Aktuell HIV-forskning 2014-05-06 Alexey Kashpersky
Aktuell HIV-forskning Bot Smittsamhet Nya läkemedel HIV och åldrande Etc
HPTN 052 Prevention Conclusion Early ART that suppresses viral replication led to 96% reduction of sexual transmission of HIV-1 in serodiscordant couples
PARTNER Observational Multicenter HIV-serodiscordant couples HIV+ on ART MSM and HS Aim: transmission risk for sex without condom
Antiretroviral drugs in pipeline TAG & i-base 2013: www.pipelinereport.org
Sverige 2014-03-27 n = 6 443 På behandling 5 962 (92.5%) Behandling >6 mån och HIV-RNA < 50 kopior/ml 5 368 av 5 688 (94.4%) snapshot-analys
Generika - efavirenz Årskostnad Atripla Truvada + Efavirenz Kivexa + Efavirenz 102 936 kr 81 408 kr 61 320 kr
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?
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) 100 90 80 70 60 50 40 30 20 10 0 100 100 100 100 100 100 100 100 100 95 95 90 Week 4 EOT SVR 4 SVR 12
Är det möjligt att bota HIV?
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.
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
Subject 1 HIV-RNA (log copies/ml) 6 4 2 0 ART 0 6 12 18 24 30 36 42 48 54 60 Months Limit of detection (50 copies/ml)
HIV-RNA (log copies/ml) 6 4 2 0 ART Subject 1 Residual viremia 1-50 copies/ml 0 6 12 18 24 30 36 42 48 54 60 Months Limit of detection (50 copies/ml)
Residual viremia during HAART 1000000 100000 10000 1000 100 10 1 0.1 0.01 0.001 Start HAART Release from stable reservoirs 0 1 2 3 Time on HAART (years) Limit of Detection (50 c/ml) Ongoing replication Shen & Siliciano. J Allergy Clin Immunol 2008
Activating latent HIV for cure ART Adapted from: Marsden M & Zack J. Future Virol 2010
Ongoing studies Katlama C et al. Lancet 2013
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
HIV gp120 - CCR5 interaction Homozygote CCR5 Δ32/ Δ32 resistance to HIV R5 infection Heterozygote CCR5 Δ32/+ slower disease progression
CCR5 Δ32 Figure 1. Shaded Contour Map of Δ32 Allele Frequency Data November et al PloS Biol 2005
Hŭtter G et al. NEJM 2009
HIV antibody levels declined Yukl SA et al. PLoS Pathog 2013
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.
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
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
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
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
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
Several important ethical issues in clinical HIV cure research