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Clinical Update April 2016

 While data on new phase III trials HCV drug trials was scant at CROI 2016, studies that broadened our knowledge of HCV epidemiology, acute infection, and drug resistance were plentiful.

 

      HCV epidemiology and natural history

      Treatment – Acute infection

      Treatment – Chronic infection 

      Drug interactions with ART


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HCV epidemiology and natural history

 

In the area of HCV epidemiology and natural history, Samandari presented for the HOPS cohort on the Incidence of hepatitis C from 2000 to 2013 as outlined below.

Some comparison was made between the whole monitoring period and more recently the 2011-2013 period. MSMs and those without private or public insurance were at greatly increased risk for HCV in the most recent time period followed.

 

 

Samandari et al.  CROI 2016

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Chemsex (the use of drugs to increase sexual disinhibition /arousal) and slamsex (use of IDU in particular) was associated with increased risk of HCV infection (London) (Pufall et al)

 

One in 3 HIV-positive MSMs in this British study reported chemsex in the past year which was associated with risky sexual behavior and the expected STIs. While the number reporting slamsex was too small to show statistical significance between the 2 behaviors, both chemsex and slamsex greatly increased the odds of acquiring HCV. While the study is limited by sample size, recall bias and possible non-response bias as only 39 percent responded, this is the first national study of these behaviors in HIV positive MSMs in Britain.

 

HIV and HCV outbreak in Scott County, Indiana

A post-mortem of the Indiana outbreak was presented by Jonathan Brooks from the CDC.

 

In this epidemic approximately 400-500 people were injecting prescription narcotics, primarily oxymorphone but also oxycodone and methadone. Shared equipment led to transmissions and could lead to more in similar scenarios where an HIV-infected person joins the injecting party.

In a separate presentation Sumathi Ramachandran from the CDC reported that HCV had been circulating in the IDU population there for several years with a large cluster of 312 cases overlapping the HIV epidemic. Global Hepatitis Outbreak and Surveillance Technology (GHOST) developed by the CDC and first used in this outbreak allowed for mapping of the HCV transmission patterns, showing the HCV cluster here was much older than the HIV outbreak. Communities with similar demographics may be able to use GHOST in the future to look for acute HCV outbreaks which could lead to HIV outbreaks.

 

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Hepatitis B and C, Alcohol, and CD4 Drive End-Stage Liver Disease in HIV+ Adults

Althoff presented data from NA-ACCORD as outlined below. This analysis examined 11 cohorts with validated diagnoses of ESLD followed from January 2000 through December 2009. 34,044 HIV-positive adults were followed for a median of 3.1 years with 387 developing ESLD during follow-up. The overall adjusted analysis found five risk factors that independently predicted ESLD: HCV, HBV, CD4 below 200, HIV viral load >/= 400 and a clinical AIDS diagnosis.

 

 

 

 

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Treatment of Acute infection


SLAM C study: Sofosbuvir and Ledipasvir versus Sofosbuvir and Simeprevir combination therapy in the management of acute hepatitis C: A randomized open label prospective clinical pilot study (drug rehabs in NYC) was presented by Rockstroh et al.

 

The study examined acute HCV with GT 1 or 4 in those with chronic HIV. ART had to be consistent with LDV/SOF co-administration and HIV viral load <200 copies/mL or not on ART with no plans to start during the trial period.

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SWIFT-C/ACTG study (A5327) by Macbrayne et. al looked at  SOF + RBV x 12 weeks for acute HCV in HIV-infected persons had a surprisingly high relapse rate.

SWIFT-C was an open label, two-cohort clinical trial with 44 participants. SVR12 rate in the 17 assigned to sofosbuvir 400mg QD + weight based ribavirin for 12 weeks was unexpectedly low at 59 %. In an effort to better understand the results the authors performed a multivariate analysis looking at traditional factors associated with relapse (baseline HCV RNA, HCV genotype and IL28B genetics) along with measured ribavirin levels. As shown below traditional factors, CD4 and duration of infection did not differ in those that achieved SVR vs. relapsers, but ribavirin concentrations were 52% higher in those that achieved SVR (p=0.01). The ribavirin concentrations over time for patients achieving SVR versus developing relapse are shown. No statistical differences were observed with regard to factors such as race, weight or inosine triphosphatase levels or self-reported adherence.

 

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Treatment of Chronic infection 

Response to DAA based therapy in HIV-HCV coinfected patients was presented by Piroth et al. from France

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HIV/HCV co-infected patients enrolled in the French nationwide ANRS CO13 HEPAVIH cohort were included in this analysis if an oral DAA-based regimen without peg-interferon was started prior to 3/1/15 (3-month regimen) or 12/1/14 (6-month regimen) and if the patients had sufficient follow-up data to evaluate DAA efficacy. Treatment success was defined as an HCV RNA of <15 UI/mL at or 12 weeks thereafter (SVR12). Patients with premature treatment discontinuation, detectable HCV RNA, or death during treatment were considered treatment failures. A total of 215 HIV/HCV co-infected patients from the ANRS HEPAVIH cohort were examined. 67% of these patients were cirrhotics and 71% were treatment experienced, thus we would expect them to be a difficult to treat population. However, no influence of cirrhosis or pre-treatment upon SVR was found for all of the oral DAA combinations. Overall, an impressive 92% of patients achieved SVR12 with all the different DAA based therapies used with no significant difference in outcome between 12 and 24 weeks of DAA therapy.

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Christensen et al. presented similar results From the German Hepatitis C Cohort (GECCO)

Up to date, 1346 patients have been included into the cohort. The HCV GT distribution was as follows: 74% GT 1, 4% GT 2, 16% GT 3, and 6% GT4. Almost a quarter of patients had advanced fibrosis (F4) based on non-invasive fibrosis markers. 282 were HIV co-infected patients with a median CD4+ cell count of 606/mm3. On average very high SVR12 rates close to 95% were observed for all oral DAA combinations. Lower response rates were seen for SOF+PEG-IFN+RBV and for GT 3 particularly in patients receiving sofosbuvir and ribavirin. SVR12 rates depending on baseline factors are shown below. Although some subgroups end up with relatively small numbers it is impressive to see in real-life cohorts there is no difference in cure rates between those with or without HIV. Even in the traditionally more hard-to-treat patients including F4 fibrotics and diabetics, similar high SVR rates are achieved with DAA therapy. Efficacy of a shorter treatment duration of 8 weeks of Ledipasvir/sofosbuvir was analyzed in various subgroups including HIV and again shows overall strong SVR12 rates independent of risk.

 

 

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Drug interactions with ART

Ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for the treatment of HCV in HIV –infected patients was studied as part of Turquoise-1 with further data being released on use of concomitant darunavir daily versus BID.

 

 

 

 

 

 

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Re-treatment of HIV/HCV coinfected patients who failed ledipasvir/sofosbuvir was presented by Cooper et al.

One of the remaining questions around RAVs (resistance- associated variants) is in case of DAA treatment failure which treatments may effect a cure if patients have relapsed with development of RAVs. Patients who had failed the ION-4 trial (GT 1 or 4 patients with HIV/HCV coinfection who were treated with 12 weeks of Ledipasvir/Sofosbuvir) were eligible for enrollment. Nine patients were retreated with the same DAA combination with treatment extended to 24 weeks and the addition of weight-based ribavirin. SVR was achieved in 8/9 subjects with only one relapse 4 weeks after EOT in a GT1a patient who was non-cirrhotic.


 

 

 

Mogalian et al. presented a study evaluating drug-drug interactions (DDIs) between SOF/VEL (400/100 mg) and boosted-ARV regimens.

 Velpatasvir is a substrate of P-gp, BCRP, OATP, CYP2B6, CYP2C8, CYP3A4 and an inhibitor of P-gp, BCRP, and OATP thereby offering at least some potential for drug-drug interactions.

 

 

 

 

HCV Update CROI 2016: In Conclusion

      Incident hepatitis C increasing among MSM as well as PWID (people who inject drugs)

      Liver disease mortality among persons with HIV attributable to alcohol and HCV

      HCV treatment is effective in the real world

      Retreatment appears to be possible despite RAVs

      DDI are an issue but can be managed


 

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