Aktuell HIV-forskning

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1 Aktuell HIV-forskning Alexey Kashpersky

2 Aktuell HIV-forskning Bot Smittsamhet Nya läkemedel HIV och åldrande Etc

3 HPTN 052 Prevention Conclusion Early ART that suppresses viral replication led to 96% reduction of sexual transmission of HIV-1 in serodiscordant couples

4 PARTNER Observational Multicenter HIV-serodiscordant couples HIV+ on ART MSM and HS Aim: transmission risk for sex without condom

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9 Antiretroviral drugs in pipeline TAG & i-base 2013:

10 Sverige n = På behandling (92.5%) Behandling >6 mån och HIV-RNA < 50 kopior/ml av (94.4%) snapshot-analys

11 Generika - efavirenz Årskostnad Atripla Truvada + Efavirenz Kivexa + Efavirenz kr kr kr

12 Behandling Hepatit C Direct-acting antivirals (DAAs) som registreras 2014 NS5B-hämmare Proteashämmare NS5A-hämmare Sofosbuvir (Sovaldi ) Simeprevir (Olysio ) Daclatasvir Sofosbuvir + Ledipasvir Fixed drug combination? AbbVie 3D kombination +/- Ribavirin?

13 Treatment Response (ITT) Sofosbuvir + Ledipasvir (n=20) Sofosbuvir + Ledipasvir + GS-9669( n=20) Sofosbuvir + Ledipasvir + GS-9451 (n=20) % of patients with HCV RNA <LLOQ (ITT) Week 4 EOT SVR 4 SVR 12

14 Är det möjligt att bota HIV?

15 HIV reservoirs: obstacles to cure Definition HIV reservoir: Infected cell population that allows persistence of replication-competent HIV-1 in patients on optimal HAART regimens on the order of years.

16 HIV reservoirs: obstacles to cure Latent infection of resting CD4 + T cells Other potential reservoirs Macrophages Hematopoietic Progrenitor Cells Anatomic sites CNS Gut-associated lymphoid tissue

17 Subject 1 HIV-RNA (log copies/ml) ART Months Limit of detection (50 copies/ml)

18 HIV-RNA (log copies/ml) ART Subject 1 Residual viremia 1-50 copies/ml Months Limit of detection (50 copies/ml)

19 Residual viremia during HAART Start HAART Release from stable reservoirs Time on HAART (years) Limit of Detection (50 c/ml) Ongoing replication Shen & Siliciano. J Allergy Clin Immunol 2008

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26 Activating latent HIV for cure ART Adapted from: Marsden M & Zack J. Future Virol 2010

27 Ongoing studies Katlama C et al. Lancet 2013

28 Är det möjligt att bota HIV? Sterilizing cure Complete eradication of all replication-competent forms of HIV Functional cure Permanent viral suppression in the absence of therapy to levels that prevent immunodeficiency and transmission Eisele E & Siliciano R. Immunity 2012

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30 HIV gp120 - CCR5 interaction Homozygote CCR5 Δ32/ Δ32 resistance to HIV R5 infection Heterozygote CCR5 Δ32/+ slower disease progression

31 CCR5 Δ32 Figure 1. Shaded Contour Map of Δ32 Allele Frequency Data November et al PloS Biol 2005

32 Hŭtter G et al. NEJM 2009

33 HIV antibody levels declined Yukl SA et al. PLoS Pathog 2013

34 The Berliner Patient The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure.

35 The Missisippi baby Vaginal delivery at w. 35 Rapid HIV test on mother during labour positive Maternal VL: 2423 c/ml, CD4: 644/µl No ARV drugs given cart started by 31 hours HIV DNA (30h) and HIV RNA pos (31h) Persaud D et al. CROI2013

36 The Missisippi baby 18 months: lost to follow-up and cart discontinued by caregiver 23 months: returned to care with undetectable viral load No HIV-specific T-cell responses to HIV-Gag and -Nef peptide pools Normal immune activation markers Normal CD4 levels during and after cart discontinuation Follow-up continues! Persaud D et al. CROI2013

37 HIV Cure Sterilizing cure Complete eradication of all replication-competent forms of HIV Functional cure Permanent viral suppression in the absence of therapy to levels that prevent immunodeficiency and transmission

38 HIV Cure Sterilizing cure Complete eradication of all replication-competent forms of HIV Functional cure Permanent viral suppression in the absence of therapy to levels that prevent immunodeficiency and transmission

39 Cumulative survival for HIV-infected patients starting HAART and persons from the general population Figure 1 Group 0: Population comparison cohort (dotted line, N=9,068). Group 1: HIV-infected patients without HIV risk factors, comorbidity or alcohol/drug abuse (N=871). Group 2: HIV-infected patients with HIV risk factors, but no comorbidity or alcohol/drug abuse (N=704). Group 3: HIV-infected patients with comorbidity, but no alcohol/drug abuse (N=379). Group 4: HIV-infected patients with alcohol/drug abuse (N=313). Obel N et al. PLoS One 2011; 6(7): e22698

40 Several important ethical issues in clinical HIV cure research

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