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1 7 th CROI, San Francisco, 2010 . Hotel AC, Barcelona – February 26 th 2010. Summary: Opportunistic Infections HCV/HBV Co-Infections & Tumors. Dr. José M. Miró Infectious Diseases Service - ICMiD Hospital Clinic - IDIBAPS University of Barcelona Barcelona (Spain).

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1 7 th CROI, San Francisco, 2010 . Hotel AC, Barcelona – February 26 th 2010


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    1. 17th CROI, San Francisco, 2010. Hotel AC, Barcelona – February 26th 2010 Summary: Opportunistic Infections HCV/HBV Co-Infections & Tumors • Dr. José M. Miró • Infectious Diseases Service - ICMiD • Hospital Clinic - IDIBAPS • University of Barcelona • Barcelona (Spain) E-mail address: jmmiro@ub.edu

    2. OIs, Hepatitis Coinfections & Tumors • When to start cART • Tuberculosis • 2009 Influenza A(H1N1) • Other opportunistic infections & IRIS • HCV & HBV co-infections • Tumors

    3. Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Study schema Opportunistic infections* Treatment Starts Immediate Arm Start ART 48 wks 12 days vs. 45 days Deferred Arm Start ART 48 wks Recommended Start window -14 0 2 28 42 84 224 Study day *TB excluded !!! Enrollment

    4. 1.00 Probability of surviving withoutdeath/new AIDS defining event 116 0.9 0.8 94 0.7 0.6 HR=0.5399%CI (0.25,1.09)P=0.023 0.5 0.4 0.3 Immediate ART Deferred ART 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Results Through 48 Weeks Early cART  less new AIDS events or death Months • No difference in primary endpoint of virologic suppression • No difference in IRIS (10 immediate, 13 deferred) or need for ART changes

    5. Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. *TB excluded !!!

    6. Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469 • Retrospective multicohort study • Hospital cohorts: Italy (6), Spain (1), UK (1) and Canada (1). • Study population: All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004. • Patients included in the study: 760

    7. Patients Presenting With AIDS in the HAART Era: A Collaborative Cohort AnalysisMussini C et al. AIDS 2008, 22:2461–2469 • P. jirovecii pneumonia (PCP) • Tuberculosis • Esophageal candidiasis • CNS toxoplasmosis • CMV disease • Kaposi’s sarcoma • NHL • Other Opportunistic Infections 268 (35%) 168 (22%) 94 (12%) 65 (9%) 51 (7%) 65 (9%) 28 (4%) 115 (15%)

    8. The objectives os this study were: 1) to analyze the clinical progression (new AIDS event or death) among persons diagnosed with HIV at the time of an AIDS-defining event (TB, PCP, other OI, KS or lymphoma); and, 2) to assess the impact on outcome of timing of cART initiation in these individuals. Survival outcomes and effect of early vs. deferred cART among HIV-1-infected patients diagnosed at the time of an AIDS-defining event in Europe and Canada: a collaborative cohort analysis (1997-2004) Miro JM, 529

    9. Characteristics of patients in study, overall and stratified by immediate/deferred treatment • Overall, the characteristics of patients receiving immediate and deferred treatment were broadly similar with the exception of some differences by country and age. Those treated immediately were slightly older. • cART regimens were similar in both groups. • Patients with KS were more likely to be treated immediately (P= 0.02). Miro JM, 529

    10. Kaplan Meier plot showing the cumulative proportion of patients with clinical progression (new AIDS event or death), according to the type of AIDS-defining diagnosis disease. Miro JM, 529

    11. Factors associated with clinical progression (new AIDS event or death) Miro JM, 529

    12. Older patients and those with a higher VL (>100K) or lymphoma at HIV diagnosis had a worse outcome. Patients who “deferred” cART had almost twice the risk of clinical progression than those who initiated cART immediately Whilst the results of this study confirm the findings from ACTG 5164, the small number of patients with KS or lymphoma in our study, and the potential for confounding, means that it remains important to conduct RCTs to validate our findings. Conclusions Miro JM, 529

    13. When to Start cART during TB treatment SAPIT CAMELIA A5221/STRIDE 800/800 660/660 429/429 No Africa, Asia, SA, NA Cambodia South Africa SITES Imm vs. 8-12 Imm vs. 8 Imm vs. 8-24 ARMS Death, AIDS Death Death ENDPT

    14. OIs, Hepatitis Coinfections & Tumors • When to start cART • Tuberculosis • 2009 Influenza A(H1N1) • Other opportunistic infections & IRIS • HCV & HBV co-infections • Tumors

    15. Isoniazid Preventive Therapy (IPT) in HIV-infected Patients Paper # 102 Effectiveness of Isoniazid Preventive Therapy in Reducing Mortality in Patients on ARTCraig Innes et al. South Africa. YES Paper # 103Efficacy of a 6-month vs a 36-month Regimen for Prevention of Tuberculosis in HIV-infected Persons in India: A Randomized Clinical TrialSoumya Swaminathan et al. India. Better 6 mo. Paper # 104LBRandomized, Placebo-controlled Trial of 6 vs 36 Months Isoniazid TB Preventive Therapy for HIV-infected Adults in BotswanaTaraz Samandari et al. Botswana. Better 36 mo.

    16. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    17. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    18. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    19. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    20. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    21. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    22. IPT in HIV-infected Patients in Botswana: 6 vs. 36 months Samandari T. 104LB.

    23. Comparing a new IP-10 based test with the QuantiFERON In Tube test for diagnosing pulmonary tuberculosis in an HIV-endemic population IP-10 (monocyte derived chemokine) is induced upon Mtb. specific antigen stimulation of whole blood with from patients with active TB infection but not from uninfected patients. Aabye MG, 770

    24. Effect of HIV Infection on 2-Month Treatment Outcome of Therapy for Pulmonary Tuberculosis Disease in Two Clinical Trials Bliven E, 782

    25. Effect of HIV Infection on 2-Month Treatment Outcome of Therapy for Pulmonary Tuberculosis Disease in Two Clinical Trials Bliven E, 782

    26. OIs, Hepatitis Coinfections & Tumors • When to start cART • Tuberculosis • 2009 Influenza A(H1N1) • Other opportunistic infections & IRIS • HCV & HBV co-infections • Tumors

    27. Number of HIV- & HIV+ patients positive for influenza A (H1N1) per calendar week in Barcelona (Spain) Martinez E, 802LB

    28. Route of transmission (n, %) MSM: 26 (46) IDU: 18 (32) Heterosexual: 12 (21) Years from HIV-1 diagnosis (median, IQR) 14 (5 – 19) Nadir CD4 (absolute) (median, IQR) 222 (134 – 379) Nadir CD4 (%) (median, IQR) 18 (14 – 22) Log HIV-1 RNA zenit (median, IQR) 5.2 (4.7 – 5.5) Prior/current C events (n, %) 16 (29) Hepatitis C (n, %) 21 (38) At influenza A (H1N1) diagnosis: CD4 (absolute) (median, IQR) 583 (370 - 715) CD4 (%) (median, IQR) 26 (23 – 33) CD4 (absolute) (median, IQR) 995 (828 – 1485) CD4 (%) (median, IQR) 50 (41 – 60) Log HIV-1 RNA (median, IQR) 1.7 (1.7 – 1.7) Patients with log HIV-1 RNA >50 copies/mL (n, log HIV-1 RNA) 3 (2.7, 3.5, and 4.3) HIV+ (n=56) Characteristics Martinez E, 802LB

    29. Absolute CD4 (cells/mm3) at influenza A (H1N1) diagnosis <200/mm3: 9% Martinez E, 802LB

    30. Demographic characteristics and comorbities Martinez E, 802LB

    31. Clinical symptoms Martinez E, 802LB

    32. Influenza A (H1N1) at presentation Martinez E, 802LB

    33. HIV+ (n=56) HIV- (n=168) P value Concommitant bacteria * (n, %) 4 (7) 13 (8) 0.8842 S. pneumoniae 3 9 S. aureus 0 4 Capnocytophaga spp 1 0 * Detected from blood cultures and/or urine antigens and/or valid respiratory samples Concommitant bacteria detected Martinez E, 802LB

    34. Prognosis Martinez E, 802LB

    35. CD4 and CD8 changes from influenza A (H1N1) diagnosis until 4-6 weeks later Martinez E, 802LB

    36. HIV infection did not make 2009 influenza A (H1N1) more severe. 2009 Influenza A (H1N1) did not have a major impact on HIV infection control. Conclusions Martinez E, 802LB

    37. Immunogenicity of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant in HIV+ adults Preliminary Report of the ANRS 151 Randomized HIFLUVAC Trial Odile LAUNAY et al, ANRS, Paris, France METHODS Ongoing randomized (1:1) patient-blinded trial, HIV-1-infected adult patients, - either receiving HAART (HIV viral load <50 copies/mL ) - or not receiving HAART (without indication for treatment) Group A: AS03A-adjuvanted H1N1v vaccine 3.75µg HAn=154 Group B: Non-adjuvanted H1N1v vaccine 15µg HAn=152 Randomization Vaccination (IM) Follow-up Samples D182 D364 D0 D21 D42 D91 Stratification according to HAART vs no HAART at baseline STUDY POPULATION: 306 patients : 237 on HAART, 69 untreated Median age : 47 years (IQR, 40-54); 19% were female; Median CD4: 536 cells/μL (IQR, 413–715) ; 556 (treated patients), 517 (untreated) Launay O, 804LB

    38. Pre and post-vaccination seroprotection rates and GMTs AS03A-adjuvanted H1N1v vaccine 3.75 µg HA (Group A) Non-adjuvanted H1N1v vaccine 15 μg HA (Group B) Seroprotection rate % (95% CI) 100 300 90 Regulatory requirements 250 80 GMT (95% CI) 70 200 60 50 150 40 100 30 20 50 10 0 0 D0 D21 D0 D21 D0 D21 D0 D21 D0 D21 D0 D21 A Total n=150 A HAART n=115 A w/o HAART n=35 B Total n=148 B HAART n=115 B w/o HAART n=33 • No short-term impact of vaccination on CD4 count or HIV viral load • Multivariate analysis: HCV/HBV co-infection and non-adjuvanted vaccine were negatively associated to seroprotection CONCLUSION A single dose of H1N1v vaccine was well tolerated and induces high immune response in this population. Higher immunogenicity (seroprotection rate and GMT) was obtained with the AS03A-adjuvanted H1N1v vaccine. Launay O, 804LB

    39. OIs, Hepatitis Coinfections & Tumors • When to start cART • Tuberculosis • 2009 Influenza A(H1N1) • Other opportunistic infections & IRIS • HCV & HBV co-infections • Tumors

    40. May Pneumocystis Prophylaxis Be Safely Discontinued in Virologically Suppressed Patients With CD4 Counts Below 200 cells/μL? <400 <400 <400 Furrer H, 789

    41. A Randomized Clinical Trial Comparing Revaccination with Pneumococcal Polysaccharide Vaccine (PPV) to Pneumococcal Conjugate Vaccine (PCV) among HIV-Infected Adults Objective  We evaluated the immunogenicity of revaccination of PCV compared with PPV in a RCT among HIV-infected adults to guide recommendations on revaccination of HIV-infected adults previously vaccinated with PPV. Study Population • HIV-infected adults previously vaccinated with PPV 3-8 years earlier were randomized 2:1 to be revaccinated with PCV (Prevnar) or PPV (Pneumovax). A group of HIV-uninfected subjects (n=25) with no prior history of pneumococcal vaccination received a single injection of PCV. Endpoints • The primary study endpoint was defined a priori as the proportion of subjects in the HIV infected PCV and PPV arms with positive antibody response to at least two of the four serotypes at day 60. - A positive response was defined as a 2-fold or greater rise in IgG level with a post-vaccination level value >1000 ng/mL Crum-Cianflone N, 814

    42. A Randomized Clinical Trial Comparing Revaccination with Pneumococcal Polysaccharide Vaccine (PPV) to Pneumococcal Conjugate Vaccine (PCV) among HIV-Infected Adults 1) Although revaccination with PCV was initially more immunogenic than PPV among HIVinfected adults, all such differences waned by day 180. 2) HIV-infected adults, despite ↑ CD4 counts and use of cART, had significantly lower immune responses to vaccination than HIV-uninfected group. Crum-Cianflone N, 814

    43. CMV-specific T Cell Responses are Higher in HIV-infected Patients Decreasing Asymptomatic CMV Replication with Valganciclovir Decreases Immune Activation in HIV+ Patients with CD4<350 despite cART Hunt et al, CROI, 2010, P#380 Naeger et al, submitted

    44. Valganciclovir Reduces CD8+ T Cell Activation among HIV-infected Patients with Suboptimal CD4+ T cell Recovery During Antiretroviral Therapy Hunt P, 380

    45. OIs, Hepatitis Coinfections & Tumors • When to start cART • Tuberculosis • 2009 Influenza A(H1N1) • Other opportunistic infections & IRIS • HCV & HBV co-infections • Tumors

    46. September 2009

    47. Genome-wide association studies Single nucleotide polymorphisms (SNPs) are identified in DNA from multiple individuals ~500,000 “tag SNPs” characterise ~10,000,000 SNPs >90% of common human genetic variants SNPs that are inherited together are compiled into "haplotypes" "Tag" SNPs are identified and genotyped www.hapmap.org

    48. Genetic variation in IL28B strongly predicts spontaneous HCV clearance and response to anti-HCV therapy with Peg-INF and RBV. IL28B encodes interferon-, an antiviral cytokine Interferon- is a promising anti-HCV drug The Interleukin 28B (IL28B) Gene and HCV Recovery

    49. rs12979860(SNP near IL28B) on chromosome 19 is strongly associated with SVR

    50. Correlation of genetic variation in IL28Bwith HCV recovery rates in diverse ethnicities Natural HCV clearance Response to HCV therapy SVR (%) rs12979860 C allele frequency (SNP near IL28B) Different frequencies in IL28B variants explain ethnical differences in HCV recovery rates Ge D, et al. Nature 2009;461:399-401. Thomas DL et al. Nature. 2009;461:798-801.