From Rome to Addis-Abéba Clincal Care highlights

1. From Rome to Addis-AbébaClincal Care highlights SP Eholié

2. Early ART

3. SPARTAC Trial: Short-Course ART vsNo ART in Primary HIV Infection • 372 patients identified within 6 months of infection randomized to 12 (ART12) or 48 (ART48) wks of therapy, which was then stopped, vs to no immediate ART • Effect of ART48 on time to primary endpoint increased when ART started within 12 wks of seroconversion (HR: 0.48; P = .003) • HIV-1 RNA setpoint 0.44 log10 copies/mL lower in ART48 arm vs SOC 36 wks after ART interruption • CD4+ cell count higher over longer-term follow-up with ART48 vs SOC ART48 vs SOC HR: 0.63(95% CI: 0.45-0.90; P = .01) 1.00 ART48 ART12 0.75 SOC Probability of Not Reaching Primary Endpoint 0.50 ART12 vs SOC HR: 0.93 (95% CI: 0.67-1.29; P = .67) ART 48 vs ART12 HR: 0.68 (95% CI: 0.48-0.96; P = .03) 0.25 0 0 1 2 3 4 Yrs Fidler S, et al. IAS 2011. Abstract WELBX06.

4. HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

5. HPTN 052: Primary Clinical Events During Follow-up • 41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy • Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) HR: 0.6 (95% CI: 0.4-0.9; P = .01) 0.25 Delayed (n = 65) 0.20 Immediate (n = 40) 0.15 Failure Probability 0.10 0.05 0 877886 701700 317333 8685 3236 2529 Number at risk 0 1 2 3 4 5 Yrs Since Randomization Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 363. 2011; 493-505

6. New drugsstrategies Co-receptorsinhibitors New NNRTI Integraseinhibitors

7. Elvitegravir QD vs Raltegravir BID in ART-Exp Pts: Phase III Results at Wk 48 Primary analysis Wk 48 Wk 96 * HIV-infected patients, * HIV-1 RNA ≥ 1000copies/mL, * resistance or 6 months of exposure to ≥ 2 ARV classes (N = 702) EVG 150 mg (or 85 mg) QD* + boosted PI† + third agent‡ + RAL Placebo BID (n = 351) RAL 400 mg BID + boosted PI† + third agent‡ + EVG Placebo QD (n = 351) *EVG dose reduced to 85 mg QD for patients taking ATV/RTV or LPV/RTV as part of background regimen. †Background regimen to include fully active ritonavir-boosted PI, selected using resistance testing. ‡Third active agent selected from ENF, ETR, MVC, or NRTI. Option of also adding FTC or 3TC for patients with M184V/I. Molina JM, et al. IAS 2011. Abstract WELBB05.

8. EVG Noninferior to RAL at Wk 48 *Difference: 1.1% (95% CI: -6.0 to 8.2; P = .001). Noninferiority: lower limit of 95% CI for difference between arms ≥ -10%. Molina JM, et al. IAS 2011. Abstract WELBB05.

9. EVG vs RAL: Resistance and Adverse Events at Wk 48 • Numerically more integrase resistance mutations at failure with EVG vs RAL • Some differences in emergent mutations with EVG vs RAL, but cross-resistance anticipated *Integrase resistance associated mutations: T66I/A/K, E92Q/G, T97A, Y143R/H/C, S147G, Q148H/K/R, and N155H/S. • Overall frequency of adverse events similar between arms • More diarrhea with EVG • More liver enzymes abnormalities with RAL Molina JM, et al. IAS 2011. Abstract WELBB05.

10. SPRING-1: Dolutegravir vs Efavirenz in ART-Naive Patients—Wk 48 Results • No integrase resistance associated mutations detected in patients failing DTG through Wk 48 • Grade 2-4 adverse events numerically higher in EFV arm vs DTG arms • DTG associated with low-level changes in serum creatinine • Thought to be inhibition of renal transporter rather than true renal toxicity 100 91 90 88 80 82 60 HIV-1 RNA < 50 copies/mL (%) DTG 10 mg QDDTG 25 mg QD DTG 50 mg QDEFV 600 mg QD 40 Each with ABC/3TC or TDF/FTC 20 0 0 2 4 8 12 16 20 24 32 40 48 Wks Van Lunzen J, et al. IAS 2011. Abstract TUAB0102.

11. Lersivirine vs Efavirenz in ART-Naive Pts Receiving TDF/FTC: Wk 48 Results LRV 500 mg LRV 750 mg EFV 600 mg 100 54/63 (86%) 100 80 88 86 82 80 51/65 (79%) 80 75 51/65 (79%) 60 62 HIV-1 RNA < 50 copies/mL Through Wk 48 (%) 60 HIV-1RNA < 50 copies/mL Through Wk 48 (%) 40 40 LRV 500 mg LRV 750 mg EFV 600 mg 20 20 0 0 45 44 41 20 21 22 n = 0 2 4 8 16 24 32 40 48 VL < 100,000 VL ≥ 100,000 Vernazza P, et al. IAS 2011. Abstract TUAB0101.

12. LRV vs EFV: Resistance and Safety Analysis • Emergent mutations detected in • 3/4 patients failing LRV 500 mg (all clade B)* • 1/5 patients failing LRV 750 mg (clade C)† • 1/3 patients failing EFV (clade B)‡ • Overall risk of adverse events comparable between arms • Higher frequency of grade 3/4 clinical events in EFV arm vs LRV arms • LRV associated with higher rate of all-grade nausea (23% in 500-mg arm; 42% in 750-mg arm), headache • EFV associated with higher rate of all-grade CNS effects, rash *1) M184M/I/V, K101E, V108I, H221H/Y; 2) M184M/I/V, Y188Y/H, F227F/L, L234L/I; 3) M184V, V90I, F227C (V90I detected at screening, BL, and failure). †M184V, V106M, F227L. ‡K103N. Vernazza P, et al. IAS 2011. Abstract TUAB0101.

13. ECHO, THRIVE: Rilpivirine vs Efavirenz in ART-Naive Patients—Wk 96 Results • More virologic failures with RPV vs EFV • 14.0% vs 7.6% • Difference due to more failures between Wks 0-48; failures consistent between arms from Wks 48-96 • Development of NRTI mutations more common with RPV vs EFV • Discontinuation for AEs more common with EFV vs RPV • 8.5% vs 4.1% RPV EFV 100 77.6 77.6 80 60 HIV-1 RNA < 50 copies/mL at Wk 96 (ITT-TLOVR) 40 20 n = 686 682 0 Pooled Cohen C, et al. IAS 2011. Abstract TULBPE032.

14. Similar Efficacy of Maraviroc QD vs BID + Boosted PI in ART-Exp Pts in MOTIVATE • Post hoc analysis of 448 pts in MOTIVATE studies who received MVC QD vs BID (plus a boosted PI*–containing regimen) vs placebo 100 Difference, % (97.5% CI)QD vs placebo: 27.8 (16.2-39.4)BID vs placebo: 30.6 (18.5-42.7) Difference, % (95% CI)QD vs BID: -2.4 (-12.5 to 7.7) 80 60 HIV-1 RNA < 50 copies/mL at Week 48 (%) 47.7 45.5 40 20 16.5 84/176 14/85 85/187 n/N = 0 Placebo MVC 150 mg QD MVC 150 mg BID *Patients on boosted FPV and boosted TPV excluded. Taylor S, et al. IAS 2011. Abstract TUAB0106.

15. MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients: Wk 48 Results • CD4+ cell count increases similar between arms • No emergent resistance mutations detected among 6 patients with virologic failure • No evidence of change in tropism among patients failing MVC • Frequency of all-grade adverse events similar between arms • Grade 3/4 adverse events, including hyperbilirubinemia, numerically higher in MVC arm HIV-1 RNA < 400 copies/mL 100 89.8 86.9 80 83.6 74.6 60 HIV-1 RNA < 50 copies/mL Patients (%) 40 MVC + ATV/RTV (n = 59)TDF/FTC + ATV/RTV (n = 61) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Wk Portsmouth S, et al. IAS 2011. Abstract TUAB0103.

16. SWIFT: Switching to TDF/FTC Noninferior to Remaining on ABC/3TC • Patients on ABC/3TC + PI/RTV with HIV-1 RNA < 200 c/mL for ≥ 3 months randomized to • Continue ABC/3TC (n = 156) • Switch to TDF/FTC (n = 155) • More patients in ABC/3TC arm vs TDF/FTC arm experienced virologic failure (confirmed or last on-study HIV-1 RNA ≥ 200 c/mL) • 11 vs 3; P = .034 Difference: 3% (95% CI: -5.1 to 11.2) 100 86 83 80 60 HIV-1 RNA < 200 copies/mL, % (TLOVR) 40 20 0 TDF/FTC ABC/3TC Noninferiority: lower limit of 95% CI for difference between arms ≥ -12% Campo R, et al. IAS 2011. Abstract WELBB03.

17. COMPLICATIONS

18. SWIFT: eGFR by Cockcroft-Gault and Change in Fasting Lipids Through Wk 48 Cockcroft-Gault TC LDL HDL TG 5 +2 (0.05) 120 0 0 100 -1(-0.03) -4.5 -3(-0.08) -5 -8.3 80 P = .26 Median Change From BL at Wk 48 (mg/dL [mmol/L]) -7(-0.18) Estimated GFR by IBW CG (mL/min) P = .012 60 -9 (-0.10) -10 P = .007 40 -15 TDF/FTC 20 ABC/3TC -18 (-0.20) -20 0 -21 (-0.54) P = .074 0 4 12 24 36 48 -25 P ≤ .001 Wk TDF/FTC ABC/3TC n = 155 153 147 144 139 137 n = 156 153 150 146 142 139 • No significant difference between groups in TC:HDL ratio at Wk 48 Campo R, et al. IAS 2011. Abstract WELBB03.

19. Cumulative Use of TDF and/or Boosted PIs and Risk of Osteoporotic Fractures • Retrospective analysis of 56,660 HIV+ male veterans enrolled from 1988-2009 • Osteoporotic fractures assessed from ICD-9 codes - 900 fractures (1.6%) • Cumulative use of TDF and/or boosted PI associated with higher risk in ART era, after controlling for risk factors • Highest risk with concomitant use • Cumulative use of LPV/RTV also associated with higher fracture risk • PI association limited to LPV/RTV • Cumulative use of ABC, thymidine analogues, NNRTIs not associated with higher risk 1.3 1.2 HR for Fracture, HAART Era 1.1 1.0 0.9 Boosted PI TDF Univariate analysis Controlled for effects of CKD, age, race, smoking, DM, BMI, and HCV Controlled for covariates in Model 1 plus concomitant exposure to ARVs • Limitations • Retrospective cohort study • BMD data not available • Fractures not verified to be osteoporotic Bedimo R, et al. IAS 2011. Abstract MOAB0101.

20. Aquitaine Cohort: TDF Use, Alone or With Concomitant PI, Associated With CKD • 2693 HIV-infected patients with baseline CrCl > 60 mL/min/1.73 m2 followed from 2004-2008 • 86 cases of incident CKD during follow-up • Among patients with CKD, 96% had baseline CrCl < 90 mL/min/1.73 m2 and 90% had ≥ 3 traditional risk factors* *Other variables associated with increased CKD: female sex, older age, diabetes, hyperlipidemia, preexisting mild renal dysfunction (CrCl 61-89 mL/min/1.73 m2), and low CD4+ cell count. †PIs used: ATV 41%, LPV 35%, FPV 11%, SQV 4%.‡PI vs without PI: P = .02. Morlat P, et al. IAS 2011. Abstract WEPDB0104.

21. Opportunistic infections

22. CARINEMO ANRS 12146 • 2NRTI + NVP 200mg BID vs EFV begun at 4-6 weeks of Rifampin containing therapy for TB • No difference in incidence of hepatitis or grade >2 rash between arms ART + RMP ART alone Bhatt WELBX05

23. Risk factors for TB-IRIS • CAMELIA- ART initiation ‘‘early’’ (at 2 weeks) vs. ‘‘late’’ (at 8 weeks) after TB treatment onset in 661 naïve HIV-infected adults with CD4 cell count ≤200/µL • 26% of patients developed TB IRIS a median of 2 weeks after ART • CAMELIA Causes of Death- 149/661 (22%) patients died, mortality was highest in the first 6 months. • -TB was the most common cause of death, occurring early in therapy. • - Drug Toxicity was the second most common cause of death, with a majority being due to D4T and occurring after 50 weeks 23 WEAX0104 Laureillard, WEPDB0202 Marcy

24. Evaluation of a Point of Care Cryptococcal Antigen Test on Serum, Plasma and Urine from Patients with HIV-associated Cryptococcal Meningitis

26. ICASA 2011Cryptococcal meningitis * Shiferaw AA. Screening for cryptococcal disease in HIV-infected patients visiting black lion ALERT ART clinics in Addis-Ababa. THLBB0303 * Georgios G. Cryptococcal meningitis. Review of Insititute Treatment Guidance in RLS. TUABO505 * Non abstract driven session. Management of Ois and co-morbidities in Adult and children: new policy guidelines in cryptococcus * Roy M. Evaluation of cryptococcal Ag sreccing program for HIV-infected persons initiating ART in South Africa TUAB0503

27. Challenges in HIV Treatment and Care in a Resource Constrained Environnement

28. Challenges to ensure the successof ART programs in low- and middle-income countries * Increase coverage * Ensure financing sustainability * Reduce AIDS and HIV non-AIDS morbidity, and mortality * Implement 2010 WHO guidelines * Improve assessment of programs efficacy * Improve prevention, diagnosis, and management of adverse events * Improve retention * Ensure comprehensive HIV care

29. Challenge 2:Financingsustainability 80-95% of funds are from international donors Achilles’ heel of ART programs Source Hecht R, Lancet 2010

30. FINANCEMENTSNeeds * 15 million people on ART by 2015 * 22-24 billion/year in 2015, 8-10 millions necessary * From Roma Addis * Necessary involvment of LMIC countries to fund HIV and sustain ART and prevention programs, no more time to delay; Economiccrisis Reduction of the donorsfunds Report of 2011 GF round

31. ART at 350 CD4 vs. 200 CD4 Where to find patients at earlier stage of HIV disease ?

32. 8 countries:3 EasternAfrica, 3 SouthernAfrica, 1 Western Africa, 1 Central Africa 267 sites (ICAP centers) 121 404 patients Median CD4 136 cells/l Nash D, AIDS 2011

33. ART at 350 CD4 vs. 200 CD4 • Find patients wiht higher CD4 counts • Change the paradigm • Target HIV negative patients • Increase Voluntary Counseling and Testing (VCT) • Facilitate or strenghten the link between VCT centers and ART clinics • Anticipate and face an increase in the number of patients on ART • Demonstrate cost effectiveness/acceptability to governments and donors

34. 1.4% of adultsreceiving ART 76.5% LPV/r 45% suboptimal NRTI regimen?? Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector Progress report 2010

35. WHO/UNAIDS/UNICEF. Progress report 2011

36. Challenges for second line • Costs • Time to switch to second line in patients failing 1st line • Effective NRTI backbone • Place of drugs already ordered or used (ABC/ddI) • Fixed Drug Combination or co-blister • Availability of ritonavir heat stable capsule • Use in TB co-infected patients • Forecasting (Renaud-Thery F, AIDS Res and Treatment 2011)

37. Comparaison of prices for ART regimen according to line of treatment X 7 MSF, AntiretroviralTherapypricereductions, 13thedition, July 2010

38. Long term monitoring issues We need tests for : • Metabolic syndrom… • Renal function … • Bone Mineral density … • Cardio-vascular assessment … • Malignancies diagnosis …

39. Conclusion

40. « A perpetual challenge willbe living up with the commitment  and courage of thosewhowentbefore- health care workers, scientists, and affectedpersons- whofaced the unknown and tookrisks. In general 30 years of AIDS confirmthatthereisindeed « more to admire in men than to despise »

41. Choukran Thankyou Grazie I ni tché Dieureudieuf Djaraman Mo Pi Wo Merci Amesegnalehu Mo Bondodi M"pussdabarka Asanti Akpé Obrigado Niyabonga