1. IAS–USA When to Start Antiretroviral Therapy Constance A. Benson, MD Professor of Medicine University of California San Diego FINAL: 07-20-12 Presented by CA Benson, MD, IAS, July 25, 2012.

2. 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

3. Slide #3 Case 1 Would 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 5,000 copies/mL 5.None of the above Presented by CA Benson, MD, IAS, July 25, 2012.

4. Slide #4 Presented by CA Benson, MD, IAS, July 25, 2012. Earlier ART Associated with Decreased Mortality and Disease Progression: Observational Studies StudyPublishedNEndpointRelative Hazard or Hazard Ratio P or 95% CI NA-ACCORDNEJM, 20098,362Death1.69 CD4 <350 vs 350-500 < 0.001 NA-ACCORDNEJM, 20099,155Death1.94 CD4 500 < 0.001 When to Start Consortium Lancet, 200924,444AIDS or Death 1.28 (HR) CD4 251-350 vs 351-400 1.04-1.57 HIV-CAUSALAnn Int Med, 2011 20,971AIDS or Death 1.38 (HR) CD4 <350 vs <500 1.23-1.56 CASCADEArch Int Med, 2011 9,455Death0.51 (HR) CD4 350-499 vs deferred 0.33-0.80 COHEREPlos Med, 2012 75,336AIDS 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

5. 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 RatesEarly ARTDeferred ART HRP-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, 2011 Presented by CA Benson, MD, IAS, July 25, 2012.

6. Slide #6 Risks and Benefits of Earlier Initiation of ART Benefits Prevention 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 Risks Reduced 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.

7. 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)

8. 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.

9. Slide #9 Case 2 Would 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.

10. 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.

11. 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.

12. 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

13. 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

14. 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.

15. 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

16. 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