HIV/HCV coinfection: early glimpses of an interferon-free future and EuroSIDA incidence data
Simon Collins, HIV i-Base
Amongst the most exciting advances in Glasgow related to preliminary results from early studies of interferon (IFN)-free studies that had just been presented at the 63rd AASLD liver disease conference in the US.
For more details, see the detailed report from AASLD by Tracy Swan later in this issue of HTB.
In Glasgow, Jürgen Rockstroh, from the University of Bonn, Bonn, Germany presented an over view of new treatment that started with results from two studies presented at the American meeting from small groups of patients with HCV monoinfection.
In the first, 100% sustained virological responses at 12 weeks (SVR12) were reported for 25 treatment naive patients with HCV genotype 1. Additional, results for 9 prior null responders reported 9/9 achieving an end of treatment response and SVR12 in 3/9 with data available (results pending for the remaining 6/9) using a uridine nucleotide analogue (sofosbuvir, GS-7977) and an NS5A inhibitor (GS-5885), both in development by Gilead.The full study is a multi-arm study (at last count, 11 arms) in 95 patients including genotype 1, 2 and 3. 
In the second study, Kowdley and colleagues reported SVR12 rates of 99% in 79 treatment naive and 93% in 45 prior null responders, in a preliminary on-treatment analysis (always a caution), using a combination from Abbott of ABT-450/r (an HCV protease inhibitor boosted with 100 mg ritonavir), ABT-267 (an NS5A inhibitor) and/or ABT-333 (non-nucleoside NS5B inhibitor) ± ribavirin. The full study includes 571 patients (n=438 naive and 133 null responders). 
Both studies also included ribavirin in the combination, and importantly, the duration of treatment was only 12 weeks. Although HIV/HCV coinfection can be more difficult to treat (higher baseline HCV viral load, higher resistance) and will involve potentially complex drug interactions and overlapping toxicity with ART, these are very positive indications of future HCV treatment.
It is notable that these advances are being reported in the year when mortality studies have shown that since 2007, HCV has overtaken HIV and the leading cause of death in the USA.  This has lead to a US CDC recommendation to move HCV screening from “at risk” groups to universal testing for people born between 1945 and 1965. 
Many people with HIV/HCV coinfection have deferred HCV treatment with PEG-IFN and ribavirin due to the low response rates in genotype 1 and toxicity. Even after approval of bocepravir and telaprevir in 2011, which increased cure rates for genotype 1 from about 40% to 65%, treatment is still being deferred, as these directly acting antivirals (DAAs) require three times a daily dosing with food and a difficult side effect profile, plus continue to require PEG-IFN and ribavirin. Response rates in these studies were also dependent on multiple factors including age, gender, race/genetics (IL28B), liver condition (stage, HCV viral load) and comorbidities (obesity, diabetes, alcohol use).
Using either bocepravir and telaprevir with PEG-IFN and ribavirin is now recommended in European treatment guidelines (EACS, 2011) as the standard of care in HIV/HCV coinfection, although optimal duration of treatment has not been establish in coinfection. The talk also included a caution on the complexity of drug-drug interactions with ART that makes some HIV drugs contraindicated. The future is exciting though, with at least eight coinfection studies planned or underway, including new studies from Vertex, Boehringer Ingelheim, Tibotec, BMS, Gilead and Abbott.
The presentation also discussed the increase of sexually acquired HCV in HIV positive gay men (but also in HIV negative gay men, largely potentially undiagnosed). In the absence of spontaneous clearance, treating during acute infection is still often recommended because of the high cure rates even with PED-IFN plus ribavirin. It is a concern that neither spontaneous clearance nor successful treatment provides protection against HCV reinfection and several case reports include examples of successive treatment and reinfection.
Professor Rockstroh highlighted that the lack of evidence explaining the exact mode for sexual HCV transmission is an essential hurdle for effective HCV prevention, especially in the context of men who serosort to limit the chance of HIV transmission. While epidemiology studies report strong associations between sexual HCV transmission and recreational drug use, group sex and fisting, there are many cases of men who have contracted HCV through sexual contact without any of these risk factors.
Biopsy studies looking for the cellular and tissue targets would enable effective interventions that would reduce transmission risks based on the actual route of infection. HCV has a higher viral burden and viral turnover than untreated HIV, is predominantly a blood-blood transmitted infection, and remains infectious outside the body for far longer than HIV (which more rapidly is destroyed on contact with air).
While HCV levels may be detectable in semen at a higher level in HIV positive compared to HIV negative men, it has not been convincingly proven that exposure to semen is the route for sexual transmission. If this is not the case, then advice to use condoms, while popular with health workers for reducing other infections, might not be appropriate or effective at reducing sexual HCV transmission.
Two further oral presentations on HIV/HCV coinfection from the large EuroSIDA cohort were also included in the same conference session.
Ole Kirk from theCopenhagen HIV Programme, Copenhagen, Denmark, presented data on the incidence of HCV infection from 2002 to 2010 in EuroSIDA, with reference to different patient groups and identifying risk factors associated with HCV infection. 
EuroSIDA reported that 150 HCV acute infections (95 [63.3%] in MSM) occurred in 4295 patients during 18,928 person years of follow-up (PYFU), giving an overall incidence of 0.79 per 100 PYFU (95% CI: 0.67-0.92).Overall incidence by calendar year appeared stable between 2002 and 2007 at approximately median of 0.5 infections per 100 PYFU (varying between 0.36 and 0.82). However, rates were higher at 1.22 in 2008, 1.10 in 2009 and 2.34 (95%CI: 1.24 – 3.44)per 100 PYFU in 2010.
In multivariate analysis, IDU was associated with a higher incidence rate ratio (IRR) than MSM: 4.59 (2.40 – 8.80; p< 0.0001), South and East Europe both had higher IRR compared to Western Europe, respectively (1.98 [1.12 – 3.49]; p = 0.018 and 2.41 [1.41 – 4.12]; p = 0.0014). Calendar year per 2 years was also associated with a higher IRR (1.29 [1.19 – 1.39]; p <0.0001).
David Grint, from UCL, Royal Free Campus, London, presented data from EuroSIDA on the uptake of HCV treatment (PEG-IFN +/- ribavirin) over the 1998-2010 period. 
Approximately a quarter of almost 2000 people with HIV/HCV coinfection (n=456/1947; 23.4%) received HCV treatment over a median follow-up time of 107 months (IQR: 57 – 156).
The incidence of HCV treatment increased significantly from 0.29 (95% CI: 0.13 – 0.45) per 100 PYFU in 1998 to 5.26 (95% CI: 3.87 – 65) in 2007, but dropped to 3.73 (95% CI: 2.40 – 5.06) in 2009.Treatment incidence increased 11.0% (95% CI: 4.0 – 18.4; p = 0.0016) per 2 calendar years. Although treatment increased in all European regions, there were considerable regional differences.
In a multivariable model, factors associated with use of treatment included:CD4 cell counts greater than 350 cell/mm3 (incidence rate ratio [IRR]: 1.75 [1.37 – 2.23; p < 0.0001]); HIV viral load <500 copies/mL (IRR: 1.58 [1.18 – 2.12; p = 0.0023]); HCV genotype 3 (IRR: 1.55 [1.21 – 1.98; p = 0.0006), compared to genotype 1; and those from south (IRR: 1.99 (1.45 – 2.72; p <0.0001) and east central Europe (IRR: 1.61 [1.11 – 2.34; p=0.011), each compared to west Europe.HCV treatment was not associated with all-cause death (355 deaths, IRR: 0.81 [95% CI: 0.54 – 1.19; p=0.28]) or liver-related death (95 deaths, IRR: 1.0 [95% CI: 0.50 – 2.02; p=0.99]).
- Rockstroh J. New agents for hepatitis C and the challenges in treating coinfected patients.11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012.Oral abstract O241.
- Gane EJ et al. Once daily sofosbuvir (GS-7977) plus ribavirin in patients with HCV genotypes 1, 2, and 3: the ELECTRON trial. 63rd Annual Meeting of the American Association for the study of Liver Diseases (AASLD), 9-13 November 2012, Boston. Oral abstract 229.
- Kowdley KV et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype1 infection. 63rd Annual Meeting of the American Association for the study of Liver Diseases (AASLD), 9-13 November 2012, Boston. Late breaker abstract LB-1.
- Ly KN et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012 Feb 21;156(4):271-8.
- CDC. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965. Recommendations and Reports. 17 August 2012 / 61(RR04);1-18.
- Kirk O et al. Increases in acute hepatitis C (HCV) incidence across Europe: which regions and patient groups are affected?11th International Congress on Drug Therapy in HIV Infection, 11-15 November 2012. Oral abstract O242.
- Grint D et al. Temporal changes and regional differences in treatment uptake of hepatitis C therapy in EuroSIDA.11thInternational Congress on Drug Therapy in HIV Infection, 11-15 November 2012. Oral abstract O243.