When to Start
Antiretroviral Therapy
Constance A. Benson, MD
Professor of Medicine
University of California San
Diego
Presented
by CA Benson, MD, IAS, July 25, 2012.
FINAL:
07-20-12
IAS–USA
Slide #2
Case 1
• 25 year old man, asymptomatic, newly
diagnosed with HIV infection after seeking
voluntary testing because he is sexually
active, with MSM as a potential risk factor
• CD4 count 750 cells/µL; plasma HIV RNA
level 1000 copies/mL
Presented by CA Benson, MD, IAS, July 25, 2012.
Case 1
Would you recommend:
Slide #3
1. Starting ART now
2. Starting ART when his CD4 cell count declines
to < 500 cells/µL
3. Starting ART when his CD4 cell count declines
to < 350 cells/µL
4. Starting ART when his CD4 cell count declines
to < 500 cells/µL and his plasma HIV RNA level
increases to > 5,000 copies/mL
5. None of the above
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #4
Earlier ART Associated with Decreased
Mortality and Disease Progression:
Observational Studies
Study
Published
N
Endpoint
Relative Hazard or
Hazard Ratio
P or 95% CI
NA-ACCORD
NEJM, 2009
8,362
Death
1.69
CD4 <350 vs 350-500
< 0.001
NA-ACCORD
NEJM, 2009
9,155
Death
1.94
CD4 <500 vs > 500
< 0.001
When to Start
Consortium
Lancet, 2009
24,444
AIDS or
Death
1.28 (HR)
CD4 251-350 vs 351-400
1.04-1.57
HIV-CAUSAL
Ann Int Med,
2011
20,971
AIDS or
Death
1.38 (HR)
CD4 <350 vs <500
1.23-1.56
CASCADE
Arch Int
Med, 2011
9,455
Death
0.51 (HR)
CD4 350-499 vs deferred
0.33-0.80
COHERE
Plos Med,
2012
75,336
AIDS or
Death
0.74 (HR)
CD4 350-<500 on ART
0.96 (HR)
CD4 > 500 on ART
0.58-0.80
Presented by CA Benson, MD, IAS, July 25, 2012.
0.92-0.99
Slide #5
HPTN 052
• 1,750 heterosexual serodiscordant couples in
resource-constrained countries randomized to
receive ART early (CD4 350-550 cells/µL) or defer
until CD4 < 250 cells/µL
Event Rates
Early ART
Deferred
ART
HR
P-value
Transmission Rate
per 100 pt-years
(95% CI)
0.3
(0.1-0.6)
2.2
(1.6-3.1)
0.11
(0.04-0.32)
< 0.001
Clinical Event Rate
per 100 pt-years
(95% CI)
2.4
(1.7-3.3)
4.0
(3.5-5.0)
0.59
(0.40-0.88)
<0.001
Presented by CA Benson, MD, IAS, July 25, 2012.
Cohen et al, NEJM, 2011
Slide #6
Risks and Benefits of Earlier
Initiation of ART
Benefits
Prevention of progressive immune
dysfunction (reduced immune activation)
Risks
Reduced quality of life
Delayed progression to AIDS and
prolonged survival
Development of drug
resistance if adherence is
suboptimal
Decreased risk of non-AIDS/HIVrelated morbidity (HIVAN,
Limitation in future choices of
ART if drug resistance occurs
malignancies, neurocognitive
dysfunction, cardiovascular disease,
progression of underlying chronic
hepatitis B or C disease)
Uncertain long-term toxicities
and duration of effectiveness
for some drugs/regimens
Decreased drug resistance
Decreased risk for some ARV
toxicities
Decreased HIV transmission
Possible transmitted drug
resistance
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #7
When to Start ART: IAS–USA
Recommendations 2012
• Patient readiness should be considered when deciding to initiate
antiretroviral therapy (ART)
• ART should be offered regardless of CD4 cell count (increasing
strength of the recommendation as CD4 decreases)
–
–
–
–
–
–
–
–
CD4 < 500 cells/µL (AIa)
CD4 > 500 cells/µL (BIII)
Pregnancy (AIa)
Chronic HBV (AIIa)
HCV (may delay until after HCV treatment if CD4 > 500) (CIII)
Age older than 60 (BIIa)
HIV-associated nephropathy (AIIa)
Acute phase of primary HIV infection, regardless of symptoms
(BIII)
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #8
Case 2
• 34 yo man admitted with a
3-week history of hectic
fevers, dyspnea, productive
cough, 10 pound weight loss
• CXR-PAL: Bilateral hazy
reticulonodular infiltrates,
L>R
• Sputum AFB smear positive
• HIV EIA positive
• CD4 cell count 32 cells/µL;
plasma HIV RNA 43,000
copies/mL
Presented by CA Benson, MD, IAS, July 25, 2012.
Case 2
Would you recommend:
1.
2.
3.
4.
5.
Slide #9
Starting both anti-TB therapy and ART
immediately
Starting anti-TB therapy, then starting ART within 2
weeks of TB treatment initiation
Starting anti-TB therapy, then starting ART after 8
weeks of intensive TB treatment
Starting anti-TB therapy, then starting ART after
completion of 6 months of TB treatment
Something else
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #10
Effect of ART Timing on TB Death (CAMELIA)
or Death/AIDS Progression (STRIDE, SAPIT)
34% ↓
p=0.004
Earlier: 2-4
weeks after TB
treatment
started
19% ↓
p=0.45
11% ↓
p=0.73
Later: 8-12 weeks
after TB treatment
started
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #11
Significant Reduction in Death/AIDS Among
Those with TB and CD4 < 50 Cells/µL
42% ↓
p=0.02
34% ↓
p=0.004
68% ↓
p=0.06
Earlier: 2-4
wks after TB
treatment
started
Later: 8-12
wks after TB
treatment
started
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #12
Greater Reduction in Mortality at
Lower CD4
P = 0.004
P = 0.45
P = 0.73
Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #13
Case 3
• 42 yo woman admitted with intermittent fever,
headache, lethargy, 2 month history of weight loss
– Heterosexual, 6 lifetime partners, one of whom had
a history of IDU and died of an unknown illness 8
years previously; tested for HIV at that time but
was negative
• CT scan in ED showed enlarged ventricles,
effaced sulci, no midline shift, no mass lesions
• HIV EIA positive, HIV RNA 143,000 copies/mL,
CD4 25 cells/µL
• CSF – 20 WBCs, 90% lymphs, protein 58,
glucose 43, and CRAG 1:1280
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #14
Case 3
What would you recommend?
1. Start treatment for cryptococcal meningitis (CM)
plus antiretroviral therapy (ART) immediately
2. Start treatment for CM, add corticosteroids, and
start ART immediately
3. Start treatment for CM now, defer ART until
after 2 weeks if clinically improved
4. Start treatment for CM now, defer ART until
after 8-10 weeks at the time of a switch to
maintenance therapy for CM
5. Do something else
Presented by CA Benson, MD, IAS, July 25, 2012.
Cryptococcal Meningitis and
Antiretroviral Therapy
Slide #15
• Randomized clinical trial in Zimbabwe; ART
started within 72 hours vs. 8 weeks after initiation
of fluconazole alone for treatment of CM
(Makadzange C, et al. Clin Infect Dis 2010)
– Trial stopped by the DSMB due to increased HR for
death (HR 2.85) in the early ART arm
• Randomized clinical trial in Uganda, South Africa
(COATS) in patients with CM
– After 7-11 days of treatment with amphotericin B +
fluconazole, patients were randomized to start ART
within 48 hours or > 4 weeks
– Trial stopped by the DSMB due to increased mortality
in the early ART arm
Presented by CA Benson, MD, IAS, July 25, 2012.
Slide #16
When to Start ART During Acute
Opportunistic Infections: IAS–USA
Recommendations 2012
• Start ART as soon as possible, preferably within
the first two weeks (AIa) except for TB and
cryptococcal meningitis as indicated below:
– Patients with cryptococcal meningitis should be
managed in consultation with experts (BIII)
– Patients with TB should start TB treatment first; start
ART as soon as possible but within the first 2 weeks
for those with CD4 < 50 cells/µL
– Within the first 2-8 weeks of TB treatment for those
with TB meningitis
– Within the first 8-12 weeks of TB treatment for others
Presented by CA Benson, MD, IAS, July 25, 2012.