Influence of Baseline HCV Genotype upon Treatment Outcome of Acute HCV Infection in HIV Co-Infected Individuals Christoph Boesecke, Hans-Jürgen Stellbrink, Stefan Mauss, Emma Page, Mark Nelson, Sanjay Bhagani, Marguerite Guiguet, Christine Katlama, Martin Vogel, Jürgen Kurt Rockstroh, and the NEAT study group
Acute HCV among HIV+ MSM Canada 24 : ~30 cases Prevalence chronic HCV/HIV 25 19%: 11.200 USA 1,2 : 55 cases Prevalence chronic HCV/HIV 12-14 15 30%: 180.000 360.000 Lebanon 22 : 1 case Prevalence chronic HCV/HIV 26 49%: 1.500 Europe: 1068 cases Prevalence chronic HCV/HIV 14,15 25%: 185.500 -UK 3,4 552 -Germany 5,18, 28 157 -France 6,7 126 -Netherlands 8,17 97 -Belgium 20 69 -Swiss 9 23 -Italy 10 21 -Denmark 21 13 -Spain 27 ~8 Australia 11 : 47 cases Prevalence chronic HCV/HIV 16,19 < 1%: 1.000 1.Luetkemeyer JAIDS 2006; 2.Cox Gastroenterology 2008; 3.Giraudon Sex Transm Infect 2008; 4.Ruf Eurosurveill 2008; 5. Vogel CID 2009; 6.Gambotti Euro Surveill 2005; 7.Morin Eur J Gastro Hepat 2010; 8.Urbanus AIDS 2009; 9.Rauch CID 2005; 10.Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11.Matthews CID 2009; 12. Sherman CID 2002; 13: Backus JAIDS 2005; 14: UNAIDS Report 2008; 15: Soriano JID 2008; 16: Matthews CID 2011; 17: Arends Neth J Med 2011; 18: Neukam HIV Med 2011; 19: Pfafferott PLoS One 2011; 20: Bottieau Euro Surveill 2010; 21: Barfod Scand JID 2011; 22: Dionne-Odom Lancet Infect Dis 2009; 23: Taylor Gastroenterology 2009; 24: Hull personal conversation 2011; 25: Remis 1 st Canadian HCV Conference 2001; 26: UNGASS Country progress Report 2010; 27: Soriano personal conversation 2011; 28: Boesecke 18 th CROI Boston 2011 abstract #113
Background I A drop in HCV-RNA of less than 2 log 4 weeks after diagnosis and still detectable HCV-RNA 12 weeks after diagnosis have been identified as predictors of chronicity. Gerlach, Gastroenterology 2003; Vogel, CROI 2010 Sustained virological response (SVR) rates of 60 80% after early antiviral therapy with pegylated interferon and ribavirin have been observed regardless of HCV genotype (GT). Gilleece, JAIDS 2005; Dominguez, AIDS 2006; Matthews, CID 2009; Vogel, Antiviral Therapy 2010
Background II The majority of viral strains isolated in chronic HCV in HIV co-infected patients are genotype 1 or 4 which are associated with significantly poorer treatment outcome than HIV/HCV co-infected patients with genotype 2 or 3 infection. Torriani, NEJM 2004; Vogel, CID 2009; Grebely, J Viral Hepat 2010 Whether genotype dependent differences in treatment outcome exist also in the setting of acute HCV in HIV co-infection remains unknown so far.
Primary objective To evaluate the impact of baseline HCV genotype (GT) on sustained virological response (SVR) rates of treated acute HCV infection in HIV co-infection
Material and Methods 238 HIV-infected male patients from 4 European countries (UK, France, Germany, Austria) with diagnosed acute HCV infection were treated early with pegylated interferon (pegifn) and ribavirin (RBV) (n=207) or pegylated interferon alone (n=31), followed prospectively since 2002 and evaluated for SVR. In 85% of cases (175/207) weight-adapted dosage of ribavirin (wt 75kg: 1000mg; wt >75kg: 1200mg/d) was used.
Acute HCV Case Definition Acute HCV was defined as (3 out of 4 within the preceding 4 months): Known or suspected exposure to HCV Detectable HCV-RNA (PCR) Documented seroconversion to positivity for anti-hcv IgG Serum alanine transferase of more than 350 U/l with a documented normal value within the preceding 12 months
Baseline Characteristics All n=238 GT 1/4 n=195 GT 2/3 n=43 p-value Median age [years] (IQR) 39 (34-43) 39 (34-43) 39 (33-45) 0,731 Transmission risk [%] 0,242 MSM 94 95 91 IVDU 3 3 2 Unknown 3 2 7 Median CD4-cells [/µl] (IQR) 474 (363-625) 473 (367-620) 486 (306-648) 0,765 [%] (IQR) 25 (20-31) 25 (20-30) 25 (18-33) 0,897 Median HIV-RNA [copies/ml] (IQR) 50 (50-15.839) 50 (50-22.100) 50 (50-940) 0,321 HAART [%] 66,4 65,1 72,1 0,476 Median HCV-RNA [IU/ml] (IQR) 770.259 (218.000-2.300.000) 740.000 (201.718-2.300.000) 850.000 (303.184-2.900.000) 0,580 HCV-RNA >800.000 IU/ml [%] 48,3 47,3 52,6 0,592 Median maximum ALT [U/l] (IQR) 378 (180-744) 382 (184-716) 367 (143-900) 1 Clinical symptoms* [%] 25,5 26,3 22 0,694 pegifn + RBV [%] 86,6 88,7 76,7 0,081 * Fatigue, abdominal pain, jaundice
HCV GT & IL28B Distribution All n=238 GT 1/4 n=195 GT 2/3 n=43 p-value HCV-Genotype [%] 82 18 1 66,4 2 5,9 3 12,2 4 15,5 IL28B CC genotype [n; n=70] 34 28 6 0,281
Treatment Response Terms RVR (rapid virological response): Negative HCV-RNA 4 weeks after start of treatment EVR (early virological response): Negative HCV-RNA 12 weeks after start of treatment ETR (end of treatment response): Negative HCV-RNA at the end of treatment SVR (sustained virological response): Negative HCV-RNA 24 weeks after end of treatment
Treatment I All n=238 GT 1/4 n=195 GT 2/3 n=43 p-value Duration of therapy* [%] 0,476 24 weeks 69,7 68,2 76,7 48 weeks 30,3 31,8 23,3 Median time to treatment initiation [weeks] (IQR) 9,6 (4,6-16) 10 (4,1-16,7) 9,4 (5-14) 0,765 Median time to first negative HCV RNA [weeks] (IQR) Median duration of therapy [weeks] (IQR) 8 (4-12) 8 (4-12) 5 (4-12) 0,139 26 (23-43) 27 (23-46) 24,6 (23-31,1) 0,219 *Based upon discretion of investigator
Treatment II HCV-Genotype Duration of therapy [weeks] EVR [%] no EVR [%] p-value 1 and 4 (n=160) 24 (n=105) 48 (n=55) 67,6 32,4 83,6 16,4 0,017 2 and 3 (n=31) 24 (n=22) 48 (n=9) 95,5 4,5 77,8 22,2 0,195
RVR & EVR 100 90 80 70 60 p=0,184 64.7 p=0,04 72,7 90.3 % 50 GT 1/4 51 GT 2/3 40 30 20 10 0 RVR (n=187) EVR (n=192)
ETR & SVR 100 90 80 70 p=0,008 76,4 94.9 p=0,046 81,4 60 64,6 % 50 GT 1/4 40 GT 2/3 30 20 10 0 ETR (n=213) SVR (n=238)
Uni- and Multivariate Analysis SVR n=161 no SVR n=77 Univariate p-value** Multivariate p-value*** Multivariate Odds-Ratio (95% CI)*** RVR [%] n=187 65,4 28,3 0,0001 0,0001 4,600 (2,336-9,059) GT 2/3 [%] 21,7 10,4 0,046 0,043 2,945 (1,034-8,385) IL28B CC genotype [%] n=70 55,3 34,8 0,271 Median baseline CD4-cells [/µl] (95% range) 484 (368-632) 433 (347-602) 0,164 Baseline HIV-RNA <50cop/ml [%] 61,3 56,7 0,551 Baseline HCV-RNA >800.000IU/ml [%] 44 58,1 0,069 Median maximum ALT [U/l] (95% range) 398 (195-761) 325 (168-706) 0,227 Clinical symptoms* [%] 27 22,4 0,523 peg IFN/RBV [%] 85,7 88,3 0,714 HAART [%] 67,7 63,6 0,559 * Fatigue, abdominal pain, jaundice; **Pearson`s Chi-Square, Fisher`s Exact, Mann-Whitney-U Test; ***Binary logistic regression, inclusion
Safety No significant differences in total numbers (p=0,724) or severity of adverse events (AE) (AE grade 1&2: p=0,672; AE grade 3&4: p=0,826) between the two GT groups. Ribavirin dose reduction occurred in 10,4% of cases with no statistically significant difference between the two GT groups (p=0,882). Interferon dose reduction occurred in 5,7% of cases with no statistically significant difference between the two GT groups (p=0,248). Treatment was stopped in 43 patients (18,1%) due to toxicities. Again, no statistical differences could be observed between the 2 GT groups (p=0,647).
Summary Early antiviral treatment of acute HCV infection in HIV coinfected individuals results in SVR rates which are far higher regardless of HCV genotype than SVR rates obtained in treatment of chronic HCV co-infection. Despite similar rates of RVR, treatment of acute HCV GT 2 and 3 infection is associated with a higher SVR rate than in GT 1 and 4 infection.
Acknowledgements United Kingdom London: Sanjay Bhagani, Mark Nelson, Emma Page, Alison Rodger Germany Berlin: Axel Baumgarten, Patrick Ingiliz, Heiko Jessen, Ingrid Leistner, Christoph Mayr Bonn: Martin Vogel, Jacob Nattermann, Jan-Christian Wasmuth, Jürgen Kurt Rockstroh Düsseldorf: Stefan Mauss Frankfurt/Main: Thomas Lutz Hamburg: Christian Hoffmann, Knud Schewe, Hans-Jürgen Stellbrink France Paris: Marguerite Guiguet, Christine Katlama Austria Vienna: Thomas Reiberger NEAT Study Group http://www.neat-noe.org/