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Efficacy of routine viral load, CD4 cell count, and clinical monitoring of adults taking antiretroviral therapy in Rural Uganda

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Efficacy of routine viral load, CD4 cell count, and clinical ... Dr. Willy Were. Dr. Paul Weidle. Dr. Sam Malamba. Dr. Elizabeth Madraa. Dr. Robert Downing ... – PowerPoint PPT presentation

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Title: Efficacy of routine viral load, CD4 cell count, and clinical monitoring of adults taking antiretroviral therapy in Rural Uganda


1
Efficacy of routine viral load, CD4 cell count,
and clinical monitoring of adults taking
antiretroviral therapy in Rural Uganda
  • Alex Coutinho MD MPH DTMH
  • Jonathan Mermin MD MPH et al
  • CROI
  • Boston, USA
  • February 2008

2
Obstacles to rural HIV care
  • Dispersed population with limited transportation
  • Access to ART associated
  • with cost of transport to health center
  • Prices for ART drugs have decreased dramatically
    in Africa and other costs now significant
    barriers for patients
  • Laboratory facilities often limited and testing
    expensive

3
Laboratory monitoring in HIV care
  • Baseline CD4 cell count and viral load associated
    with prognosis
  • CD4 cell count useful in determining eligibility
    for ART
  • Viral load during ART associated with clinical
    outcomes
  • Routine CD4 cell count and viral load every 3
    months is norm in U.S. and Europe

4
Home-based AIDS Care Program
  • Adds ART and TB to care and prevention package
    for 1,000 people with HIV
  • Family VCT, basic care package and drug adherence
  • ART provided to all eligible adults and children
    in household
  • Weekly home visits by lay workers no scheduled
    clinic visits after enrollment

5
HBAC monitoring evaluation
  • Open cohort of 1,000 adults with HIV
  • and their family members

Arm A
Arm C
Arm B
Weekly home visits CD4 cell counts Viral loads
Weekly home visits CD4 cell counts
Weekly home visits
Severe morbidity and mortality at 3 years
6
Setting
7
Eligibility criteria
  • CD4 cell count 250 cells/µL or WHO clinical
    stage III or IV
  • Excluding isolated pulmonary TB
  • AST or ALT lt5 times upper limit of normal
  • Creatinine clearance 25 ml/min
  • Karnofsky Performance Score 40

8
Antiretroviral regimens
  • 1st line was nevirapine, lamivudine, and
    stavudine
  • Efavirenz for concomitant TB treatment
  • 2nd line was lopinovir/ritonovir, didanosine, and
    tenofovir

9
Data collection
  • Viral load and CD4 collected quarterly
  • Data collected from home visits, clinic visits
    and hospitalizations
  • Clinical conference on all deaths,
    hospitalizations, opportunistic illnesses,
    abnormal labs and changes in ART regimens

10
Treatment failure definition
  • First response adherence support
  • Arm A
  • 2 consecutive detectable viral loads
  • However, if 50-5000 copies/ml and clinically
    well, could continue
  • CD4 cell count

11
Treatment failure for Arms B and C
  • Arm B
  • Persistently declining CD4 count measured on two
    separate occasions
  • Clinical failure
  • Arm C
  • Unintentional weight loss of gt10
  • CDC category C illness
  • Diarrhea or fever for gt1 month without
    correctable cause
  • New or recurrent oral, esophageal, vaginal
    candidiasis

12
Analyses
  • Kaplan-Meier analysis of time to first event of
    severe morbidity or mortality, and death alone
  • Cox proportional hazard models
  • Poisson regression analyses for hospitalizations,
    morbidity
  • Intention-to-treat from date of randomization and
    per protocol from gt90 days after initiating ART

13
Results
  • 1116 ART-naïve individuals randomized
  • 1094 started ART
  • 8 WHO stage IV 31 stage III
  • Median follow-up 3 years
  • 126 deaths (11.2)
  • 47 in first 3 months
  • 148 AIDS-defining illnesses
  • 57 in first 3 months
  • 61 (5.8) had 2 viral loads gt500 copies/ml
  • 28 (2.7) changed to 2nd line drugs

14
Participant characteristics at baseline
Arm A Clinical monitoring CD4 counts VL N 368 Arm B Clinical monitoring CD4 cell counts N371 Arm C Clinical monitoring N377 P-value
Median age in years 37 38 39 P0.96
Female () 75 75 67 P 0.01
Median CD4 cell count (cells/ µL) 128 61 - 194 127 62 - 130 131 70 - 197 P0.65
HIV viral load (copies/ml)
Median IQR 233,000 77,900 - 513,000 201,000 63,600 - 520,000 210,000 74,600 - 570,000 P0.63
Depression Scale
Depressed (23-60) 148 (40) 169 (46) 153 (41) P0.59
Not depressed (0-22) 205 (56) 189 (51) 208 (55) P0.59
Missing 15 (4) 13 (4) 16 (4) P0.59
15
Time to event of severe morbidity or mortality
Per protocol
Intention-to-treat
A vs. B p0.46 B vs. C p0.034 A vs. C
p0.004
A vs. B p0.27 B vs. C p0.22 A vs. C p0.02
16
Time to death
Intention-to-treat
Per protocol
A vs. B p0.73 B vs. C p0.36 A vs. C p0.21
A vs. B p0.75 B vs. C p0.14 A vs. C p0.25
17
Cox proportional hazards model First morbidity
or mortality event
Intention-to-treat
Number participants Events Follow-up Time Rate per 100 PYO Adjusted Hazard Ratio Adjusted Hazard Ratio Adjusted Hazard Ratio
Compared to A P-value Compared to B P-value
Arm A 368 47 979.4 4.8 -- --
Arm B 371 58 971.6 6.0 1.28 0.84-1.97 0.26 --
Arm C 377 72 950.9 7.6 1.88 1.25-2.84 0.002 1.47 1.00-2.15 0.047
18
Cox proportional hazards model First morbidity
or mortality event
Per protocol
Number participants Events Follow-up Time Rate per 100 PYO Adjusted Hazard Ratio Adjusted Hazard Ratio Adjusted Hazard Ratio
Compared to A P-value Compared to B P-value
Arm A 349 24 884 2.7 -- --
Arm B 346 29 878 3.3 1.25 0.71-2.19 0.44 --
Arm C 352 47 852 5.5 2.25 1.35-3.76 0.002 1.80 1.12-2.91 0.016
19
Specific disease morbidity
  • IRR p-value
  • Tuberculosis
  • C vs. A 1.7 p0.043
  • C vs. B 1.7 p0.045
  • Pneumocystis jiroveci pneumonia
  • C vs. A 8.7 p0.01
  • C vs. B 17.2 p0.009
  • Cryptococcal disease
  • C vs. A 2.3 p0.044
  • C vs. B 3.1 p0.013
  • Kaposis sarcoma
  • C vs. A 3.3 p0.07
  • C vs. B 1.6 p0.39

20
Cox proportional hazards models comparison of
mortality
  • Intention-to-treat adjusted hazard ratio
  • Arm C compared with A 1.58 (0.97-2.6)
    p0.07
  • Arm C compared with B 1.38 (0.9-2.2)
    p0.18
  • Arm B compared with A 1.14 (0.7-1.9)
    p0.60
  • Per protocol adjusted hazard ratio
  • Arm C compared with A 1.58 (0.9-2.8)
    p0.14
  • Arm C compared with B 1.72 (0.9-3.2)
    p0.09
  • Arm B compared with A 1.23 (0.7-2.1)
    p0.43

21
Treatment failure
  • Similar number of people with 2 viral loads gt500
    copies/ml per arm
  • Arm A 16, Arm B 26, Arm C 19
  • Having viral loads gt500 copies/ml was associated
    with increased severe morbidity or mortality (18
    vs. 10 p0.049)

22
Response to treatment
90 complete viral suppression at 1 year
2 viral loads gt500 copies/ml after 90 days Of these, changed to 2nd line Total changed to 2nd line Changed to 2nd line with detectable viral load
Arm N () N () N N ()
A 16 (5) 7 (44) 7 7 (100)

B 26 (8) 4 (15) 4 4 (100)

C 19 (5) 2 (11) 17 2 (12)

ALL 61 (6) 13 (21) 28 13 (46)
23
Viral load response
Arm A Arm B Arm C P-value
Median viral load prior to change (copies/ml) 2500 13855 65750 0.25
Median viral load 6 months after change lt50 lt50 348 0.66
Days with viral load gt500 before change 189 170 548 0.0053
Median viral load prior to not changing 60200 2735 6330 0.37
Median viral load 6 month after not changing lt50 1340 7340 0.0082
24
Arm C
  • 15 people changed to 2nd line therapy with
    undetectable viral load, all were changed because
    of AIDS-defining events
  • Number of cases
  • Cryptococcal disease 6
  • Tuberculosis 6
  • Kaposis Sarcoma 4
  • Cervical cancer 2
  • Cytomegalovirus 1
  • Recurrent pneumonia 1
  • All occurred gt1 year after starting therapy

25
Why did Arms A and B do better?
  • Not only because of earlier regimen change in
    failing patients
  • lt50 in Arms A and B with VL gt500 copies changed
  • Adherence resulted in subsequent suppression
  • Viral load and CD4 cell count monitoring detected
    adherence issues before the occurrence of
    morbidity or mortality
  • Clinical criteria were poorly sensitive and
    poorly specific to detect adherence challenges

26
Conclusions
  • All study arms performed well
  • 1 year mortality in Arm C (9) lower than all but
    one study in Africa
  • Rates of viral suppression high
  • Lay workers can effectively deliver drugs,
    support adherence, and monitor patients without
    scheduled clinic visits
  • Supporting adherence is the important determinant
    of success

27
How should ART be monitored?
  • Clinical monitoring alone was associated with
    increased rate of new AIDS-defining events and
    trend towards increased mortality
  • Build laboratory capacity
  • No benefit seen for adding quarterly viral load
    measurements to CD4 cell counts
  • However there is need to determine long-term
    outcomes and cost-effectiveness

28
Acknowledgements
  • Dr. David Moore
  • Dr. Rebecca Bunnell
  • Dr. Jordan Tappero
  • Dr. Willy Were
  • Dr. Paul Weidle
  • Dr. Sam Malamba
  • Dr. Elizabeth Madraa
  • Dr. Robert Downing
  • Paul Ekwaru
  • Dr. Richard Degerman
  • HBAC participants
  • CDC-Uganda staff in Tororo and Entebbe
  • Uganda Ministry of Health
  • TASO Uganda
  • Uganda PEPFAR Team
  • CDC-Atlanta
  • USAID
  • OGAC
  • DSMB
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