IAS–USA

When to Start When to Start Antiretroviral TherapyAntiretroviral Therapy

Constance A. Benson, MDProfessor of Medicine

University of California San Diego

FINAL: 07-20-12Presented by CA Benson, MD, IAS, July 25, 2012.

Slide #2

Presented by CA Benson, MD, IAS, July 25, 2012.

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

Slide #3Case 1Would you recommend:

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

Presented by CA Benson, MD, IAS, July 25, 2012.

Earlier ART Associated with Decreased Mortality and Disease Progression:

Observational StudiesStudy Published N Endpoint Relative Hazard or

Hazard RatioP 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

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

Cohen et al, NEJM, 2011Cohen et al, NEJM, 2011Presented by CA Benson, MD, IAS, July 25, 2012.

Slide #6

Risks and Benefits of Earlier Initiation of ART

BenefitsPrevention of progressive immune dysfunction (reduced immune activation)

Delayed progression to AIDS and prolonged survival

Decreased risk of non-AIDS/HIV-related morbidity (HIVAN, malignancies, neurocognitive dysfunction, cardiovascular disease, progression of underlying chronic hepatitis B or C disease)

Decreased drug resistance

Decreased risk for some ARV toxicities

Decreased HIV transmission

RisksReduced quality of life

Development of drug resistance if adherence is suboptimal

Limitation in future choices of ART if drug resistance occurs

Uncertain long-term toxicities and duration of effectiveness for some drugs/regimens

Possible transmitted drug resistance

Presented by CA Benson, MD, IAS, July 25, 2012.

Slide #7

Presented by CA Benson, MD, IAS, July 25, 2012.

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)

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.

Slide #9

Case 2Would you recommend:

1. Starting both anti-TB therapy and ART immediately

2. Starting anti-TB therapy, then starting ART within 2 weeks of TB treatment initiation

3. Starting anti-TB therapy, then starting ART after 8 weeks of intensive TB treatment

4. Starting anti-TB therapy, then starting ART after completion of 6 months of TB treatment

5. 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

19% ↓ p=0.45

11% ↓ p=0.73

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Earlier: 2-4 weeks after TB

treatment started

Later: 8-12 weeks after TB treatment

started

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

34% ↓ p=0.004

42% ↓ p=0.02

68% ↓ p=0.06

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Earlier: 2-4 wks after TB

treatment started

Later: 8-12 wks after TB

treatment started

Presented by CA Benson, MD, IAS, July 25, 2012.

Slide #12

Presented by CA Benson, MD, IAS, July 25, 2012.

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

Slide #13

Presented by CA Benson, MD, IAS, July 25, 2012.

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

Slide #14Case 3What 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 elsePresented by CA Benson, MD, IAS, July 25, 2012.

Slide #15

Presented by CA Benson, MD, IAS, July 25, 2012.

Cryptococcal Meningitis and Antiretroviral Therapy

• 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

Slide #16

Presented by CA Benson, MD, IAS, July 25, 2012.

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