Summary from CROI for Hepatitis Coinfection –

Summary from CROI for Hepatitis Coinfection –

What are the challenges and how can we improve management of Hepatitis coinfection
in HIV-Infected Patients?



Jürgen K. Rockstroh M.D., Professor of Medicine
University of Bonn, Germany

As one of the most important causes of non-AIDS death Hepatitis coinfection has evolved over the last conferences as an extremely important research area which is reflected by the many posters on this topic as well as an oral session on hepatitis coinfection and a plenary on hepatitis C entry at this year 17th Conference on Retroviruses and Opportunistic Infections in San Francisco. This includes studies on the role of genetic determinants in outcome of HCV therapy as well as more general issues on outcome of liver disease, screening for hepatocellular carcinoma (HCC) and management of acute HCV.


Genetic variation in the interleukin 28B Gene and impact on outcome of HCV therapy

Around 30% of individuals infected with the hepatitis C virus (HCV) spontaneously resolve the infection. Of those progressing to chronic hepatitis C, interferon-based therapy leads to permanent recovery from HCV infection in over 50% of cases. The divergent outcomes (particularly between African Americans and Caucasians as well as geographical differences) despite similar exposure to HCV and identical treatment regimens strongly point to genetic determinants for the natural and treatment-induced control of HCV infection. Last year, several groups independently screened the entire human genome for common genetic variation associated with spontaneous or treatment-induced recovery from HCV infection. These genome-wide association studies (GWAS) consistently identified genetic variation in interleukin 28B (IL28B) as the strongest predictor for the control of HCV infection1,2. Importantly, genetic variation in IL28B also strongly predicted both spontaneous and treatment-induced HCV recovery, with a similar effect in HCV mono-infected and HCV/HIV co-infected individuals³. IL28B on chromosome 19 encodes interferon-λ, a type III interferon which appears to play a role in interferon alpha regulation. Indeed interferon-λ has been used in phase 1 studies for treatment of HCV with some promising results. Now at CROI first results of this newly described genetic marker and its impact on treatment outcome in HIV/HCV coinfected patients was presented for a first time. In a German study the IL28B gene polymorphism (rs 12979860) was evaluated with regard to its impact on treatment outcome in HCV/HIV co-infection4. IL28B genotypes were determined in 183 HCV/HIV co-infected patients treated with pegylated interferon-α, including 74 patients with acute and 118 with chronic hepatitis C. Rates of sustained virological responses (SVR) were compared patients carrying different genotypes. As a control, 136 healthy and 156 HCV mono-infected subjects were studied. IL28B genotype distribution did not differ significantly between the groups. In HIV/HCV co-infection carriers of C/C genotype had significantly higher SVR rates than patients with other genotypes (C/T and T/T) (58.1% vs 40.6%; P =0.041). Interestingly, this effect reached statistical significance only in HIV+ patients with chronic (50% vs 29%; P =0.04) but not in those with acute (73.3% vs 60%; P =n.s.) hepatitis C. After performing multivariate analysis including gender, HCV viral load, HCV genotype and IL28B-genotype only HCV genotype remained as a significant predictor for SVR in HIV/HCV coinfection. This was contrasted by 2 Spanish studies 5,6. The first from Vincent Soriano’s laboratory studied a cohort of 650 HIV/HCV co-infected patients receiving care at a single clinic in Madrid, Spain, from which 198 patients completing therapy with pegylated interferon-ribavirin with validated outcomes (92 SVR versus 106 non-responders; overall SVR 46%) were included who had provided informed written consent for DNA testing5. The SNP near the IL28b gene, rs12979860, was examined using the 5’ nuclease assay with allele specific TaqMan probes. Genotyping was conducted in a blinded fashion. In this study, 164 patients were included in the IL28b genotyping final analysis; 34 patients had inadequate samples for analysis. HCV genotype distribution included: HCV-1 58%, HCV-3 31%, and HCV-4 11%. The SVR rate was significantly higher in patients with the CC alleles than in those with CT/TT alleles across all HCV genotypes (75% (56/75) versus 38% (34/89)). In the multivariate analysis, the rs12979860 CC genotype was a strong predictor of SVR (OR = 3.4; 95%CI 1.4 to 7.9; P =0.006), independent of other well-known predictors such as HCV genotype 3 (OR = 8.1; 3.0 to 21.7; P <0.0001), baseline serum HCV-RNA <600,000 IU/mL (OR = 13.9; 3.9 to 48.1; P <0.001) and fibrosis < F3-F4 (OR = 3.4; 1.3 to 9.2; P =0.016). Similarly the group von Seville also identified presence of the rs1297860 CC genotype as an independent predictor of SVR6. In summary, the rs12979860 SNP located near the IL28b gene is also associated with SVR in HIV/HCV co-infected patients. The magnitude of the predictive potency for obtaining SVR however was different between studies and reflects that possibly in the setting of HIV coinfection this association may be weaker than in HCV monoinfection as level of immunedeficiency may independently also affect HCV treatment outcome. As there also are a substantial number of patients which obtain SVR even in the presence of the unfavourable IL28B genotype this genetic marker so far does not allow treatment decisions based on this marker alone. Nevertheless, the evaluation of genetic markers will help to further elucidate the pathogenesis of HCV and to help understand why there are substantial differences in SVR rates between various patient groups despite similar HCV treatment schedules.

Which outcome is associated with baseline Liver Disease in HIV?

In the US Liver biopsy is recommended for disease staging in HIV/HCV co-infected persons; however, the degree to which histologic stage predicts clinical outcomes is unknown. At the oral hepatitis session Mark Sulkowski presented a study from John Hopkins which prospectively assessed the incidence of clinical outcomes or death according to hepatic fibrosis stage in well-characterized HIV/HCV co-infected adults. All HIV/HCV coinfeceted adults from his cohort were prospectively followed after liver biopsy for clinical outcomes (hepatocellular carcinoma, HCC; end-stage liver disease, ESLD; all-cause mortality). Between July 1993 and March 2009, 631 co-infected adults underwent liver biopsy and were followed for a median of 5.4 years (range 0.1 to 13.5). At baseline the main characteristics of the participants were: a median age of 45.5 years, 66% were male and 80% were Black. 77% had a history of injection drug use (IDU); 31% and 19% had a CD4 cell count > 500/mm3 and < 200/mm3, respectively; 27% and 56% had a HIV RNA level > 10,000 copies/mL and < 400 copies/mL, respectively; 67% were on highly active antiretroviral therapy.

The incidence rate of HCC, ESLD, or death was significantly higher in patients with fibrosis stage > 1 compared to those with F = 0/1 [Incidence rate per 1000 patient years was 20.3 (13.7-30.1) for F0 versus 73.8 (50.2-108.3) for F4]. After adjusting for age, sex, race, IDU, longitudinal control of HIV disease (time-varying HIV RNA level and CD4 cell count), fibrosis > stage 1 was independently associated with clinical outcomes [adjusted incidence rate ratio, 95% confidence interval (CI): F2 = 2.4 (1.1 to 5.1); F3 = 3.6 (1.6 to 8.5); F4 = 3.2 (1.7 to 5.9)]. Also, no history of IDU and control of HIV disease were independently associated with a decreased incidence of clinical outcomes. The conclusions of the study were the high risk of clinical outcomes in persons with > stage 1 fibrosis independent of HIV disease. Clearly every effort should be made to improve HCV management in HIV infected persons.

Why is screening for hepatocellular carcinoma so important?

No studies are available examining the effect of HCC screening in HIV/HCV-coinfected patients. Sonographic screening for HCC in patients with chronic hepatitis B has been shown to prolong life. This has not yet been proven in HCV-infected patients. In the poster session a multi-center study was presented evaluating the possible impact of screening for HCC in HIV/HCV coinfected individuals8. The study was a retrospective analysis from 22 centers in 6 countries: Canada, United States, Brazil, Argentina, United Kingdom, Spain. All HCC cases in HIV/HCV-coinfected patients diagnosed between 1992 – 2009 with data on initial presentation were included (n=70). Diagnosis of HCC was done according to the previously publishes AASLD criteria9. Patients were then either defined as unscreened when HCC was diagnosed during work-up initiated by symptoms and not on the basis of screening results or as screened when patients were asymptomatic and HCC diagnosis was made on the basis of abnormal AFP screening or imaging studies. In addition information on tumor characteristics, staging, therapy, and survival was obtained. Overall a large proportion of HIV/HCV-infected patients with HCC (43%) were not screened. The actuarial median survival for the HCC screen group was 12.8 months versus only 3.7 months in the unscreened group. HCC screening was associated with better liver function and earlier HCC stages. In addition HCC screening was associated with higher eligibility for liver transplantation and more frequent use of effective HCC therapy. After adjustment of lead time bias, survival was better in screened than in unscreened patients. As a consequence this study clearly supports the European current coinfection guidelines to screen all HIV/HCV-coinfected patients with cirrhosis by ultrasonography every 6 months.

In HIV/HCV coinfected patients achieving SVR under HCV therapy: what is the impact on further disease progression?

At last years CROI the Spanish group from Madrid led by Juan Berenguer demonstrated that the achievement of a sustained virological response (SVR) after therapy with interferon plus ribavirin (IFN-RBV) reduces liver-related complications and mortality in HIV/HCV+ patients10. Now at this year CROI they investigated the effect of achieving an SVR after anti-HCV therapy on HIV progression and mortality not related to liver disease11. Again it was a large group of HIV/HCV coinfected patients (n=1428) undergoing HCV combination therapy with IFN and RBV. SVR defined as negative HCV-RNA 24 weeks after stopping IFMN/RBV therapy was obtained in 36% of patients. Most interestingly patients achieving a SVR did not only have a reduced risk for liver-related complications and mortality, but also for HIV progression and mortality not related to liver disease. These findings where explained by the authors by a poorer immune response non-dependent on HIV control and/or complications of HCV viremia in patients that did not achieve an SVR. One could imagine that in the setting of further liver disease progression (median follow-up was 48 months) in the non-SVR group per se but also in connection with the emergence of portal hypertension leading to a decrease in total white blood cell count a higher risk for new infections or complications results despite having similar amount of patients under successful HAART (defined as HIV-RNA below 50 copies/ml). This observation underlines the clinical benefits associated with achieving SVR in HIV/HCV coinfected patients.

What are the new findings in the management of acute hepatitis C in HIV?

Despite relatively high efficacy of interferon based therapy in HIV-positive patients presenting with acute hepatitis C (sustained virological response rates are between 60 - 70 %) the treatment associated toxicities remain a difficult challenge in treating these patients. Because of spontaneous viral clearance in around 20-30% in patients presenting with acute hepatitis C it would be extremely helpful to identify predictive factors for such spontaneous resolution of HCV in order to not expose patients to HCV treatment toxicities who would clear HCV by themselves. In a study from the NEAT study group the positive and negative predictive value of a week 4 HCV-RNA determination on the rate of spontaneous clearance of acute hepatitis C was determined in 92 HIV-positive individuals with at least 24 weeks of follow-up after diagnosis or presumed date of infection and no HCV treatment intervention12. Overall a >2log drop in HCV RNA 4 weeks after diagnosis (partial rapid virological response =pRVC) was observed in 25/52 (48%) patients. Positive (PPV) and negative (NPV) predictive values of pRVC for reaching spontaneous clearance of HCV was 88% and 85%, respectively. In clinical management of acute hepatitis C this means that determination of HCV-RNA levels 4 weeks after the diagnosis of acute hepatitis C may help to early identify patients who are more likely to take a chronic course of HCV-infection and therefore should be considered for HCV therapy. In another study the results from a kinetically guided peginterferon alfa 2a and ribavirin study for HIV-infected adults with acute hepatitis C were presented13. 21/54 screened patients with acute HCV entered the treatment protocol in which all patients received PEG-IFN/RBV for 12 weeks and then were simplified to PEG-IFN alone in case of an undetectable HCV-RNA at week 8 and 12 for a total treatment duration of 24 weeks. Overall 13/21 subjects stopped RBV at week 12 per protocol and none has rebounded through end-of-treatment response so far. These results suggest that in patients with RVR ribavirin may not be necessary throughout the entire course of HCV therapy.

Summary

* Genetic markers such as IL28B polymorphisms will help to further elucidate the pathogenesis of HCV and to help understand why there are substantial differences in SVR rates between various patient groups despite similar HCV treatment schedules.
* However, genetic markers at this time are not ready for clinical use in making HCV treatment decisions.
* Baseline advanced stages of liver fibrosis (>F1) in HIV/HCV-coinfected patients are associated with an increased rate of unfavorable liver disease associated clinical events over time; Fibrosis stage assessment and liver disease work-up are highly recommended in HIV/HCV coinfected patients.
* All HIV/HCV-coinfected patients with cirrhosis should be screened for the presence of hepatocellular carcinoma by ultrasonography every 6 months.
* Achievement of an SVR after IFN-RBV therapy in HIV/HCV coinfected patients reduces not only liver-related complications and mortality, but also HIV progression and mortality not related to liver disease.
* Determination of HCV-RNA levels 4 weeks after the diagnosis of acute hepatitis C may help to early identify patients who are more likely to take a chronic course of HCV-infection and therefore are likely candidates of early HCV therapy.
* In HIV patients with acute hepatitis C a negative HCV-RNA at week 4 after starting PEG-IFN/RBV therapy is associated with a high rate of SVR; most likely these patients do not require additional ribavirin (after week 12) and can be treated for 24 weeks only.


References



1. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399-401.

2. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M,Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V,Müller T, Bahlo M, Stewart GJ, Booth DR, George J. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100-4.

3. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI,Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP,McHutchison JG, Goldstein DB, Carrington M. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798-801.

4. Nattermann J, Vogel M, Baumgarten A, Naumann U, Stellbrink H-J, Danta M, Tural C, Bruno R, Spengler U and Rockstroh J. Genetic Variation in IL28B and Treatment-induced Clearance of HCV in HCV/HIV Co-infected Patients. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 164

5. Rallon N, Naggie S, Benito J, Medrano J, Restrepo C, Goldstein D, Shianna K, McHutchison J and Soriano V. Strong Association of a Single Nucleotide Polymorphism Located Near the Interleukin-28b Gene with Response to Hepatitis C Therapy in HIV/HCV Co-infected Patients. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 165LB

6. Pineda J, Caruz A, Camacho A, Neukam K, Salas I, Martinez A, Macias J, Mira J, Palomares J and Rivero A. Interleukin 28B Genotype is a potent predictor of response to therapy with pegylated interferon plus ribavirin in HIV(HCV co-infected patients. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 6

7. Sulkowski M, Mehta S, Sutcliffe C, Torbenson M, Higgins Y, Limketkai B, Moore R, and Thomas D. Baseline Liver Disease is independently associated with risk of death among 631 HIV/HCV coinfected adult with histological staging. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 166

8. Nunez M, Kikuchi L, Barreiro P, Nelson M, Vispo E, Page E, Fox R, Bini E, Sherman M, Bräu N, and Atlantic Liver Cancer in HIV Study Group. Screening for hepatocellular carcinoma in HIV/HCV coinfected patients: Impact on staging, therapy and survival. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 685

9. (Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepaticellular carcinoma. Hepatology 2005;42:1208-1236.

10. Berenguer J, Alvarez-Pellicer J, Martín PM, López-Aldeguer J, Von-Wichmann MA, Quereda C, Mallolas J, Sanz J, Tural C, Bellón JM, González-García J; GESIDA3603/5607 Study Group. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology. 2009 ;50:407-413.

11. Berenguer J, Crespo M, Galindo M, Tellez M, Barros C, Guardiola J, Rubio R, Barquilla E, Bellon J, Gonzalez-Garcia J, and GESIDA 3603 Study Group. Sustained virological response to interferon plus ribavirin reduces HIV-progression and non-liver-related mortality in patients coinfected with HIV and HCV. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 167

12. Vogel M, Page E, Matthews G, Guiguet M, Dominguez S, Dore G, Katlama C, Nelson M, Bhagani S, Rockstroh J, and the NEAT Study Group. The use of week 4 HCV-RNA after acute HCV infection (AHC) to predict chronic HCV infection. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 640

13. Bradley H, Marks K, Luetkemeyer A, Charlebois E, Glesby M, Talal A, Havlir D, and Peters M. Kinetically guided peg-alpha 2a and RBV therapy for HIV+ adults with acute HCV infection. 17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010; abstract 639