Acute HCV Infection in HIV+ MSM: Sexual Transmission of a Non-Sexually Transmitted Disease?
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Acute HCV in HIV + MSM: Sexual Transmission of a non-Sexually Transmitted Disease? David Wyles, MD
Case32 MSM with HIV well controlled on TDF/FTC/ATV/r(CD4 540) referred for evaluation of abnormal LFT’schecked on routine follow-upAlso with LTBI on INHNo complaints; normal examALT/AST 470/141 TB 1.7/DB 0.4
CaseOn further questioning was taking creatine andmuscle building supplements.Had relapsed with meth (smoked) in JanuaryMultiple sexual partners (>6)h/o GC, syphilisLast LFTs in January 2012: ALT 26, AST 23
Acute Infection• Incubation period is 6-7 weeks – RNA+ : 1-2weeks – Ab + : 4-12 weeks• Majority of patients will have elevated transaminases• 25-30% will have mild symptoms• Fulminant hepatitis is rare
HCV Incidence•Incidence of new infections is decreasing – Peaked in the 80’s at 291,000 CDC.gov
Where does the “myth” that HCV is not sexually transmitted come from?895 monogamous sexual partners• 8,060 person-years of follow-up – 3 incident HCV infections • 1 with different genotype • 2 others not be phylogenetically linkedCross-sectional study of 234 females partners• 2.6% were HCV AB+ – All 5 were partners of HIV/HCV co-infected men Vandelli C. Am J Gastro 2004. Eyster ME. Annals 1991.
Clearance of HCV in Symptomatic Patients 66% initially cleared BUT… only 44% remained persistently HCV RNA negative Gerlach Gastro 2003.
IL28B Allele HCV Clearance in Acute Infection Thomas DL. Nature 2009. Rauch A. Gastro 2010.
Acute HCV in HIV+ MSMMultiple reports of increasing acute HCV – majority lacking classical risk factors• 49 cases from 2000-2008 in Amsterdam – 58% with seroconversion within 12 months• Ongoing sexually transmitted HCV 4d outbreak in Paris van den Berk G et al. #804 16th CROI, 2009. Ghosn J et al. #800 16th CROI, 2009.
Acute HCV in HIV+ MSM• Molecular phylogenetic study – 226 HIV + MSM with acute HCV • Sero-conversion within 12 months • Majority denied IDU – NS5B sequence comparison • 850 reference sequences• 11 clusters (bootstrap values >70) – 84% of strains most closely related to another in the study (over reference)• Majority of transmissions after 1996 van de Laar T et al, Gastroenterology, 2009.
Acute HCV in HIV+ MSM• 45 acute HCV infections in HIV+ MSM in New York – Age: 40 (25-61) CD4: 525 (200-969) – 91% genotype 1 76% on HAART• 24 biopsied at a median of 4.3 months (0.6 to 53) Fierer DS et al. #802 16th CROI, 2009.
Cohort Studies CASCADE collaborationACTG ALLRT Cohort: 1996-2008• 5.1 cases/1000 PY – 26.7 cases/1000 PY IDU, 4.0 cases/1000PY non-IDU van der Helm JJ. AIDS 2011. Taylor L. CID 2011.
The Swiss HIV Cohort data• 100 of 167 incident HCV infections in MSM.• Inconsistent condom use [HR 2.13 (1.35-3.35)], history of syphilis [HR2.08 (1.38-3.15), and HBV infection [HR 1.98 (1.07-3.65)] were risk factors for HCV seroconversion Wandeler G. CID 2012.
Risk factors for HCV Sexual transmissionCase-control study60 HCV/HIV; 130 HIV matched controls – Receptive UAI – Fisting/use of sex toys – Group sex/increased number of partners – Non-injection recreational drug use Danta M. AIDS 2007.
30 cases, 67 controls• Rectal trauma with visible blood during/after sex – AOR 6.19 (1.17-32.81); p=0.03• Other factors associated with cases: – Snorting cocaine/amphetamines – Group sex – Fisting
Screening for Acute HCV in those with HIVDelayed antibody response in those with HIV – Mean time to seroconversion 7 months – 5% with seroconversion at >1 year • 88% with elevated ALT NEAT Consensus Statement Screening Recommendations Natouli E. J Clin Virol 2009. Thomson EC. AIDS 2009. NEAT AIDS 2011.
Rapid progression of HCV in acute HCV/HIV? FPR = 4.3±2.7 U/yr Fierer D. JID 2008. Fierer D. #879 AASLD 2010.
Rapid progression of HCV in acute HCV/HIV? Vogel M. CID 2011.
Treatment of acute HCV infection• Why treat acute HCV infection? – Increasing incidence (especially in MSM) – High rate of chronic infection (~90%) – Potential for rapid progression? – Poor response to treatment of chronic infection• Few studies have looked at treatment of acute HCV in co-infected patients – Variable regimens and response rates – Largely retrospective
Where it all began. 5 mu QD x 4 weeks 5 mu TIW x 20 weeks HCV-1 61% Average start: day 89 Gerlach: SVR=81% Jaeckel E. NEJM 2001.
Acute HCV treatment in co-infection NEAT consensus conference. AIDS 2011.
Treatment of acute HCV infection: The Australian Trial in Acute Hepatitis C• Prospective, longitudinal cohort – +HCV Ab within 6 months of entry and either: 1. Acute clinical hepatitis within 12 months of +Ab 2. +Ab within prior –Ab within 24mo HIV/ HCV – 27/103 HIV co-infected HCV • Mean CD4 614 cells/mm3 Non-IDU 56% 19% • 59% on HAART Duration 22 39 (weeks) GT1 60% 42% – 20 HCV/HIV treated* HCV RNA • 24wks PEG-2a/Ribavirin 65,187 30,769 (IU/ml) Matthews GV et al. CID, 2009.
Treatment of acute HCV infection 100 95 90 80 80 64 60 ITT% 40 35 OT GT1 20 0 RVR EVR ETR SVR SVR rates did not differ based on estimated duration of infection: <24wks (“acute”): 77% >24wks (“early chronic”): 86% Matthews GV et al. CID, 2009.
NEAT cohort- you should probably use ribavirinObservational study of acute HCV treatment• 284 HIV/HCV co-infected – 94% risk for acute HCV was MSM • 68% gt1 GT 1/4 GT 2/3 – P/R: 92% of gt 1/4, 77% gt 2/3 100 94 – 24wks: 60% gt 1/4, 75% gt 2/3 80 67 70 60 60 40 – SVR: 69.7% 20 0 Boesecke C. #50LB CROI 2012.
Re-infection after successful acute HCV therapy 7 of 26 re-infected within 2 years Incidence rate: 19.6/100 PY Lambers F. CROI 2012.
Take home points: Acute HCV infection• Sexual transmission plays a major role in incident HCV infection in HIV+ MSM – A re-emphasis on prevention and screening is needed• Data suggest significantly improved cure rates with PEG/RBV treatment for 24 weeks – Benefit may persist into “early chronic” phase – Treatment should be strongly considered in suitable candidates – Studies with new HCV DAAs are needed
Research questions in Acute HCVWhat role do new antiviral medications play inacute HCV treatment?What are the pathologic and immunologicfactors that facilitate HCV sexual transmission inHIV+ MSM?
Question 3HCV replicates in extrahepatic tissues/reservoirs?A. YesB. NoC. Maybe
Are there HCV replication compartments?Extrahepatic clinical manifestations – cryoglobulinemia (B cell) – B cell lymphomas – Neurocognitive effectsPBMC replication and sequence data – HCV RNA can be detected in PBMCs • Found more frequently in those with immunosuppression • Sequences cluster and are unique (compared to serum)Genital compartment
Analysis of Hepatitis C virus (HCV) sexual transmission pairs using ultra deep sequencingGoals:• To describe HCV viral quasispecies and their evolution in the blood and genital tract compartments of transmitting pairs during acute infection in order to begin to generate more detailed hypotheses on the mechanisms of sexual transmission of HCV (Aim1).• To compare the distribution of HCV quasispecies between compartments in HCV and HCV/HIV co-infected transmitters (Aim2).
Specific Aim 1. To perform a detailed HCV quasispecies analysis in five HCV transmission pairs.Suspect sexual transmission of HCVUltradeep sequencing of HCV 5’UTR and E2(HVR1) – Index: Serum and PBMC sequences – Source: Serum, PBMC, seminal plasma and cells – STI testing, IL28B, HLA – CASI to assess risk behaviors
Specific Aim 2. To perform a comparison ofHCV quasipecies distribution in the plasma, PBMC, and genital tract compartments in chronically infected HCV and HCV/HIV co- infected subjects.Recruit 5 additional “potential” transmitterswith different HIV co-infection status from the 5source patients.
Please send us your acute HCV patients!Susan Little Paula PotterDavey Smith Jason YoungJill Kunkel Sanjay MehtaDeeDee Pacheco Roxanna FloresAmanda ReschBryan CallahanSusan CahillAngela KozakowskiOwen Clinic NIH/NIAID: R21 AI097061