**6. Unique populations**

**Trial Phase** *n* **Regimen SVR Comments**

wks

wks

for 12 wks

for 12 wks

for 12 wks

**Trial Phase** *n* **Regimen SVR Comments**

for 12 wks

wks

for 12 wks

12 wks

SOF + RBV for 12 or 24

OMB/PARr ± RBV for

DAC + SOF ± RBV for 24 wks

LONESTAR II [34] II <sup>47</sup> SOF + RBV + peg-IFN

PROTON [35] II <sup>25</sup> SOF + RBV + peg-IFN

ELECTRON [36] II <sup>50</sup> SOF + RBV ± peg-IFN

**Table 4.** Results of DAA treatment in genotypes 2 and 3 patients

II 60

II 86

NEUTRINO [31] III 327\* SOF + RBV + peg-IFN

RESTORE [42] III <sup>107</sup> SIM + RBV + peg-IFN

SOF + RBV for 12 or 24

SOF + RBV for 12 or 16

>78%

>88%

92%

100%

96%

>79%

>65%

>91%

3 patients.

>86% Previously treated patients with and without cirrhosis.

>96% Previously treated patients with and without cirrhosis

> Among the SOF + RBV arms of the study SVR was high, the SOF only group reported an SVR of 60%

> > Patients with genotypes 1, 4, 5, and 6. Of these 27/28 genotype 4 patients and 7/7 genotype 5 and 6 achieved SVR.

SVR was lowest in the 12 wk, treatment naïve

Preliminary data, patients in the RBV group achieved 100% SVR

SVR of 83% in the treatment naïve group, 40% in the prior null

group.

responders

G-2 was treated for 12 wk and G-3 was treated for 24 wks in patients with and without cirrhosis who were and were not previously treated. Lowest SVR(78%) was noted in the previously treated, cirrhotic genotype

VALENCE [33] III 419

64 Recent Advances in Liver Diseases and Surgery

FUSION [32] III 201

A144040 [37] II 44

Legend: Wks: week; DAC: daclatasvir

Egypt Ancestry Trial

[41]

PEARL I [43, 44]

Large phase III trials convincingly show favorable SVR in patients who are naive to treatment, noncirrhotic, and in non-HIV coinfected. However, what about patients who do not fit into these categories? Furthermore, concern for side effect profile, inadequate practitioner training, and concern for drug-drug interaction have led to avoidance in all but treatment-naive and otherwise healthy patients.

In addition to the unique groups of patients described below, other factors should also be taken into consideration as they can complicate the decision as to which treatment should be initiated. These include patients with renal failure, heart failure, and comorbid psychiatric illness to name a few. The medical comorbidities of each individual is a hornet's nest of potential failure, and as such, each case embarked upon should be done so with careful consideration of all coexisting medical and psychological conditions. To ensure of this, it is helpful to have a trained multidisciplinary team made up of physicians, pharmacists, nurses, psychologists, and social workers. Aside from making medication dose adjustments when required, current guidelines recommend that in the presence of complex comorbid medical conditions, treatment of HCV be initiated and managed by a hepatologist and potentially at a medical center affiliated with liver transplantation [47].

#### **6.1. Treatment experienced**

Patients who have been previously treated pose perhaps one of the most common dilemmas that practitioners face. Often times, patients get retreated due to initial therapeutic failure (typically to peg-IFN and RBV) or HCV relapse. Patients may be presenting for retreatment following previous partial treatment or after being lost to follow-up. Rarely, patients can become reinfected with HCV. In all scenarios, therapy with new HCV drug regimens should be offered.

Initial studies with TEL, BOC, and SIM showed encouraging results. In the REALIZE trial, nonresponders, partial responders, or those who have suffered a relapse were randomized into three treatment groups separated by treatment duration. An SVR rate of 66% was achieved in the 12-week treatment arm of TEL, peg-IFN, and RBV [48]. Similarly, BOC in combination peg-IFN and RBV was able to achieve rates of SVR of 63% overall, however only 38% in prior nonresponders [49]. Larger trials and trials utilizing SIM showed similar results [50-53]. In general, all studies reported adverse side effects of severe anemia, requiring treatment discontinuation, dose reduction, or transfusion. Given the poor response of prior null res‐ ponders, treatment utilizing TEL, BOC, or SIM in combination with peg-IFN and ribavirin is not recommended in the treatment experienced population.

Several promising trials evaluating the therapeutic benefit of newer DAAs have been reported with high overall SVRs, few side effects, and minimal drug interactions. (Tables 3-5). Based on these trials, recommendations regarding appropriate therapy as tailored to the genotype have been made. In general, genotype 1 patients have several options as convincing results as to effectiveness has been produced with either SOF/LED, SOF/SIM, or the four-drug combination of PARr/OMB/DAS/RBV. For those with genotype 2 or 3, reassuring data from the LONE‐ STAR-2 trial that achieved SVR rates of 83-96% in these patients confirmed that a 12-week regimen of SOF, RBV, and peg-IFN be used [34]. For those not eligible for peg-IFN, SVRs of 80-90% were still achievable with SOF and RBV alone [32, 33]. In genotype 4 patients, options include SOF/LED, SOF/RBV with or without peg-IFN, or the four-drug combination of PARr/ OMB/DAS/RBV. As with the treatment-naive patients, genotype 5 or 6 has few reported data, but an SOF-based regimen will likely be efficacious.

#### **6.2. Decompensated cirrhosis**

Cirrhosis, regardless of its level of compensation, is known to result in a decreased SVR in patients being treated for HCV. On decompensation with the development of ascites, variceal hemorrhage, encephalopathy, or coagulopathy, the probability of survival is only 50% at 5 years, with a median survival of only 2 years [54, 55]. Thus, it remains imperative to provide rapid and effective treatment for HCV.

A meta-analysis done by Vierling *et al*. [56] examined several phase III clinical trials of patients undergoing HCV treatment with biopsy proven cirrhosis. In the trials of patients receiving the standard therapy of peg-IFN and RBV, an overall SVR of 20% was found. In 2011, riding the momentum of improved SVR in noncirrhotic patients receiving triple therapy, BOC, TEL, and SIM were given in combination with peg-IFN and RBV, and the rate of SVR increased significantly to 55% and 74%, respectively, in this previously dismal population [53, 56]. Improvement in SVR was not without its drawbacks. In the BOC- and TEL-treated groups, significant side effects of anemia and diarrhea were noted. Slightly less severe side effects of flulike illness and pruritus were noted in those treated with SIM; however, significant resistance was found in genotype 1A patients who possessed a specific genetic polymorphism known as the Q80K mutation. A screening test for detection of this mutation is available, and given that nearly 50% of United States and 20% of European patients had the mutation at baseline, testing should be conducted prior to treatment with SIM [57].

Following on the success of a trial conducted by Gane *et al.* [58], which showed an SVR in 9 out of 9 patients with decompensated cirrhosis treated with SOF, LED, and RBV, the SOLAR-1 trial was conducted. This trial was a multicenter, randomized trial of 108 patients with genotypes 1 and 4 HCV whom also had Child-Pugh class B or C cirrhosis. Excluding 6 patients who underwent eventual liver transplant, an SVR of 87% and 89% was attained in the 12- and 24-week treatment groups, respectively. Given the larger chance of adverse events observed in the 24-week group, consensus guidelines for treating genotypes 1 and 4 patients with decompensated cirrhosis support a 12-week course of SOF, LED, and RBV [47]. Most impor‐ tantly, the patients with virologic response had significant improvement in liver function, including improvements in bilirubin, albumin, modified end-stage liver disease (MELD) scores, and Child-Pugh scores. These guidelines recommend that for genotypes 2 and 3, daily SOF and RBV should be utilized up to 48 weeks for treatment. These recommendations are based on sparse data showing an achieved SVR in 10 of 11 patients [59]. Further data is needed in this group and is expected to change guidelines further. Preliminary data reported on the use of SOF, LED, and RBV for 12 weeks in genotype 3 patients showed favorable results with an SVR being achieved in all 26 patients treated [60].

Further research is needed in this group, including studies evaluating larger groups of patients to delineate a specific regimen. As it stands, similar to other unique populations, it appears that second-generation agents such as SOF, LED, and the like provide a superior benefit to first-generation protease inhibitors like SIM, TEL, and BOC. In addition to the pan-genomic action, improved dosing regimens, less drug-drug interactions, and more tolerable side effect profiles make them a first choice in patients with decompensated cirrhosis regardless of liver transplant candidacy.

#### **6.3. HIV coinfected**

into three treatment groups separated by treatment duration. An SVR rate of 66% was achieved in the 12-week treatment arm of TEL, peg-IFN, and RBV [48]. Similarly, BOC in combination peg-IFN and RBV was able to achieve rates of SVR of 63% overall, however only 38% in prior nonresponders [49]. Larger trials and trials utilizing SIM showed similar results [50-53]. In general, all studies reported adverse side effects of severe anemia, requiring treatment discontinuation, dose reduction, or transfusion. Given the poor response of prior null res‐ ponders, treatment utilizing TEL, BOC, or SIM in combination with peg-IFN and ribavirin is

Several promising trials evaluating the therapeutic benefit of newer DAAs have been reported with high overall SVRs, few side effects, and minimal drug interactions. (Tables 3-5). Based on these trials, recommendations regarding appropriate therapy as tailored to the genotype have been made. In general, genotype 1 patients have several options as convincing results as to effectiveness has been produced with either SOF/LED, SOF/SIM, or the four-drug combination of PARr/OMB/DAS/RBV. For those with genotype 2 or 3, reassuring data from the LONE‐ STAR-2 trial that achieved SVR rates of 83-96% in these patients confirmed that a 12-week regimen of SOF, RBV, and peg-IFN be used [34]. For those not eligible for peg-IFN, SVRs of 80-90% were still achievable with SOF and RBV alone [32, 33]. In genotype 4 patients, options include SOF/LED, SOF/RBV with or without peg-IFN, or the four-drug combination of PARr/ OMB/DAS/RBV. As with the treatment-naive patients, genotype 5 or 6 has few reported data,

Cirrhosis, regardless of its level of compensation, is known to result in a decreased SVR in patients being treated for HCV. On decompensation with the development of ascites, variceal hemorrhage, encephalopathy, or coagulopathy, the probability of survival is only 50% at 5 years, with a median survival of only 2 years [54, 55]. Thus, it remains imperative to provide

A meta-analysis done by Vierling *et al*. [56] examined several phase III clinical trials of patients undergoing HCV treatment with biopsy proven cirrhosis. In the trials of patients receiving the standard therapy of peg-IFN and RBV, an overall SVR of 20% was found. In 2011, riding the momentum of improved SVR in noncirrhotic patients receiving triple therapy, BOC, TEL, and SIM were given in combination with peg-IFN and RBV, and the rate of SVR increased significantly to 55% and 74%, respectively, in this previously dismal population [53, 56]. Improvement in SVR was not without its drawbacks. In the BOC- and TEL-treated groups, significant side effects of anemia and diarrhea were noted. Slightly less severe side effects of flulike illness and pruritus were noted in those treated with SIM; however, significant resistance was found in genotype 1A patients who possessed a specific genetic polymorphism known as the Q80K mutation. A screening test for detection of this mutation is available, and given that nearly 50% of United States and 20% of European patients had the mutation at

Following on the success of a trial conducted by Gane *et al.* [58], which showed an SVR in 9 out of 9 patients with decompensated cirrhosis treated with SOF, LED, and RBV, the SOLAR-1

baseline, testing should be conducted prior to treatment with SIM [57].

not recommended in the treatment experienced population.

but an SOF-based regimen will likely be efficacious.

**6.2. Decompensated cirrhosis**

66 Recent Advances in Liver Diseases and Surgery

rapid and effective treatment for HCV.

HIV-infected individuals with concomitant hepatitis C are known to have an increased morbidity and mortality [61]. Following the development of highly active antiretroviral therapy (HAART), there has been an ever-increasing percentage of HIV-infected patients who are dying from liver disease. In HIV-infected patients, death from liver disease remains far more prevalent than death attributable to HIV-related complications [62, 63].

Historically, having coinfection with HIV also leads to poor responses to peg-IFN and RBV therapy [64, 65]. Additionally, coinfection with HIV also lead to increased risk for progression to cirrhosis [66]. On a molecular level, it has been postulated that the higher viral load of HCV RNA noted in this population is secondary to both increased replication of HCV RNA by HIV proteins as well as a generalized state of immunodeficiency [67, 68].

Up until recently, treating patients with coinfection of HIV was felt to be difficult secondary to the historically poorer responses to peg-IFN and RBV. Recently, however, concern regarding potential drug-drug interactions has existed and has lead to practitioner trepidation [69, 70]. This has fortunately not panned out, and several large trials have shown excellent results in treatment of the HCV/HIV coinfected.

With protease inhibitors approved first, trials utilizing a triple therapy of either TEL or BOC in combination with peg-IFN and RBV were conducted. Sulkowski *et al*. [71] treated 62 coinfected genotype 1 patients with TEL, peg-IFN, and RBV achieved an SVR of 74%. In another study, using triple therapy with BOC in combination with peg-IFN and RBV, an SVR of 63% was attained; however, significant side effects leading to dropout in 12 of 65 patients occurred. This dropout continues to be a concern and is thought to be secondary to side effects, high pill burden, and pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs [72, 73].

Following on the success of first-generation DAAs, trials utilizing SOF were later conducted. In a study of genotype 1 patients, Osinusi *et al.* [74] treated 50 HCV and HIV coinfected patients with 12 weeks of SOF and LED. Grouping based on HAART naive versus on HAART showed no difference in the 100% SVR rates achieved in both groups. No adverse events or discontin‐ uations were noted during the treatment period. Sulkowski *et al.* [75] was able to achieve an SVR of 67-88% based on genotype following a 12- to 24-week course of SOF and RBV. Of note, this approach was void of significant drug-drug interactions. In an even larger trial conducted by Molina *et al.* [76], 275 patients with genotypes 1-4 HCV underwent treatment with a 12 week course of SOF and RBV. The overall SVR rate achieved was 85% in genotype 1, 88% in genotype 2, 89% in genotype 3, and 84% in patients with genotype 4. Given the results of these trials, an SOF-based regimen, free of peg-IFN, is recommended; however, with new drug regimens being approved, further studies and head-to-head trials will need to be conducted in order to truly determine the best choice for these select patients.

#### **6.4. Recurrence after liver transplant**

Graft failure and fibrosis remain a feared complications among patients transplanted for HCV. Invariably, HCV recurs in all patients following transplantation. Similar to the pretransplant state, patients with HCV progress to fibrosis and eventual decompensation of the transplanted liver. Patients who undergo liver transplantation as a whole have been shown to have higher rates of mortality for this reason [77-79]. Routine monitoring has gone far to anticipate these changes; however, treatment needs continued improvement. Until recently, treatment with peg-IFN and RBV was only marginally effective, and use in this population was off-label. With the newly discovered DAAs, great promise for treatment exists. In addition to the superb ability to achieve SVR, DAAs offer favorable side effect profiles with manageable drug interactions with common immunosuppressive regimens. Some of the DAAs have been shown to do this better than others.

Complicating factors that must be discussed in this patient population include donor and recipient variables. Independent of the treatment regimen, certain characteristics have been shown in large retrospective analysis to negatively impact progression to fibrosis and cirrhosis following LT. The presence of advanced donor age or steatosis as well as specific genetic polymorphisms in both the donor and the recipient can lead to advanced progression of fibrosis [80-83]. Factors such as living vs. deceased donor, human leukocyte antigen (HLA) matching, and HCV positive donor status have not been shown to reliably contribute to fibrosis progression [84, 85]. Within the context of HCV-related liver transplantation, several studies have also attempted to identify specific allelic variants that may contribute to either poor response to standard antiviral therapy or a more rapid progression of fibrosis [86, 87]. Further studies are needed to confirm these, however, and as it stands due to the limited supply, the allocation of available livers for transplant based on the presence of nucleotide polymorphisms is not practiced (Table 6).


**Table 6.** Factors leading to worse outcomes following liver transplantation

study, using triple therapy with BOC in combination with peg-IFN and RBV, an SVR of 63% was attained; however, significant side effects leading to dropout in 12 of 65 patients occurred. This dropout continues to be a concern and is thought to be secondary to side effects, high pill burden, and pharmacokinetic interactions between HCV NS3/4A protease inhibitors and

Following on the success of first-generation DAAs, trials utilizing SOF were later conducted. In a study of genotype 1 patients, Osinusi *et al.* [74] treated 50 HCV and HIV coinfected patients with 12 weeks of SOF and LED. Grouping based on HAART naive versus on HAART showed no difference in the 100% SVR rates achieved in both groups. No adverse events or discontin‐ uations were noted during the treatment period. Sulkowski *et al.* [75] was able to achieve an SVR of 67-88% based on genotype following a 12- to 24-week course of SOF and RBV. Of note, this approach was void of significant drug-drug interactions. In an even larger trial conducted by Molina *et al.* [76], 275 patients with genotypes 1-4 HCV underwent treatment with a 12 week course of SOF and RBV. The overall SVR rate achieved was 85% in genotype 1, 88% in genotype 2, 89% in genotype 3, and 84% in patients with genotype 4. Given the results of these trials, an SOF-based regimen, free of peg-IFN, is recommended; however, with new drug regimens being approved, further studies and head-to-head trials will need to be conducted

Graft failure and fibrosis remain a feared complications among patients transplanted for HCV. Invariably, HCV recurs in all patients following transplantation. Similar to the pretransplant state, patients with HCV progress to fibrosis and eventual decompensation of the transplanted liver. Patients who undergo liver transplantation as a whole have been shown to have higher rates of mortality for this reason [77-79]. Routine monitoring has gone far to anticipate these changes; however, treatment needs continued improvement. Until recently, treatment with peg-IFN and RBV was only marginally effective, and use in this population was off-label. With the newly discovered DAAs, great promise for treatment exists. In addition to the superb ability to achieve SVR, DAAs offer favorable side effect profiles with manageable drug interactions with common immunosuppressive regimens. Some of the DAAs have been shown

Complicating factors that must be discussed in this patient population include donor and recipient variables. Independent of the treatment regimen, certain characteristics have been shown in large retrospective analysis to negatively impact progression to fibrosis and cirrhosis following LT. The presence of advanced donor age or steatosis as well as specific genetic polymorphisms in both the donor and the recipient can lead to advanced progression of fibrosis [80-83]. Factors such as living vs. deceased donor, human leukocyte antigen (HLA) matching, and HCV positive donor status have not been shown to reliably contribute to fibrosis progression [84, 85]. Within the context of HCV-related liver transplantation, several studies have also attempted to identify specific allelic variants that may contribute to either poor response to standard antiviral therapy or a more rapid progression of fibrosis [86, 87]. Further studies are needed to confirm these, however, and as it stands due to the limited supply, the

in order to truly determine the best choice for these select patients.

antiretroviral drugs [72, 73].

68 Recent Advances in Liver Diseases and Surgery

**6.4. Recurrence after liver transplant**

to do this better than others.

Currently, three treatment strategies for management of HCV in the transplant setting are being used. The first strategy involves treatment of patients currently listed for transplantation. Until recently, the barrier with this strategy has been that with peg-IFN, RBV and the early DAAs patients often either do not tolerate therapy or do not achieve SVR [88]. The second strategy that is not being used thus far involves treating HCV recurrence immediately following liver transplantation. Whether or not this method of treatment increases in popu‐ larity will be determined by the tolerability and side effects of the new DAAs. The third and most commonly used strategy involves initiating treatment after several months following transplantation and noted progression of HCV.

Several trials have evaluated the effectiveness of using peg-IFN and RBV in order to treat HCV recurrence in patients following LT. The results have not been favorable, and side effects, particularly anemia, have posed barriers to treatment completion. Overall SVR, in patients with minimal fibrosis, following 48 weeks of therapy was only 48% [89]. Follow-up studies have had even less favorable results [90]. Therefore, peg-IFN and RBV alone is not recom‐ mended in this treatment group.

In the largest series evaluating the use of TEL and BOC for the treatment of HCV recurrence following liver transplantation, Burton et al. [91] successfully treated 81 patients with genotype 1 HCV and achieved an SVR at 12 weeks of 63%. Despite its success, TEL and BOC in combi‐ nation with peg-IFN and RBV led to severe side effects of anemia requiring a transfusion in nearly 50% of patients. Additionally, close monitoring of immunosuppressant drug levels was required, and frequent dose adjustments were needed. Given these results, the use of BOC and TEL are not recommended unless newer, better-tolerated agents are unavailable.

Recent trials report favorable tolerability and highly effective results with the use of new DAAs. In a trial evaluating 40 patients treated with RBV and SOF, an SVR12 of 70% was achieved [92]. Slightly better results were achieved in the HCV-TARGET consortium, which evaluated 189 patients being treated with SOF-based regimens. Overall, SVR among the groups ranged from 69% to 88%. Additionally, SOF and SIM regimens achieved SVR12 of 80-88% depending if RBV was used [93]. The utilization of SOB in combination with LED is also being looked at and has shown that in patients with compensated disease and minimal cirrhosis, a highly favorable SVR12 of 96% could be attained. This regimen is also appealing as it only required 12 weeks of therapy [94]. Current guidelines put in place by the AASLD-ISDA recommend treatment of genotype 1 infection with combination SOF and SIM. For genotype 2 or 3, SOF or RBV alone is recommended [47]. These recommendations are likely subject to change given approval of LED as well as favorable results of a trial looking at ritonavir-boosted paritaprevir, coformulated with ombitasvir, plus dasabuvir [95]. The treatment of post-LT patients with more advanced cirrhosis (Child-Pugh B or C) continues to require further study; however, preliminary results reveal that even in this highly difficult-totreat group, an SVR of 81% could be achieved [94]. Other regimens continue to be under investigation at this time.

It is anticipated that all-oral DAA regimens will be both highly effective as well as highly tolerated in the liver transplant setting. Continued research evaluating safety profiles of these medications should be done, but in the meantime, given the amount of evidence currently available and in accordance with current guidelines, the initiation of a sofosbuvir-based regimen in this patient population is highly recommended.
