    services provided by PEPFAR, GFATM
  • Equal gain for the collaborating institutions
    from the North
  • What we dont need is a token or a Saint from
    the North.

What type of clinical trials that are appropriate
for the South?
  • When to start ARV in children (CD4 lt15 vs.
    15-25) and in TB co-infected patients (2-8 wks
    vs. gt8 wks in CD4 lt200)
  • Drug interaction studies (RFM NVP 400 vs. 600
    mg, EFV 600 vs. 800 mg)
  • Reduced dose regimens to save cost and reduce
    side-effects, e.g., ZDV 200 mg vs. 300 mg bid,
    d4T 20 vs. 30 vs. 40 mg bid in BWgt60 kg, IDV 400/
    600/ 800 mg boosted with RTV 100 mg bid, ATV
    200/r OD

What type of clinical trials that are appropriate
for the South (2)?
  • Equivalence study of generic drugs in countries
    where only few can afford brand name drugs
  • Regimens that one knows that it is safe but
    contra-indicated such as EFV in 2nd-3rd
    trimesters or NVP in pregnancy
  • PMTCT regimens such as ZDV/3TC/TDF vs. ZDV/3TC/PI
  • STI to reduce cost side-effects

Structured treatment interruptions
  • Treatment interruption is common in real life.
  • STI is proposed to guide safe treatment
  • Dybul et al were strong advocates for 1 week on,
    1 week off STI
  • Both of 2 small cohorts (8-10) showed no rebound
    viremia in any patients for as long as 72 weeks
  • PNAS 2001 9815161 (4/10 on NNRTI, 6 PI)
  • JID 2004 1891974 (ddI/3TC/EFV OD)

1 week on, 1 week off STI was proved ineffective
by RCT
  • Ananworanich et al, AIDS 2003 17F33 (Staccato
    study, planned N600 randomized in continued
    treatment arm, CD4-guided arm and
    1-week-on-1-week- off arm). Scheduled preliminary
    safety analysis showed 53 (19/36) virologic
    failure (i.e., 2 consecutive VLgt500 copies/ml) in
    wk-on-off arm, as compared to 2/37 in continuous
    arm (plt0.001) and 0/39 in CD4-guided arm. Thus,
    wk-on-off arm was terminated. Most (11/19) who
    failed were on d4T/ddI/SQV/r (1600/100 OD).

Obstacles of doing trials in the South
  • Less pharmaceutical interest because not being
    the market or uncertainty about the quality of
    the trials
  • Certain limitations from funding agencies such as
    grant cannot be used for ARV, needles, generic
  • Too much paper work site preparation
  • Limitations on boundaries, territories
    networking for international collaboration

  • RCT is most reliable to establish treatment
  • Its researchers innovation, not
    epidemiologists imagination.
  • It can be accomplished rapidly and can be adopted
    rapidly by policy maker practitioner.
  • Moving clinical trials to the South is
  • Observational cohorts are fun data collection and
    analysis to prove or disprove things.
  • If disprove, then another RCT, i.e.,
    RCT is the ultimate goal. Then, why to
    bother about observational cohorts?