1. 19 th CROI, Seattle, WA, 2012. La Pedrera, Barcelona – March 13 th 2012 19 th CROI, Seattle, WA, 2012. La Pedrera, Barcelona – March 13 th 2012 Dr. José M. Miró Infectious Diseases Service - ICMiD Hospital Clinic - IDIBAPS University of Barcelona Barcelona (Spain) Dr. José M. Miró Infectious Diseases Service - ICMiD Hospital Clinic - IDIBAPS University of Barcelona Barcelona (Spain) Summary I: Opportunistic Infections HCV/HBV Co-Infections & Tumors E-mail address: jmmiro@ub.edu

2. Egger, #100

6.  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors OIs, Hepatitis Coinfections & Tumors

7. A5221/STRIDE CAMELIA SAPIT Endpoints Sites No. Arms 800/800 Africa, Asia, SA, NA 215/215 660/660 Cambodia South Africa Imm vs. 8-24 wk Imm vs. 8 wk Imm vs. 8-12 wk Death, AIDS Death Death, AIDS When to Start cART During TB Treatment (N Engl J Med, October 20th, 2011) Immediate = First 2 weeks.

8. Effects of ART timing on outcomes in CAMELIA and patients with CD4 < 50 in STRIDE and SAPIT 34% ↓ p=0.004 42% ↓ p=0.02 68% ↓ p=0.06 NEJM, 2011 AIDS or death

9. p=0.67 p=0.34 NEJM, 2011. Effects of ART timing on outcomes in CAMELIA and patients with CD4 > 50 in STRIDE and SAPIT

10. Wondwossen Amogne Degu, #144 Study Design RCT to Determine Efficacy and Safety of cART 1 Week after TB Therapy in Patients with CD4 <200 Cells/µL - Ethiopia

11. Wondwossen Amogne Degu #144 Wondwossen Amogne Degu #144 RCT to Determine Efficacy and Safety of cART 1 Week after TB Therapy in Patients with CD4 <200 Cells/µL - Ethiopia

12. P=0.4 RCT to Determine Efficacy and Safety of cART 1 Week after TB Therapy in Patients with CD4 <200 Cells/µL - Ethiopia Degu #144 Degu #144

13. RCT to Determine Efficacy and Safety of cART 1 Week after TB Therapy in Patients with CD4 <200 Cells/µL - Ethiopia Degu #144 Degu #144

14. Degu #144 Degu #144 RCT to Determine Efficacy and Safety of cART 1 Week after TB Therapy in Patients with CD4 <200 Cells/µL - Ethiopia 95% CI 0.5-2.9 0.8-7.7 1.1-15.2

15. TB Incidence Increase after Cessation of 36 Months’ Isoniazid Prophylaxis (IPT) in HIV+ Adults: Botswana Samandari #147 Samandari #147

16. Samandari #147 Post-trial (no IPT) n=1678 6H 36H Cumulative TB incidence in the in-trial & post-trial period by study arm for all participants Cumulative TB incidence P=0.04 P=0.52 6H36H In trial n=1995 6H 36H

17. Nuermberger #127

22. OIs, Hepatitis Coinfections & Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors

23. Effects of ART timing on TB-IRIS among patients in STRIDE, SAPIT and CAMELIA trials P<0.01 NEJM; 2011 P<0.05

24. Severity and Timing of Paradoxical TB-IRIS TB IRIS occurred 7.6% (61/806) * Significant interaction between CD4 + and arm, p =0.014 CD4 + < 50 n= 285 CD4 + ≥ 50 n=521 11.5% (33/285) 5.4% (28/521) Earlier ART (n=405) 10.4% (42/405) 18.8% (27/ 144) 5.5% (15/261) Later ART (n=401) 4.7% (19/401) 4.3% (6/141) 5.0% (13/260 ) Luetkemeyer #145

25. Luetkemeyer #145

26. Luetkemeyer #145 Management of TB IRIS 31% required hospitalization for TB IRIS No deaths attributed to TB IRIS 54% received corticosteroids, median treatment 15 days (IQR 7,32) Infrequent interruption of TB treatment (3) or ART(3) 34% of those diagnosed with IRIS underwent ≥ 1 invasive procedure: Lumbar puncture (2) Thoracentesis (1) Liver biopsy (1) Surgical pleural drainage (2) FNA (10) Outpatient abscess drainage (3) Surgical abscess drainage (1) Lymph node biopsy (5)

27. CRP rapidly decreased on prednisone

28. Meintjes #146 Research questions 1.What is the effect of prednisone on mycobacterial-specific T-cells and cytokine/chemokine concentrations in TB- IRIS? 2.What is the cellular source of pro- inflammatory cytokines in TB-IRIS?

29. Meintjes #146

30. Meintjes #146

31. Meintjes #146 Neutrophils and monocytes an important source of TNF , IL-6 and IL-12p40 in HIV-TB with higher production of IL12p40 and TNF  by neutrophils in TB-IRIS (preliminary)

32. OIs, Hepatitis Coinfections & Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors

33. Early vs. Deferred (10 weeks) cART in Cryptococcal Meningitis (N=54) –Rx: Fluconazole 800 mg daily and d4T/3TC/NVP –No use of amphotericin or management of raised intracranial pressure Mortality: 87% early vs. 37% delayed ( P =0.002) –Most deaths in immediate ART group occurred within the first month, possibly due to IRIS –Fluconazole-NVP drug interaction postulated Early vs. Deferred (10 weeks) cART in Cryptococcal Meningitis (N=54) –Rx: Fluconazole 800 mg daily and d4T/3TC/NVP –No use of amphotericin or management of raised intracranial pressure Mortality: 87% early vs. 37% delayed ( P =0.002) –Most deaths in immediate ART group occurred within the first month, possibly due to IRIS –Fluconazole-NVP drug interaction postulated HIV-associated Cryptococcal Meningitis (Uganda): Immediate vs. Deferred cART Makadzange A, et al. Clin Infect Dis. 2010; 50(11):1532-8. Comparison of Kaplan-Meier Survival Estimates by Treatment Group 1.00 0.75 0.00 0.25 0200400600800 Time to Death (in days) 0.50 Time to Death (days) P=0.028 Deferred Early Survival

34. Immediate vs. Deferred cART in Fungal OIs (ACTG A5164) Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Epub 2009. Immediate cART is beneficial in the ACTG trial !

35. Chang #955 Chang #955

36. Chang #955 Chang #955

37. Benson #96 Benson #96 ZOSTAVAX Is Generally Safe and Immunogenic in HIV+ Adults Virologically Suppressed on ART: Results of a Phase 2, Randomized, Doubleblind, Placebo-controlled (3:1) Trial Risk of recurrent/severe herpes zoster (HZ) is increased in HIV+ patients. ZOSTAVAX ® (ZV; zoster vaccine live ) is generally safe and effective in reducing HZ incidence/severity in HIV– adults ≥50 years old, but has not been evaluated in HIV+ adults. Two doses (day 0, week 6) Risk of recurrent/severe herpes zoster (HZ) is increased in HIV+ patients. ZOSTAVAX ® (ZV; zoster vaccine live ) is generally safe and effective in reducing HZ incidence/severity in HIV– adults ≥50 years old, but has not been evaluated in HIV+ adults. Two doses (day 0, week 6) Conclusions: Administration of 2 doses of ZV in HIV+ adults (CD4 ≥200 copies/μL) virologically suppressed on ART was generally safe (HZ 2 ZV vs. 2 PBO), and immunogenic (mainly CD4>350).

38. Tebas #97 Tebas #97 Improved Immunogenicity with High-dose Seasonal Influenza Vaccine in HIV+ Individuals: A Double-blinded, Randomized Trial Comparing Fluzone High-Dose with Fluzone Fluzone-HD was approved by the FDA in December of 2009 for adults 65 years and older.

39. Tebas #97 Tebas #97 Improved Immunogenicity with High-dose Seasonal Influenza Vaccine in HIV+ Individuals: A Double-blinded, Randomized Trial Comparing Fluzone High-Dose with Fluzone Standard DoseHigh Dose P (n = 93),(n = 97), % subjects (95% CI) *Seroprotection H1N187(80-94)96(92-100)0.029 H3N292(87-98)96(92-100)0.315 B80(71-88)91(85-97)0.03 Seroconversion H1N159 (49-69)75(67-84)0.018 H3N274(65-83)78(70-87)0.5 B34(25-44)56(46-66)0.003 *Seroprotection defined as antibody titers ≥ 1:40. Seroconversion defined as a four-fold increase in antibody titers from baseline.

40. Tebas #97 Tebas #97 Improved Immunogenicity with High-dose Seasonal Influenza Vaccine in HIV+ Individuals: A Double-blinded, Randomized Trial Comparing Fluzone High-Dose with Fluzone H1N1H3N2 FluB *p=0.008 p=0.001 P<0.001 * Comparison between arms at day 21

41. Tebas #97 Tebas #97 Standard DoseHigh Dose (n = 8),(n = 14), % subjects *Seroprotection H1N17593 H3N25079 B3664 Seroconversion H1N15079 H3N25071 B2536 *Seroprotection defined as antibody titers ≥ 1:40. Seroconversion defined as a four-fold increase in antibody titers from baseline. Overall response is lower, but HD also superior

42. Maldarelli #375 Maldarelli #375 No Effect of Influenza Vaccination on Levels of Persistent Viremia in Individuals on Suppressive cART

43. OIs, Hepatitis Coinfections & Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors

44. Boesecke, #133 pegIFN + RBV in Acute HCV: EVR & SVR all GT 284 HIV-infected male patients from 4 European countries (UK, France, Germany, Austria) with diagnosed acute HCV infection were treated early with pegylated interferon and ribavirin (n=254) or pegylated interferon alone (n=30). In 88% of cases weight-adapted dosage of ribavirin (wt ≤75kg: 1000mg; wt >75kg: 1200mg/d) was used.

45. Boesecke, #133 pegIFN + RBV in Acute HCV: EVR & SVR only GT 1/4

46. Boesecke, #133 pegIFN + RBV in Acute HCV: EVR & SVR only GT 2/3

47. Boesecke, #133 pegIFN + RBV in Acute HCV Summary  For GT 2/3 infections addition of Ribavirin shows beneficial effect on cure rates.  For GT 1/4 infections the role of RBV needs further evaluation.  In addition the role of DAAs in treatment of AHC needs to be explored.

48. Ingiliz #752 Hepatitis C Reinfection in HIV+ MSM 45 HIV+ MSM with acute HCV infection 40 SVR 5 SC Episode 1 16 SVR 3 SC Episode 2 (8 pending) 4 SC 12 C 2 SVR Episode 3 (1 pending) 1SC 1SVR2 SVR2 C Episode 4 1SC SC=spontaneous clearance, SVR=sustained virological response, C=chronification

49. Ingiliz #752 Hepatitis C Reinfection in HIV+ MSM Patients (n) Genotype distribution at first and second HCV episode (n=45) and genotype switches (n=26) 1  31 1  41 1a  4, 4d6 1a  3a1 1a  1b1 1b  1a1 1b  4, 4d2 3  1a4 3  41 3a  11 4  1a,b6 4d  1b1 26 (58%)

50. Hepatitis C Reinfection in HIV+ MSM Ingiliz, CROI 2012, Abstract # Q-1004 Switche r Non-SwitcherClearerNon-Clearer Median HCV-RNA [IU/mL]310000360000n.s.210200507400n.s. Median ALT [U/L]301463n.s.498306n.s. Median AST [U/L]138203n.s.296139n.s. Median GGT [U/L]194179n.s.268180n.s. Median CD4 cells [/mm 3 ]498492n.s.681472p=0.03 ART [n] (%)19 (73)11 (61)n.s.4 (57)26 (68)n.s. IL28B C/C [n] (%)5 (33)5 (38)n.s.4 (80)7 (29)p=0.05 Patients with or without genotype switch and with or without viral clearance at second HCV episode Ingiliz #752

51. Treatment Targets against HCV Protease Inhibitors Boceprevir* Telaprevir* *NS3/4A PIs

52. Study 110: Telaprevir in HIV/HCV co-infected patients Part A: no ART 2404872Weeks1236 PR T/PR TVR + PR Follow-up SVR Follow-up PR48 (control) SVR Pbo + PR PR Follow-up PR48 (control) SVR Pbo + PR T/PR TVR + PR Follow-up SVR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) PR – Pegylated interferon/ribavirin, TVR – Telaprevir,SVR – Sustained virologic response Dieterich D #46

53. Dieterich D #46 71 33 69 50 80 50 74 45 0 10 20 30 40 50 60 70 80 90 100 Patients with Undetectable HCV RNA (%) No ARTEFV/TDF/FTCATV/r/TDF/FTCTotal n/N =5/711/1612/1528/38 T/PRPR 2/64/8 10/22 Study 110: SVR Rates 12 Weeks Post-Treatment (SVR12) *Patient was defined as SVR12 if HCV RNA was < LLOQ in the visit window

54. Sulkowski #47 Study Design: BOC + PEG/RBV for HCV/HIV co-infection (SVR12 results) Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV –2:1 randomization (experimental: control) –Boceprevir dose 800 mg TID 4-week lead-in with PEG2b/RBV for all patients –PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered open-label PEG2b/RBV+BOC via a crossover arm Weeks 12 24 28 48 72 PEG2b +RBV 4 wk Placebo + PEG2b + RBV 44 wk Boceprevir + PEG2b + RBV 44 wk Follow-up SVR-24 wk Follow-up SVR-24 wk PEG2b +RBV 4 wk Arm 1 Arm 2 Futility Rules

55. Sulkowski #47 % HCV RNA Undetectable 3/343/645/3427/648/3438/6411/3447/64 Virologic Response Over Time † 10/349/3442/6437/61 † Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.

56. Tolerability and safety: first signals from pilot trials 34% and 23% of T/PR and PR patients, respectively had rash; no severe rashes were reported in either group Preliminary safety data of B/PR in co-infected patients showed a profile consistent with that observed in mono-infected patients (anemia 41% vs. 26%) HIV Breakthroughs were observed in 3/64 patients in the B/PR group and 4/34 patients in the control group Dieterich, # 46 Sulkowski # 47

57. Management Issues with Co-medications http://www.interaccionesVIH.com Resumen VII – Interacciones farmacológicas y farmacocinética Dr. Esteve Ribera

58. Dieterich, # 46 Sulkowski # 47 Futility rules W4 W12 W24W4 W12 W24 W48 HCV-RNA >1000 IU/ml PEG-IFN+RBV Stop Telaprevir HCV-RNA >1000 IU/ml Stop HCV-RNA >20 IU/ml Stop PEG-IFN+RBV Boceprevir HCV-RNA >100 IU/ml Stop HCV-RNA >20 IU/ml Stop Initial HCV RNA decline provides information on treatment prediction outcome

59. HCV GT-1 SVR Rates Over Time According to the Type of anti-HCV Therapies IFN IFN + RBV Peg-IFN + RBV + Boceprevir/Telaprevir 15-20% 35-40% 45-50% 70-75% - 17-35% 61-74% 1990 1998 2001 2011 HCVHCV/HIV

60. F0F1F2F3 F4 naiverelapser non-responder Individual decision Individual decision/triple therapy defer Triple therapy Triple therapy defer* Triple therapy Triple therapy Discuss Triple Therapy on a case- by-case basis *Monitor fibrosis stage annually, preferably with two established methods. Treat with triple therapy, if rapid progression. Management of HCV/HIV Coinfected GT-1 Patients According to Fibrosis Stage & Prior Rx Outcome Rockstroh #72

61. INX-184 (Inhibitex) DAA in the Pipeline (2012-20) phase 1phase 3phase 2 NS3 protease inhibitors NS5B polymerase inhibitors Telaprevir (Vertex/Johnso n& Johnson) Boceprevir (MSD) NS5A inhibitors ACH-1625 (Achillion) BMS-650032 (BMS) PHX1766 (Phenomix) VX-813 (Vertex) GS-9256 (Gilead) GS-9451 (Gilead) MK-0608 (Merck) VCH-222, -759, 916 (ViroChem) ABT-450 (Abbott/Enanta) BI 201335 (Boehringer) CTS1027 (Conatus) ITMN-191-Danoprevir-R7227 (InterMune/Roche) MK-7009-Vaniprevir (MSD) Narlaprevir (MSD) TMC435 (Medivir/J&J) ABT-333 (Abbott) ANA598 (Anadys) BI 207127 (Boehringer) Filibuvir (Pfizer) GS 9190 (Gilead) BMS-790052 ( BMS ) PPI-461 (Presidio) GS-5885 (Gilead) Nucleos/tide IDX184 (Idenix) PSI-7851/7977 (Pharmasset) R7128 (Pharmasset/Roche) GS7977 (Gilead) Non-nucleoside

62. GS-7977 is a potent, specific HCV nucleotide analog Safe and well-tolerated in clinical studies Once daily, with or without food Potent antiviral activity High barrier to resistance – No virologic breakthrough to date O CH F HO O N NH O O P O O N H O O CH 3 GS-7977 Background Lawitz E, et al. J 2011; 54: S543. Lawitz E, et al. J Hepatol 2011; 54: S543.

63. To evaluate the antiviral activity of 12 weeks GS-7977 + RBV in genotype 1 patients who were either: –Prior null responders (<2 log 10 reduction in HCV RNA at Week 12 of a Peg/RBV regimen) –Treatment-naïve RBV dosing in all arms, independent of HCV genotype, was 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg ELECTRON Study Design for HCV Genotype 1 - Interferon-Free/-Sparing Regimens Genotype 1 Treatment-naïve (GS-7977 + RBV) Genotype 1 Null Responders (GS-7977 + RBV) n=25 SVR12 n=10 4 8 Wk 0 12 24 Gane #54LB

64. Assay LLOD 15 IU/mL Rapid Rapid Viral Suppression in Prior Null and Treatment-Naïve Genotype 1 Patients Genotype 1 null responders Genotype 1 treatment-naïve Genotype 2/3 treatment-naïve Gane #54LB

65. Gane #54LB 100% Genotype 1 Prior Null Responders Had HCV RNA <LOD at End of Treatment Genotype 1 Null Responders (N=10) Genotype 1 Treatment-naïve (N=25) Genotype 2/3 Treatment-naïve (N=10) n/N% <LODn/N% <LODn/N% <LOD Week 11/10107/25282/1020 Week 27/107017/247110/1080 Week 410/1010025/2510010/10100 Week 109/910025/2510010/10100 Week 119/910016/1610010/10100 Week 129/91006/610010/10100 SVR 41/911-- 10/10100

66. OIs, Hepatitis Coinfections & Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors  Tuberculosis  TB-IRIS  Opportunistic infections  Hepatitis co-infections  Tumors

67. Cancer Stage, Age at Diagnosis, and Survival Comparing HIV+ vs. HIV- Individuals with Common Non-AIDS-Cancers Silverberg, #903 Silverberg, #903 Source population: 22,081 HIV(+) and 230,069 HIV( ‐ ) individuals matched by age, sex, clinic, and initial year of follow ‐ up. Objective: To compare age at diagnosis, stage at diagnosis and 5 ‐ year survival for HIV(+) and HIV( ‐ ) individuals diagnosed with prostate, anal, lung and colorectal cancers, and Hodgkin lymphoma.

68. Cancer Stage, Age at Diagnosis, and Survival Comparing HIV+ vs. HIV- Individuals with Common Non-AIDS-Cancers Silverberg, #903 Silverberg, #903

69. Cancer Stage, Age at Diagnosis, and Survival Comparing HIV+ vs. HIV- Individuals with Common Non-AIDS-Cancers Silverberg, #903 Silverberg, #903

70. Incidence and Predictors of Non-Hodgkin Lymphoma Among HIV-Infected Persons on Suppressive ART Achenbach, #131 Achenbach, #131 HIV-infected persons continue to have high incidence of NHL despite suppressive ART – Our study: 15 cases per 10k py –U.S. SEER rate (2004-2008): 2 per 10k py –Kaiser Permanente HIV-negative: 1.7 per 10k py Level of immune suppression continues to be an independent predictor of NHL after controlling for age, race, and sex. HIV viremia, even low level, also likely contributes to NHL risk. HIV-infected persons continue to have high incidence of NHL despite suppressive ART – Our study: 15 cases per 10k py –U.S. SEER rate (2004-2008): 2 per 10k py –Kaiser Permanente HIV-negative: 1.7 per 10k py Level of immune suppression continues to be an independent predictor of NHL after controlling for age, race, and sex. HIV viremia, even low level, also likely contributes to NHL risk.

71. AIDS-PCNSL Treated with HAART and Radiation- Sparing Therapy: Rituximab, Methotrexate and Leucovorin [NCT00267865] Uldrick #911 Uldrick #911 Median (range) follow-up 42 months (7 months ‐ 7 years) 78% (60 to 90%)

72. Treatment of Anal Intraepithelial Neoplasia in 148 HIV+ MSM: A Triple-arm RCT of Imiquimod, Topical 5-Fluoruracil (5FC), and Electrocautery Richel #135LB Richel #135LB Imiquimod 5FC Electrocautery P value Complete response Recurrence at 6 months Severe Side Effects Complete response Recurrence at 6 months Severe Side Effects 26% 25% 43% 26% 25% 43% 17% 57% 27% 17% 57% 27% 41% 17% 18% 41% 17% 18% =0.03 - =0.02 =0.03 - =0.02 Imiquimod, 3 times weekely; 5-fluoruracil (5FC), twice a week; Electrocautery, monthly Duration of the treatment: 4 months. Evaluation: high-resolution anoscopy with biopsies 4 weeks and 6 months after treatment. Imiquimod, 3 times weekely; 5-fluoruracil (5FC), twice a week; Electrocautery, monthly Duration of the treatment: 4 months. Evaluation: high-resolution anoscopy with biopsies 4 weeks and 6 months after treatment.

73. CJ Achenbach C. Boesecke C. Chang K. Dooley M. Egger X. Forns CJ Achenbach C. Boesecke C. Chang K. Dooley M. Egger X. Forns Acknowledgements http://retroconference.org A. Luetkemeyer G. Meintjes E. Nuermberger J. Rockstroh W. Simons P. Tebas A. Luetkemeyer G. Meintjes E. Nuermberger J. Rockstroh W. Simons P. Tebas