HCV Co-infection Report by David Shepp MD
IAS Conference on Pathogenesis, Treatment and Prevention
Vancouver, BC, Canada, July 19-22, 2015
David H Shepp, MD
Associate Professor of Medicine
Hofstra-North Shore LIJ School of Medicine
HCV Treatment Regimens for Co-infected Patients.
Historically, treatment of HCV in co-infected patients has presented some unique challenges. Interferon-based therapies that work by stimulating an innate immune response were less effective in the presence of immune dysfunction, even when CD4 counts were normalized by antiretroviral therapy (ART). Safety and tolerability also were less good. First generation HCV protease inhibitors added new adverse effects and daunting drug-drug interactions. The HCV treatment landscape has now been completely transformed by multiple new directly-acting antivirals (DAAs) approved in the past 1-1/2 years, or are likely to be approved in the near future. Trials to establish the safety and efficacy of these HCV regimens in co-infected patients are critically important. Two phase 3 single arm trials of interferon-free regimens conducted in co-infected patients were reported at IAS 2015 [1,2], simultaneously published on-line [3,4], and gave remarkably similar results. The C-EDGE study (n=218) used the HCV protease inhibitor grazoprevir plus the NS5a inhibitor elbasvir, both investigational agents in late stage clinical development. The ION-4 study (n=335) used the approved combination of the nucleotide polymerase inhibitor sofosbuvir plus the NS5a inhibitor ledipasvir. Both regimens were given as one co-formulated tablet once daily for 12 weeks. Both studies had only a single treatment arm, enrolled genotype (GT) 1 or 4 infected, cirrhotic or non-cirrhotic patients, included HCV treatment-naive patients, and those on ART with undetectable HIV RNA. ION-4 also included substantial numbers of HCV treatment-experienced patients (55%), but enrolled very few with GT 4. C-EDGE allowed patients not on ART with >500 CD4 and GT 6 infection, but few of either were enrolled. Both treatments achieved 96% sustained virologic response (SVR). Both trials reported serious adverse event rates of 2-3%, none drug-related, and no discontinuations for adverse events. Commonly reported adverse events were headache, fatigue, and nausea. Resistance to the NS5a inhibitor was present in most who had virologic failure in both studies. Resistance to grazoprevir was also seen in 2 of 5 who failed in C-EDGE, while no resistance to sofosbuvir was reported in ION-4. Both studies demonstrated treatment benefits across various subsets of participants, but ION-4 found a difference between responses in black (90%) and non-black (99%) subjects. This difference was not seen in mono-infection studies. Pharmacokinetic data was not presented, but the authors stated differences in drug levels were not found for either HCV or HIV drugs. Compared to C-EDGE, ION-4 enrolled 3 times as many black subjects, so it is possible this trend was identified due to a much greater power to detect it. In ION-4, all participants were receiving tenofovir as part of the ART regimen. Mean creatinine clearance remained stable throughout treatment, an important finding since ledipasvir increases plasma levels of tenofovir. However, 4 patients experienced increases in serum creatinine ≥0.4 mg/dL and two had tenofovir treatment modified. Both of these regimens appear to be safe and highly effective to treat HCV in co-infected individuals, including black patients who had a lower response rate with sofosbuvir/ledipasvir that was still 90%. Although cirrhotics were included in both trials, neither enrolled large numbers (16% in C-EDGE and 20% in ION-4). Although neither trials identified cirrhosis as a risk factor for treatment failure, it is possible such a pattern would emerge with larger numbers treated. The response rates seen in these two studies are at least as good as those reported in HCV mono-infected patients, suggesting that HIV no longer need be considered a risk factor for reduced treatment response. Both regimens are compatible with only a limited menu of antiretroviral anchor drugs (raltegravir and rilpivirine for both, plus efavirenz for sofosbuvir/ledipasvir, and dolutegravir for grazoprevir/elbasvir). Therefore, initial regimens for co-infected patients must be selected carefully and those already on incompatible regimens must be switched, something that is not always accomplished smoothly.
links to webcast are in these reports:
IAS: C-EDGE CO-INFECTED: Phase 3 Study of Grazoprevir / Elbasvir in Patients with HCV/HIV - (07/22/15)
IAS: Ledipasvir/sofosbuvir for 12 Weeks in Patients Coinfected With HCV and hiv-1: ION-4 - (07/22/15)
IAS: Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1 - (07/24/15)
This was reported at the Clin Pharm Wk this year regarding substituting TAF for TDF in HCV therapy:
Drug Interactions Between Anti-HCV Antivirals Ledipasvir/Sofosbuvir and Integrase Strand Transfer Inhibitor-Based Regimens......"LDV/SOF may be coadministered with E/C/F/TAF without monitoring" - (06/03/15)
One of the most attractive regimens for co-infected patients is the combination of sofosbuvir and the NS5a inhibitor daclatasvir, two potent once-daily agents with pangenotype activity. A recent on-line publication demonstrated that 12 weeks of treatment with this regimen achieved SVR in 97% of 127 co-infected patients with GT1 infection and 100% of 26 with GT 2-4 . Most commonly used antiretrovirals were permitted, although dose adjustment of daclatasvir is required with some. However, the extraordinarily high treatment success rates seen in clinical trials may not be reproducible in routine clinical practice. To address this issue Lacombe et al reported an interim analysis of the French compassionate use program employing sofosbuvir plus daclatasvir in patients with advanced fibrosis (metavir score ≥F3) or other severe disease manifestations . Addition of ribavirin and duration of treatment (12 vs. 24 weeks) were at the discretion of the treater. Of more than 4000 enrolled, 147 were co-infected and had week 12 post-treatment data available. GT1 infection was present in 71% and 76% had cirrhosis. Ribavirin was used in 10% and 68% were treated for 24 weeks. SVR was achieved in 98% and 97% of those treated for 12 or 24 weeks, respectively. All treated with ribavirin were cured (n=14). Response rates were nearly identical in those with and without cirrhosis. Safety was studied in the much larger number of patients (n=564) who had at least one completed visit.
Serious adverse events were seen in 3.9% and 2 patients discontinued treatment due to asthenia. Given the severity of underlying illness in the study population, it is not surprising that there were 9 (1.6%) deaths, 7 unrelated to treatment and 2 for which causality was not reported. This study suggests that high response rates are possible with 12 weeks of the sofosbuvir/daclatasvir regimen without ribavirin, even in co-infected patients with advanced liver disease. However, given the nature of the compassionate use program and the very large number of enrollees with incomplete data, the reported results are more like an "as-treated" analysis rather than "intention-to-treat". Compassionate use participants are likely different from both formal clinical trials participants and ordinary care patients. They are often sicker than formal trials participants, but also may be more motivated and are followed-up more closely than regular clinical practice patients. The true response rates achieved in routine clinical practice may still in fact be lower. Daclatasvir has been recently approved for use in the US, but at present only combined with sofosbuvir for treatment GT3, and not specifically for co-infected patients.
IAS: DACLATASVIR PLUS SOFOSBUVIR WITH OR WITHOUT RIBAVIRIN IN PATIENTS WITH HIV-HCV COINFECTION: INTERIM ANALYSIS OF A FRENCH MULTICENTER COMPASSIONATE USE PROGRAM (AI444-258) - (07/22/15)
IAS: Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1 - (07/24/15)
this was reported at the Clin Pharm Wk this year:
Assessment of Drug-Drug Interactions Between Daclatasvir and Darunavir/Ritonavir or Lopinavir/Ritonavir - (06/01/15)
Evaluation of Drug Interactions between Dolutegravir and Daclatasvir in Healthy Subjects - (05/29/15)
Population Viral Kinetic Modeling: SVR Prediction in HCV GT-3 Cirrhotic Patients With 24 Weeks of Daclatasvir + Sofosbuvir Administration - (05/29/15)
In a previously published study, the "3D" regimen, which includes 5 drugs (an NS5a inhibitor ombitasvir, a protease inhibitor parataprevir boosted with ritonavir, a non-nucleoside polymerase inhibitor dasabuvir plus ribavirin) was given for 12 or 24 weeks to co-infected patients with GT1 HCV on suppressive ART that could only contain atazanavir or raltegravir as anchor drugs . Treatment was highly successful with 94% and 91% SVR in the 12 and 24 week arms, respectively. Wyles et al presented a reanalysis of data from this trial to identify risk factors for virologic failure . However, with only 60 evaluable patients and 2 virologic failures, there was no way this analysis could achieve its stated goal. A much larger data set would be needed.
IAS: Abbvie 3D in HCV/HIV Update ......HIGH SVR RATES IN HCV/HIV-1 CO-INFECTED PATIENTS REGARDLESS OF BASELINE CHARACTERISTICS........(note IDUs had 100% SVR) - (07/22/15)
Treatment of HCV Mono-infection.
The combination of sofosbuvir plus the HCV protease inhibitor simeprevir is a simple, safe and effective treatment of HCV GT1 infection, given as one tablet of each drug once daily for 12 weeks, or 24 weeks in the presence of cirrhosis. This regimen was approved based on promising results from a small phase 2 study . The OPTIMIST-1 and -2 studies, conducted in non-cirrhotic and cirrhotic subjects, respectively, were larger follow-up studies done to verify the findings of the earlier trial [10,11]. Both studies found 12 weeks of treatment to be more effective than historical controls from interferon/ribavirin/DAA trials with similar patient types. Non-cirrhotics achieved a SVR of 97%, while in cirrhotics the rate was 83%. Treatment for 8 weeks was less effective overall in OPTIMIST-1 (SVR 83%), but worked well in those with a baseline HCV RNA < 4 million (SVR 96%). The NS3 polymorphism Q80K, which confers some degree of resistance to simeprevir, was present at baseline in 41% and 47% of GT 1a infections in OPTIMIST-1 and -2, respectively. In non-cirrhotics treated for 12 weeks, the presence of Q80K had no effect on SVR in GT 1a patients (96% with and 97% without Q80K), but in cirrhotics SVR was reduced from 92% to 74%. In OPTIMIST-2, patients with less advanced cirrhosis also did better, including those with an albumin ≥4 (SVR 94%) and transient elastography (TE) results between 12.6 and 20.0 kPa (SVR 100%), although only 11 subjects fell into this latter subset. Emergence of NS3 resistance variants was common among those failing treatment in OPTIMIST-2, (79%) but was seen in only 2 cases in OPTIMIST-1. Headache, nausea and fatigue were the most commonly reported adverse events. There were 3 discontinuations for adverse events, all in OPTIMIST-2, and only one was thought to be treatment-related (rash).
The sofosbuvir/simeprevir regimen provides another treatment option, especially for non-cirrhotic patients for whom 12 weeks of treatment was highly effective and 8 weeks could be considered for those with lower HCV RNA. For cirrhotic patients, SVR after 12 weeks of treatment was better than historical controls, but left room for improvement. Longer treatment durations for cirrhotic patients were not studied but may be needed to optimize SVR rates. Another obstacle to use of this regimen may be cost. Like sosbuvir plus daclatasvir, the components of this regimen are manufactured by different pharmaceutical companies and command higher prices when purchased separately than do co-formulated and pre-packaged complete regimens offered by a single manufacturer. Unless shorter treatment durations are as effective as longer durations with the other regimens, or drug prices are substantially reduced, cost may prevent wider adoption of these regimens.
A Phase 3, randomised, open-label study to evaluate the efficacy and safety of 12 and 8 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-na•ve and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: OPTIMIST-1.......http://www.natap.org/2015/EASL/EASL_72.htm
A Phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-na•ve or -experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTIMIST-2......http://www.natap.org/2015/EASL/EASL_76.htm
Regression of Fibrosis and Outcome after HCV Treatment.
SVR is an accepted surrogate marker of HCV treatment success because long-term follow-up data, mostly from mono-infected patients, show a correlation with reduced risk of liver-related morbidity and mortality. The reduction in risk occurs because of stabilization or regression of fibrosis in most but not all patients. To assess the effect of SVR and regression of fibrosis in HIV/HCV co-infected patients, Casado et al analyzed a cohort of 133 treated with peg-interferon plus ribavirin in Madrid . Those with both baseline and one or more post-treatment assessments of fibrosis by biopsy or TE were included. The overall SVR rate was 32%, including 56% in those with GT 3 infection (26% of the cohort) and 18% with GT 1. Regression of fibrosis, defined as ≥1 point decline in metavir score with no worsening on further assessments, if any, occurred in 55% achieving SVR as well as 15% without SVR, illustrating that in some cases, there is a treatment benefit even without SVR. Time-to-event curves showed regression of fibrosis was a better indicator than SVR of reduced risk of subsequent liver-related or all-cause mortality. The combination of SVR plus fibrosis regression, achieved in only 17% of the study population, identified a group at very low risk of liver-related death. In multivariable analysis, fibrosis regression was the only factor independently associated with reduced liver-related complications, liver-related mortality and all cause mortality.
Several factors may limit applicability of these results to contemporary practice. Treatment was interferon-based rather than with the new DAAs. A much higher proportion of treatment recipients achieving both SVR and fibrosis regression should be seen with interferon-free regimens. Long-term follow-up studies to assess fibrosis regression and clinical events after interferon-free treatment are needed. Also, it is unclear how many patients in this study had advanced vs had low grade fibrosis at baseline. Patients entering treatment with little fibrosis should still have a favorable prognosis even if regression is not documented, as long as stabilization occurs.
This study helps validate the benefit of HCV treatment in co-infected patients and the role of TE as a tool to monitor residual fibrosis after SVR. The findings also emphasize the importance of residual fibrosis as a marker of prognosis after HCV treatment. Those with advanced fibrosis before treatment who do not regress constitute a group with a significant residual residual risk of liver-related illness. Such patients will need medical management to prevent and treat liver-related illness and to detect hepatocellular cancer. In this study, only slightly more than half of patients who achieved SVR had fibrosis regression. Similar results, if confirmed in patients with advanced fibrosis treated with DAA regimens, would create a powerful rationale to treat early in the course of HCV to avoid progression of fibrosis that for some is not reversible, and constitutes an ongoing health risk even after achieving SVR.
IAS: Frequent Fibrosis Regression With SVR in HCV/HIV+, Cutting Death Risk - (07/28/15)
IAS: Treat HCV Early or you are at risk of cirrhosis & then not achieving regression of fibrosis which increases death rate & liver-related complications.....study finds fibrosis regression is required even with an SVR to reduce all-cause death & liver-related death.....THUS, early HCV treatment is crucial, waiting until cirrhosis is tantamount to a 50% chance of a death sentence .......http://natap.org/2015/IAS/IAS_63.htm
Another study also reported the probability of fibrosis regression among 254 patients treated for HCV . The majority (61%) of treated patients in this cohort from Montreal, Canada were treated with peg-interferon plus ribavirin, but 30% added a DAA and 10% were treated with an interferon-free regimen. One quarter were HIV co-infected and 40% had cirrhosis. The overall SVR rate was 59%. Regression of fibrosis was common among those who attained SVR, but was seen less reliably in those with metavir F4 at baseline (74%) compared to F3 (87%) or F2 (96%). This study shows regression of fibrosis is a frequent consequence of successful HCV treatment, but does not occur in a significant minority of those with advanced fibrosis at baseline. As discussed above, this has important implications for the cost and complexity of post-SVR care. The findings also suggest treatment of HCV should not be restricted to those with advanced fibrosis, since regression does not uniformly occur in such patients.
ART Regimen and HCV Progression.
The hepatotoxic potential of current antiretrovirals is controversial. Cases of acute drug induced hepatitis have been reported for virtually all agents. Mitochondrial toxicity, immune-mediated reactions and metabolic toxicity leading to steatosis may be caused by antiretrovirals. Transaminase elevations and discontinuations for suspected drug-related liver injury are most common in patients with viral hepatitis co-infection. Certain older antiretrovirals were associated greater risk of liver injury. Among regimens currently recommended in the DHHS guidelines, there is little evidence that one is more hepatotoxic than another, but there is little information on the long-term effects of contemporary ART on HCV progression. To evaluate the effect of PI- vs. NNRTI-based ART, Brunet et al performed a longitudinal analysis of a Canadian HIV/HCV co-infection cohort . Only those on a tenofovir DF/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) backbone and on their first anchor drug at cohort entry were in included. Patients treated for HCV were excluded. Because PIs and NNRTIs are often prescribed for patients with different characteristics, a propensity score was used to create two treatment groups with similar baseline characteristics. The PIs evaluated were atazanavir/ritonavir, lopinavir/ritonavir and darunavir/ritonavir. The vast majority of NNRTIs users were on efavirenz. The AST-to-platelet ratio index (APRI) was used to assess liver fibrosis over time. Change in APRI score did not differ between the PI and NNRTI groups. However, when analyzed by NRTI backbone, APRI increased significantly over time on ABC/3TC, but not TDF/FTC, regardless of the anchor drug. The APRI increases were small and median values remained well below the levels associated with advanced fibrosis. The results confirm that contemporary PI- and NNRTI-based ART have similar safety in HCV co-infected patients. However, since HCV can now be cured in a large proportion of patients, choice of anchor drugs should be driven mainly by pharmacologic compatibility with anti-HCV regimens. Since integrase inhibitors have few interactions with anti-HCV drugs, they may now be preferable for many co-infected patients. The meaning of the differences seen with NRTI backbones is unclear. Assignment to treatment was not randomized and matching was done to improve the comparability of groups according to anchor drug, not backbone. Another analysis done with matching of the backbone groups could clarify the result and provide information that may improve the choice of ART for those co-infected patients who fail HCV treatment or cannot be treated.
link to webcast: there were some questions raised after the slide presentation in the Q&A regarding the study design & clinical significance:
1. Naggie S, et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0202.
2. Rockstroh, JK et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0206LB.
3. Naggie S, et al. New Engl J Med 2015. Published on July 21, 2015 at NEJM.org. DOI: 10.1056/NEJMoa1501315
4. Rockstroh JK, et al. Lancet HIV 2015; 2: e319-27. Published Online July 10, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00114-9.
5. Wyles DL et al. New Engl J Med 2015. Published on July 21, 2015 at NEJM.org. DOI: 10.1056/NEJMoa1503153.
6. Lacombe K, et al, IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0207LB.
7. Sulkowski, M, et al. JAMA 2015;313:1223-31. doi: 10.1001/jama.2015.1328.
8. Wyles D, et al IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0203.
9. Lawitz E et al. Lancet 2014;384:1756-65. Published Online July 28, 2014. http://dx.doi.org/10.1016/S0140-6736(14)61036-9.
10. Ruane PJ et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TULBPE10.
11. Lawitz E et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TULBPE11.
12. Casado JL, et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0204.
13. Trottier B, et al. IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUPEB241.
14. Brunet L, et al. 8th IAS Conference on Pathogenesis, Treatment and Prevention. Vancouver, Canada 19-22 July 2015, abstract TUAB0201.