UCSF Research Admin Board Presentation on CTSI Global Health Program
Royce
1.
2. ART scale up – where are we now?
<350 CD4
but not on ART
<200 CD4
but not on ART
54%
6%
Slide from Tony Harries, Strategic Use of ARVs, IAC Satellite, 7/22/2012
http://pag.aids2012.org/session.aspx?s=157#3
3. Scenarios for the incremental expansion of ARV
provision to treat and prevent HIV
Slide from Tony Harries, Strategic Use of ARVs, IAC
Satellite, 7/22/2012
http://pag.aids2012.org/session.aspx?s=157#3
4. WHO Consolidated ART Guidelines
Expanded Guidance Clinical, programmatic, operational
Addressing all ages and Adults, women, children, MSM, IVDU,
populations sex workers, prisoners
Guidance across HIV testing, eligibility for ART, pre-
continuum of HIV care ART care, ART care, ART retention
Expanded evidence-base Systematic reviews, modelling, cost-
effectiveness
Public health approach Universal access and prioritization
Slide from Tony Harries, Strategic Use of ARVs, International AIDS Conference SUSA40, 7/22/2012
http://pag.aids2012.org/session.aspx?s=157#3 4
5. Systematic review of TB/HIV service
delivery for WHO guidelines on
antiretroviral therapy (ART)
September 19, 2012
Sarah Royce, MD, MPH
Assistant Clinical Professor
Department of Epidemiology and Biostatistics
Global Health Sciences
SarahRoyceMD@gmail.com
5
7. • 34 million people living with HIV
• 350,000 dying with TB
WHO estimates for 2010
7
8. • Strong WHO recommendations to start ART
– In all HIV+ TB patients, regardless of CD4 count
– Start TB treatment first, followed by ART as soon as
possible within the first 8 weeks
– Immediately within the first 2 weeks if CD4 count
< 50 cells mm3
• Less than half (46%) of the world’s HIV-positive
TB patients in 2010 were known to begin ART
8
9. PICO-4a
• Population: HIV+ TB patients
• Intervention: ART provided at the TB clinic
along with TB treatment
• Comparator: referring HIV+ TB patients for
ART to specialized HIV clinics
• Outcomes: important to the patient
9
10. Outcomes
• ART uptake
• Timeliness of ART initiation
• Adherence, retention on ART
• TB treatment outcomes: success, death,
loss to follow-up
• Response to ART:
– Immune recovery, viral suppression
– AIDS-defining illnesses, IRIS
• Cost
• Clinical skills of staff
10
11. • Grading of Recommendations Assessment,
Development and Evaluation
• Transparent, structured process for
– Developing and presenting summaries of evidence
– Making recommendations for guidelines on
alternative management approaches
http://www.gradeworkinggroup.org/index.htm
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12. • Frame the question
• Chose outcomes of interest, rate importance
• Generate estimate of effect for each outcome
• Rate the quality of evidence for each outcome
• Develop strong or weak recommendations based
on quality of evidence, balance of (un)desirable
outcomes, values and preferences
• Consider resource use
12
13. Search results
• Found 461 articles
• Conference abstracts, contacted authors
• Included
– 9 full text articles
– 13 conference abstracts
from
– Africa (19 studies in 13 countries)
– Latin America (3 studies in 3 countries)
13
14. PICO 4a. Does ART provided with TB
treatment at the TB clinic result in
better outcomes than referring HIV
positive TB patients for ART in
specialized HIV clinics?
HIV TB
TB
I: Provides ART C: Refers for ART
14
15. After vs. Before
TB
Provides ART
Kambale, Pevzner, Howard, van Rie
HIV TB
TB/HIV
Refers for ART
Same nurse provides
TB treatment and ART
Brown, Bygrave
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16. After vs Before
HIV TB
HIV TB
TB staff Refers for ART
provides ART Chifundo, Huerga, Morse, Mugo, Phiri
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17. After vs. Before
HIV TB
HIV TB
TB staff Refers for ART
provides ART Chifundo, Huerga, Morse, Mugo, Phiri
Co-located vs. Geographically separate
HIV TB HIV TB
Dube, Ikeda, Kaplan, Louwagie, Muvuma, 17
Schwartz
18. Outcome: ART uptake
• After vs. before the TB (or TB/HIV) clinic began
providing ART. Relative Risks (RR)
– Improved in 8 studies (RR ranged from 1.2 to 4.8)
– Worse (RR 0.9) in 1 study
• Co-located vs. geographically separated TB
and HIV clinics (during same period)
– Improved in 2 studies (RR 2.5, RR 8.8)
– No difference in 2 studies
18
19. Very low quality of evidence for
improvement in ART uptake
• Little confidence in measures of effect
• Observational studies start as low
• Downgraded for
– Indirectness: geographically co-located (different
I), referral within facility (different C)
– Risk of bias: no adjustment for confounding
(other interventions between “after” and
“before,” patient characteristics)
– Imprecision: small numbers of patients
19
20. HIV+ patients HIV+ TB patients
in care at HIV clinic; vs. referred from TB
found to have TB; Clinics to specialized
start ART HIV clinic to start ART
and TB treatment
TB
HIV
TB
Referrals for ART
Lawn
20
21. Outcome: Timeliness of ART initiation
• Estimates of effect (since start of TB treatment)
– I: HIV clinic providing TB treatment (RR 4.9 in 1st
month for TB patients with CD4 counts <50 cells)
– C: referral in same facility (RR 2.2 in 1st 2 mos)
– I: referral to co-located clinic (no difference in 1st 2
mos of TB treatment)
• Very low quality of evidence
– Indirectness in all 3 studies
– Risk of bias: new policy to start ART early in 1 study
– Imprecision in 1 study
21
22. TB treatment outcomes in
HIV+ TB patients
• Estimates of effect (# studies)
– Improved (2), no change (4)
– Worse in 1 (except no difference in failure)
• Very low quality of evidence
– Indirectness
– Risk of bias: no adjustment for ART, CD4
count, differential follow-up
– Imprecision
• Utility as an effect measure?
22
23. Summary (# of studies)
Very low quality evidence suggests that when
TB clinics provide ART,
– ART uptake improved (10), no change
(2), lower (1)
– Timeliness of ART initiation improved (2), no
change (1)
– TB treatment outcomes in HIV+ improved
(2), no change (4), worse (1)
23
24. 2012 WHO guidelines
A. Deliver integrated TB
and HIV services
B. Reduce burden of TB
in people living with HIV
--intensified TB case
finding
C. Reduce burden of
HIV in patients with TB
--ART
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25. PICO 4b. Does TB diagnosis and/or TB
treatment at specialized HIV clinics result
in better outcomes than referring HIV-
positive patients to TB clinics for TB
diagnosis and/or treatment?
HIV HIV TB
Treat and/or Refer for TB treatment
diagnose TB and/or diagnosis
25
26. 159 HIV sites vs. 22 HIV sites that refer
that treat TB
HIV HIV TB
Treat TB Refer for TB treatment
Howard, 6 countries in Africa: Higher proportion of
screened for TB (RR 1.4). Very low quality (bias)
26
27. After vs. Before
TB/HIV HIV TB
Same nurse diagnoses
Refers for TB diagnosis
TB,* provides TB treatment
*”Mobile doctor” diagnoses and treatment
extrapulmonary TB
Brown (S Africa): Increased % of extrapulmonary TB
cases among all HIV-positive TB cases (RR 1.5). Very
low quality (inadequate adjustment for confounding)
27
28. After creation
of TB/HIV unit vs. Before
HIV
HIV TB/HIV
TB
Refers for TB treatment
Hermans (Uganda): Higher % starting ART during TB
treatment intensive phase (RR 2.6). Very low quality
(imprecision, indirectness, confounding)
28
29. Outcome: ART uptake
• Measures of effect
– Improved (RR 2.2) comparing nurse-run “one stop
shop” with referral to separate facility for TB
treatment
– Worse (RR 0.9) comparing TB/HIV unit to TB clinic
referral (both within HIV service)
• Very low quality of evidence
– Indirectness
– Risk of bias: confounding
– Imprecision
29
30. HIV team visits Patient travels
patient’s home to to TB clinic for
provide TB vs. TB treatment
treatment
TB
Bento,* Cerda
*organization of TB and HIV services in outpatient department is not specified
30
31. TB treatment outcomes in
HIV+ TB patients
• Hermans
– On ART--no difference
– Not on ART-- improved
• Home TB treatment—mixed
Very low quality of evidence: indirectness, bias
(confounding, differential ascertainment of
death), imprecision
31
32. Summary (# of studies)
Very low quality evidence suggests that when
HIV services provide TB treatment,
– TB screening and diagnosis improved (2)
– ART uptake improved (1), decreased but
was more timely (1)
– TB treatment outcomes in HIV+ (3 studies
with mixed results)
32
34. Possible advantages of integration
(Uyei, 2011)
• Efficiency, share scarce resources,
strengthen health system
• Point of entry to early diagnosis,
treatment, other services
• Facilitates joint care
TB services more decentralized than HIV
services: 1 ART facility for every 5 health
facilities where TB treatment was available
(2007 WHO survey of 8 high-burden countries)
34
35. Considerations
• Patient: costs and other barriers (time, stigma)
• Healthcare worker: cross training, management
of 2 diseases, volume/experience, task shifting
to less specialized cadres
• System: primary care vs. district hospital,
urban/rural, record keeping, infection control,
community involvement
• Epidemiology: concentrated vs. generalized HIV
epidemic
35
Editor's Notes
operational
Input as we prepare to present in Geneva, prepare a manuscript
Why not translated to practiceA key means to achieve this goal is ensuring that all HIV-infected TB patients receive antiretroviral therapy (ART), an intervention proven to markedly decrease mortality (WHO 2010). While WHO strongly recommends starting ART as soon as possible in all HIV-positive TB patients (WHO 2012), only 46% began ART in 2010 (WHO 2011).Low ART coverage is related in part to barriers TB patients face when they are referred to a specialized HIV clinic. A 2007 survey of eight high-burden countries found that ART services are much more centralized than TB treatment; there was one ART facility for every five health facilities where TB treatment was available (WHO 2009).
PIC form the search criteria:Had to have a comparator
PICO formed inclusion criteriaHad to have a comparator
I on left, C on RShow you models of care, comparisons the studies made, then the measures of effect
TBclnics more decentralizedDirectly address PICO
Comparator becomes the intervention!Bottom row: Not exactly what the PIC was asking therefore indirect
Comparator becomes the intervention!Bottom row: Not exactly what the PIC was asking therefore indirect
Statistically significant results only (CI quite wide for some—imprecision we’ll talk about soon)Estiamtes of effect: Intervention v. comparatorCouldn’t combine estimatesPublication bias?
Indirectness: pop (applicability),intervnetion, outcome (surrogate not pt important), lack of head to head comparisonAfter vs. before:New guidelines to start ART at higher CD4 counts. Just 2 points in time, what was trend before? Interrupted time seriesPackage of interventionsOther bias: eligibilty criteria to select exposed, unexposedFlawed measures of E, O (differential surveillance)Incomplete f/up
In HIV positive: directly relevant to PICO populationLess compelling outcome: many other factors feed in We don’t need to prove ART works to decrease mortalityFocus on more proximate measure of service deliverY: timely art uptakeSeveral authors commented on no worsening in treatment outcomes for all tB pts, or for HIV neg as evidence that already overburdened services did not get worse when they took on ART
