David L. Wyles, MD of UC San Diego Department of Medicine presents"Acute HCV Infection in HIV+ MSM: Sexual Transmission of a Non-Sexually Transmitted Disease?"

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2. Acute HCV in HIV + MSM: Sexual
Transmission of a non-Sexually
Transmitted Disease?
David Wyles, MD

3. Case
32 MSM with HIV well controlled on TDF/FTC/ATV/r
(CD4 540) referred for evaluation of abnormal LFT’s
checked on routine follow-up
Also with LTBI on INH
No complaints; normal exam
ALT/AST 470/141 TB 1.7/DB 0.4

4. Case
On further questioning was taking creatine and
muscle building supplements.
Had relapsed with meth (smoked) in January
Multiple sexual partners (>6)
h/o GC, syphilis
Last LFTs in January 2012: ALT 26, AST 23

5. 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

6. HCV Incidence
•Incidence of new infections is decreasing
– Peaked in the 80’s at 291,000
CDC.gov

8. 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 linked
Cross-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.

9. Clearance of HCV in Symptomatic Patients
66% initially cleared BUT…
only 44% remained persistently HCV RNA negative
Gerlach Gastro 2003.

10. Question 1

11. Spontaneous HCV clearance in co-
infection.
Hopkins Cohort
• 7% overall (5% in CD4 <200)
– 14% in HIV-
– 96% African-American
EuroSIDA
• Cross-sectional analysis
• 23% were HCV Ab+ but RNA negative
Timing of HCV acquisition probably matters!
Thomas DL. JAMA 2000. Soriano V. JID 2008.

12. Predictors of HCV Clearance
Symptomatic onset of disease
Immunogenetics
– IL28B polymorphisms
– HLA-KIR Interaction
– HLA type
Female sex
HIV Co-infection
Gerlach, Gastroenterology, 2003

13. IL28B Allele HCV Clearance in Acute Infection
Thomas DL. Nature 2009. Rauch A. Gastro 2010.

14. Acute HCV in HIV+ MSM
Multiple 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.

15. 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.

16. 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.

17. Cohort Studies
CASCADE collaboration
ACTG 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.

18. 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.

19. Risk factors for HCV Sexual transmission
Case-control study
60 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.

20. 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

21. Screening for Acute HCV in those with
HIV
Delayed 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.

22. Rapid progression of HCV in acute HCV/HIV?
FPR = 4.3±2.7 U/yr
Fierer D. JID 2008. Fierer D. #879 AASLD 2010.

23. Rapid progression of HCV in acute HCV/HIV?
Vogel M. CID 2011.

24. 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

25. 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.

26. Question 2

27. Acute HCV treatment in co-infection
NEAT consensus conference. AIDS 2011.

28. 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.

29. 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.

30. NEAT cohort- you should probably use
ribavirin
Observational 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.

31. 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.

32. 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

33. Research questions in Acute HCV
What role do new antiviral medications play in
acute HCV treatment?
What are the pathologic and immunologic
factors that facilitate HCV sexual transmission in
HIV+ MSM?

34. Question 3
HCV replicates in extrahepatic tissues/reservoirs?
A. Yes
B. No
C. Maybe

35. Are there HCV replication
compartments?
Extrahepatic clinical manifestations
– cryoglobulinemia (B cell)
– B cell lymphomas
– Neurocognitive effects
PBMC 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

37. Analysis of Hepatitis C virus (HCV)
sexual transmission pairs using
ultra deep sequencing
Goals:
• 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).

38. Specific Aim 1. To perform a detailed
HCV quasispecies analysis in five HCV
transmission pairs.
Suspect sexual transmission of HCV
Ultradeep 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

39. Specific Aim 2. To perform a comparison of
HCV quasipecies distribution in the plasma,
PBMC, and genital tract compartments in
chronically infected HCV and HCV/HIV co-
infected subjects.
Recruit 5 additional “potential” transmitters
with different HIV co-infection status from the 5
source patients.

40. Please send us your acute HCV
patients!
Susan Little Paula Potter
Davey Smith Jason Young
Jill Kunkel Sanjay Mehta
DeeDee Pacheco Roxanna Flores
Amanda Resch
Bryan Callahan
Susan Cahill
Angela Kozakowski
Owen Clinic NIH/NIAID: R21 AI097061