Transcript HIV Related Research in Uganda

Monitoring ART in Resource
Limited Settings
Elly T Katabira, FRCP
Department of Medicine
Makerere University Medical School
2nd Global Experts Summit: Leading by
Example in Public Health Approach to
ART. Vancouver, Canada, 13 Feb 2009
The ART response
• Success story of WHO 3 by 5 campain
Over 2M on ART
Scaling up access to ART continues with
unprecidented enthusiasm, supported by
GFATM, PEPFAR and others
Short term gaols being achieved
Emphasis is on putting patients on treatment
Morbidity and mortality down
• Longterm goals needs to be addressed now
Monitoring for drug failure, resistence & adherence
ARV therapy coverage in low and
middle income countries, Dec 2003
Geographical Region
Number of people receiving
ARV therapy
Estimated
need
Coverage
Sub-Saharan Africa
100,000
4,400,000
2%
Latin America and the Caribbean
210,000
250,000
84%
East, South and South-East Asia
60,000
900,000
7%
Europe and Central Asia
15,000
80,000
19%
1,000
75,000
5%
400,000
5,900,000
7%
North Africa and the Middle East
Total (All WHO regions)
ARV therapy coverage in low and
middle income countries, Dec 2005
Geographical Region
Number of people receiving
ARV therapy
Estimated
need
Coverage
(low estimate –
high estimate)
Sub-Saharan Africa
810,000
(730,000 –890,000)
4,700,000
17%
Latin America and the Caribbean
315,000
(295,000 –335,000)
465,000
68%
East, South and South-East Asia
180,000
(150,000 –210,000)
1,100,000
16%
Europe and Central Asia
21,000
(22,000 – 22,000)
160,000
13%
North Africa and the Middle East
4,000
(3,000 –5,000)
75,000
5%
1,330,000
(1.2 –1.46 million)
6.5 million
15%
Total
Common monitoring practices in
Resource Limited Settings
• At the time of ART initiation:
Pre- and post-test counseling
ART related counseling
Baseline screening
FBC, LFTs, RFTs, etc.
CD4 cell counts
Rarely VL evaluation (in research centers)
Common monitoring practices in
Resource Limited Settings
• During follow-up
Regular counseling
Adherence
Behavior change
Clinical evaluation looking for:
ART complications
New or worsening OIs
Lab evaluation
CD4 cell counts – 0-2x a year if no problems
LFTs, etc. – only in big sites
Short comings of common ART
monitoring strategies
• Quality of clinical monitoring depends on:
Quality/experience of monitoring health staff
Health seeking behavior of patients
Patient interactions with other providers &
relatives/friends
• Lab services inadequate and expensive
Lab costs/access are prohibitive at smaller units
• Adherence adversely affected by poor
health systems
Frequent stock outs, etc.
What happens elsewhere
• HIV care (including ART monitoring) is
individualized in the North
Expensive screening services
E.g. Resistance testing at ART initiation
Frequent vs non-frequent lab tests – CD4 & VL
• In spite of these advances:
Primary resistance is on the increase
Need for multiple, complicated, expensive
regimens on the increase
• A road RLS should avoid at all costs
CDC Survey: Drug-Resistant
HIV Among Newly Diagnosed
Patients
Prevalence of Drug Resistance, %
1998[1]
(n = 257)
1999[1]
(n = 239)
2000[1]
(n = 299)
20032004[2]
(n = 633)
20032006[3]
(n = 3130)
Any drug
5.5
8.8
10.7
14.5
10.4
NRTI
5.1
7.1
7.7
7.1
3.6
NNRTI
0.4
2.1
1.7
8.4
6.9
PI
0
0.8
3.0
2.8
2.4
≥ 2 drug classes
0
1.3
1.3
3.1
1.9
1. Bennett D, et al. CROI 2002. Abstract 372. 2. Bennett D, et al. CROI 2005. Abstract 674.
3. Wheeler W, et al. CROI 2007. Abstract 648.
Increasing prevalence of NNRTI-associated
drug-resistance mutations in patients with
acute, early HIV in San Francisco
Prevalence of Drug-Resistance Mutations
2003
(n = 58)
2004
(n = 54)
2005
(n = 43)
2006
(n = 29)
2007
(n = 40)
Any resistance
10%
11%
19%
17%
28%
NRTI
7%
6%
12%
7%
15%
NNRTI
2%
6%
9%
10%
8%
PI
9%
4%
0%
7%
8%
Jain V et al. UCSF San Francisco – CROI 2009 Abstract 673
When to Use Resistance Testing
IAS-USA[1]
DHHS[2]
European[3]
Primary/acute
Recommend
Recommend
Recommend
Postexposure
prophylaxis
--
--
Recommend*
Chronic, tx naive
Recommend
Recommend
Recommend
Failure
Recommend
Recommend
Recommend
Pregnancy
Recommend
Recommend
Recommend
--
Recommend
Recommend
Pediatric
*Test source patient especially if treated with antiretroviral drugs.
1. Hirsch MS, et al. Clin Infect Dis. 2008;47:266-285. 2. DHHS guidelines. Available at:
http://www.aidsinfo.nih.gov. Accessed January 12, 2009. 3. EACS Guidelines Version 3.
Available at: http://www.eacs.eu/guide/index.htm. Accessed October 24, 2008.
PREDICT-1: HLA-B*5701 Allele
Screening to Reduce ABC-HSR
6-week observation period
HIV-infected
abacavir-naive
patients
(N = 1956)
No Screening Control
ABC regimen + standard
monitoring for HSR
(n = 976)
HLA-B*5701–positive
subjects excluded
from ABC treatment
Screen for HLA-B*5701
(n = 980)
HLA-B*5701–negative
subjects* treated with ABC +
standard monitoring for HSR
*Physicians not informed of screening status.
Incidence of ABC HSR
Clinically suspected
Skin patch test positive
Screened for
HLA-B*5701,
% (n/N)
Not Screened, %
(n/N)
OR
(95% CI)
P Value
3.4 (27/803)
7.8 (66/847)
0.40 (0.25-0.62)
< .001
0 (0/802)
2.7 (23/842)
0.03 (0-0.18)
< .001
Mallal S, et al. N Engl J Med. 2008;358:568-579.
Possible solutions
• WHO guidelines – based on expert opinions
Probably not sensitive or specific enough
• Intensified & improved clinical monitoring
But poorly reflects Virologic failure
• More frequent CD4 (immunological
monitoring)
But also poorly reflects Virologic failure
• VL monitoring, though superior over CD4,
no significant benefit to CD4 monitoring
Performance of WHO immunologic failure
criteria at various viral load thresholds
Sensitivity Specificity
PPV
NPV
Viral load >
10,000 copies /mL
23% (18/80)
90%
(946/1053)
14%
(18/125)
94%
(946/1008)
Viral load >
10,000 copies /mL
28% (10/36)
90%
(982/1097)
8%
(10/125)
97%
(982/1008)
23%
(26/112)
90%
(922/1021)
21%
(26/125)
91%
(922/1008)
Viral load > 400
copies /mL
They propose periodic viral load measurements as a better alternative
Reynolds S et al. Rakai, Uganda – CROI 2009 Abstract 144
HIV-related symptoms or signs
predicting treatment failure
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Prurigo
Unexplained persistent diarrhea
Unexplained persistent fever
Unexplained weight loss
Unexplained polynueritis
Unexplained cognitive impairment
Loss of individual milestones in children
Growth retardation in children
Colebunders et al. The Lancet Vol 6 2006
Proposed steps to assess
virological treatment failure
• Colebunders et al – The Lancet vol 6 2006
Obtain an ART treatment history
Including monotherapy for PMTCT
Assess quality of HAART regimen and
concomitant medication
Assess adherence to treatment
Need good and experienced counselors
Assess clinical symptom development and lab
test results
VL testing in selected patients
Some suggested monitoring
strategies
• Selected VL for problem cases
Need guidelines for selection criteria
OR for effectiveness of such guidelines
• Refine clinical monitoring with enhanced
supervision – The Senegal model
• Use CD4 count gain to triage for VL
VL if CD4 gain <50 cells/µl in 6 months –
particularly if had low BL CD4 count
Bisson G et al. AIDS 2006, 20:1613-1619
Conclusions
• All patients on ART should have a VL at
least once a year
• Clinical monitoring, adherence profile and
CD4 testing should be used to prioritize VL
needs
• Operation research should be done to refine
the criteria as who should have a VL when
resources are limited