• •

  All patients with chronic HCV infection should be considered for treatment, whether or not they have been previously treated (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

For complete and satisfactory elimination of the hepatitis C virus (HCV), it is necessary to have a solid plan involving the entire country and to have the resource availability and support of the healthcare sector to have effective and easily-accessed treatments. The benefit of curing the infection has important clinical advantages. The goal of treatment is to define a sustained virologic response (SVR) as the persistent absence of HCV for at least 12 weeks after treatment completion. That was demonstrated in a prospective study in which the majority of patients achieved an SVR that lasted for more than 5 years, through a first-line HCV treatment, showing that recurrence was rare after a prolonged follow-up period.1

Patients with SVR have an excellent clinical response, manifested by a significant decrease in fatigue, improved physical activity, a biochemical response with normalized aminotransferase levels, and reduced fibrosis progression.

Over the last 5 years, the treatment of chronic HCV infection has improved considerably with the introduction of new direct-acting antiviral agents (DAAs) that are targeted at different sites of the viral genome, preventing the replication cycle.2

• •

  Treatment should be a priority for patients with advanced fibrosis or cirrhosis (METAVIR F-3 F-4) (A1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

Today, patients with advanced disease can receive treatment. That group of patients is at greater risk for complications due to hepatic decompensation (encephalopathy, ascites, gastrointestinal bleeding from esophageal varices, and the appearance of hepatocellular carcinoma). The HALT-C study, supported by the U.S. National Institutes of Health, demonstrated a rise in hepatocellular carcinoma development in patients with chronic hepatitis C under long-term surveillance, with mortality rates increasing 7.5 to 10% per year.3

SVR has been shown to reduce decompensation episodes in patients with advanced disease. There is less need for liver transplantation and a lower mortality rate in patients with advanced liver disease that have SVR, than in untreated patients.3,4 Those data have been reproduced in a European study,5 but there are still no long-term results.

• •

  Expedited treatment is recommended for patients with cirrhosis of the liver that have Child-Pugh class A or B disease. Patients with decompensated cirrhosis (Child-Pugh class B and C) should also be urgently treated with an IFN-free regimen, even if they are not going to undergo transplantation. Patients with Child-Pugh class C and a MELD score above 20 that are indicated for liver transplantation can undergo the transplant first, and then receive treatment (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

IFN use is absolutely contraindicated for patients with decompensated cirrhosis. Post-liver transplantation IFN use is currently not indicated, due to multiple adverse effects and the low SVR rate. With the introduction of the new DAAs, treatment is more effective, with better pretreatment and posttreatment response.

Liver transplantation is the treatment of choice for patients with advanced cirrhosis. It is well-known that post-transplantation hepatitis C recurrence is universal and is associated with reduced graft survival.6 Whether decompensated patients with chronic liver disease should receive pretransplantation or posttransplantation treatment is a subject of debate. At present, there are no controlled studies on which to base an ideal time of treatment.

Prevention of post-transplantation graft infection in patients waiting for liver transplantation is attempted by having them achieve SVR and biochemical response, thus reestablishing liver function. An initial analysis was conducted in France on transplantation waiting list patients that had MELD scores above 14 points. The authors of that study showed that sofosbuvir and ribavirin were well tolerated and SVR was achieved in > 70% of the cases.7 Patients with a history of decompensations or functional Child-Pugh class B or C should not receive treatment with protease inhibitors, due to the toxicity of those antivirals. It is recommended to use only a combination of sofosbuvir plus an NS5A inhibitor.8

Patients with a MELD score > 18-20 should undergo upfront primary liver transplantation, and then be treated. Depending on the transplantation center, patients on the waiting list for more than 6 months can be treated to obtain the benefits of virus elimination.9

• •

  Treatment should be a priority in patients with any of the following conditions: HIV or HBV coinfection; pre-transplantation or post-transplantation status; clinically significant extrahepatic manifestations (symptomatic vasculitis associated with mixed HCV-related cryoglobulinemia); nephropathy due to immune complexes related to HCV and B-cell non-Hodgkin lymphoma; and debilitating fatigue (A1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

Patients coinfected with HIV and treated with DAAs have a similar response to those infected only with HCV. Therefore, the former should be treated as if they only had HCV infection, in conjunction with infectious diseases specialists.10,11

There are several management modalities and response rates are similar. The daclatasvir + sofosbuvir regimen was evaluated over a 12-week period in the ALLY-2 study on a group of patients with HIV/HCV coinfection. Some of the patients were treatment-naïve and others were treatment-experienced. The patients were stratified by HCV genotype (1/83%, 2/9%, 3/6%, 4/2%) and doses were adjusted according to the concomitant antiretroviral treatment. Ninety-seven percent of the treatment-naïve patients had SVR, as did 98% of the treatment-experienced patients.12 In the non-randomized open C-EDGE CO-INFECTION study,13 the grazoprevir/elbasvir regimen was evaluated in treatment-naïve patients infected with HCV genotypes 1, 4, or 6 and HIV with or without cirrhosis, resulting in a 96% SVR12 (in 210/218 patients). In the phase II ERADICATE14 study, the ledipasvir/sofosbuvir regimen was assessed in a small group of 50 patients with no cirrhosis. The treatment-naïve group achieved 100% SVR12 (13/13) and the treatment-experienced group had 97% SVR12 (36/37). There is not enough information for treating those patients for 8 weeks, and therefore it is not recommendable to consider short periods. In the TURQUOISE-1 study,11 the combination of paritaprevir/ritonavir/ombitasvir + dasabuvir was evaluated in treatment-naïve and treatment-experienced patients, resulting in SVR12 of 93% and 90-96%, respectively. The COSMOS study 15 produced similar results with the simeprevir/sofosbuvir regimen in patients with genotype 1b infection (92% SVR). Finally, patients with genotypes 1-4 treated with the combination of sofosbuvir/velpatasvir had 100% SVR12.16

Patients coinfected with hepatitis B tend to have a low viral load, making HCV the central focus of treatment. Nevertheless, HBV can reactivate after virus C clearance. Thus, all patients that start treatment with a DAA should have a complete HBV viral panel that includes the DNA of the virus. If the results are positive or there is evidence of occult hepatitis B, treatment should be begun with nucleoside/nucleotide analogs to prevent hepatitis B virus reactivation. Patients coinfected with hepatitis B/C should be treated with a regimen similar to that used in patients with HCV monoinfection.

Those subjects with occult hepatitis B (positive for anti-HB core antigen, but negative for HBsAg and anti-HBs) are at risk for reactivation as soon as they are in treatment for HCV. 17–19 Monitoring of ALT and AST levels is recommended every 4 weeks in patients positive for isolated anti-HB core antigen, during DAA treatment for HCV. If there is an increase > 2-fold the upper limit of normal, HBV DNA levels should be determined, and if positive, treatment for HBV should be considered. Treatment for HBV should begin before (preferably 2 to 4 weeks before) or concomitant with the start of DAA treatment for HCV. The recommended treatment for HBV is entecavir 0.5mg PO once-daily or tenofovir 300mg PO once-daily. Treatment for HBV should be continued for at least 3 weeks after completing DAA treatment for HCV. If the patient has no indication for chronic HBV treatment, treatment for HBV can be discontinued.

DAA and immunosuppressant use, including rituximab, has shown good response in patients with mixed cryoglobulinemia and HCV.20 Non-Hodgkin lymphoma can be associated with HCV and the diffuse B-cell variant is the most common. Lymphoma should be treated with the customary regimen (R-CHOP) plus rituximab. However, rituximab can increase viral replication. Isolated cases of lymphoma remission with antiviral therapy for HCV eradication have been reported.21

There is an association between HCV and immune complex-mediated kidney damage with vasculitis and focal glomerulosclerosis. Those cases should be managed with antivirals adjusted to the grade of kidney damage, in addition to rituximab, plasmapheresis, steroids, and cyclophosphamide. There is no evidence at present of a rapid response to treatment with DAAs, and as stated above, rituximab can be useful. Multidisciplinary management is recommended in such cases.

• •

  Treatment should be a priority in individuals at risk for transmitting HCV, such as: intravenous drug addicts, homosexuals with high-risk sexual practices (promiscuity, several partners, unprotected sex, sex with persons infected with HBV, herpes virus, or HIV), women trying to get pregnant, patients on hemodialysis, and prisoners (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

HCV transmission is unlikely in patients that have experienced cure. The most common risk for acquiring HCV is injection drug use. De novo HCV infection in subjects that are injection drug users (IDUs) is above 70%.22 In a meta-analysis that evaluated the results of HCV treatment (based on pegylated interferon [pegIFN]) in IDUs, 37% SVR was reported for the patients with genotype 1 or 4, and 67% with genotypes 2 or 3.23 Unfortunately, there is little information on treatment with DAAs and the exact prevalence of reinfection is unknown. Likewise, that group of patients requires a multidisciplinary approach that includes a psychiatrist, a specialized drug and alcohol abuse department, an infectious diseases specialist, and aspects of intense social work.

High-risk homosexuals are defined as those that are promiscuous, have sexual contact with several partners or with partners infected with HBV, HCV, or HIV, that engage in unprotected sex, and men with HIV infection that have sex with men.22,24 Opportune recognition and treatment of HCV infection in that special group of patients is a determining factor in the prevention of later infections, including that of acute HCV. Those patients should receive immediate treatment, as well as information on their disease, so they do not infect other sexual partners.25

Persons in prison are another special group of great epidemiologic importance due to risk for transmission and they have poor access to HCV treatment. Studies conducted in the United States show that seroprevalence varies from 30 to 60%, and of those cases, acute infection occurs in 1%.26 The use of older treatments in that group of patients is not free from side effects and most certainly antiviral therapy could change HCV incidence and reinfection rates, given that many of those patients are IDUs.

In women that wish to become pregnant, there is no possibility of maternal-fetal transmission if the mother does not present with viremia. Those patients can receive treatment before becoming pregnant, but treatment should not be given during pregnancy.

• •

  Patients with moderate fibrosis (F2) should receive treatment (A2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

It is very useful to treat patients with moderate fibrosis because it reduces liver fibrosis progression, which is one of the basic goals of HCV treatment, and thus treatment should not be delayed. Treatment improves quality of life and increases life expectancy. Noninvasive serologic tests and imaging studies provide better information on early disease-stage patients.27,28

• •

  Patients infected with HCV, with or without mild fibrosis (METAVIR F0 F1) and with no extrahepatic manifestations, should receive treatment, but the time of treatment can be individualized (B1).

Level of agreement: in complete agreement 88%.

In agreement with minor reservations: 12%.

Beginning treatment in disease stages F0 or F1 increases the SVR rate.

In the past, when patients were treated with interferon (IFN) and ribavirin, the SVR rate was influenced by fibrosis grade, and was more favorable in cases of early-stage fibrosis. Today, with the use of DAAs, that is no longer as relevant.

Patients with early-stage fibrosis documented through biopsy benefit from treatment. In a preliminary study by Jezequel et al.,29 after a 15-year follow-up, they showed greater survival in the treated patients (93%) that had SVR. Survival was lower in the patients that did not respond to treatment (82%) and in untreated patients (88%). Fibrosis progressed 15% in the patients with treatment delay.

Treatment should be individualized in patients with early-stage liver disease (compensated patients with Child A). We believe it is important to evaluate the best therapy or therapies accessible in Mexico and carefully study the group of patients that “can wait” (risk-benefit) in relation to treatment. Unfortunately, there is no solid evidence from Mexican analyses on the theme. Other studies have documented reduced mortality rates and complications, with quality of life improvements upon achieving SVR, in patients receiving treatment at early stages of fibrosis.30–32

• •

  Treatment should be individualized in patients with a limited life expectancy due to non-hepatic comorbidities (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

There are patients with a very limited life expectancy due to age or severe comorbidities with a short natural history. In those patients, treatment for HCV, as well as liver transplantation or other therapy that does not change the course of their progression, should not be recommended.33,34

• •

  The goals of treatment are to cure the hepatitis C infection, prevent cirrhosis of the liver and its decompensation, and to prevent the development of hepatocellular cancer (HCC), severe extrahepatic manifestations, and death. Treatment goals also include the prevention of disease transmission, as well as recurrence after liver transplantation (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  The goal of treatment is to achieve an undetectable level of HCV RNA through a sensitivity test (≤ 15 IU/ml) at 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion (A1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

• •

  HCV eradication reduces the decompensation rate and reduces, but does not eliminate, the risk for HCC in patients with advanced fibrosis or compensated cirrhosis. Surveillance for complications and HCC should be continued in those patients (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  HCV eradication reduces the need for transplantation in patients with decompensated cirrhosis that have a MELD score of 18-20. It is not known whether HCV eradication modifies medium-term and long-term survival in that group of patients (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  All patients with confirmed HCV infection and viral load should be treated unless there is a contraindication (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Comorbidities that influence liver disease progression should be evaluated and treated (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Liver disease stage should be evaluated before beginning treatment. It is indispensable to identify the patients with cirrhosis because its prognosis is different, and treatment must be modified (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  The grade of fibrosis must be evaluated. It can first be done through noninvasive methods. Liver biopsy should be considered when there is diagnostic doubt or suspicion of other associated causes (A1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  HCV RNA should be identified and quantified through a sensitivity test capable of detecting ≤ 15 IU/ml (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  It is essential to identify HCV genotype and subtype (1a-1b) before beginning treatment. It is a crucial factor in choosing the treatment regimen (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  The new direct-acting antivirals have made IL28B genotype testing for predicting treatment response unnecessary (A1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  Determining the baseline resistance-associated polymorphism is unnecessary in patients that have not had previous treatment with DAAs. It should only be considered in patients with treatment regimens that include elbasvir/grazoprevir or daclatasvir/asunaprevir (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Regimens based on pegIFN/RBV or pegIFN/RBV/SMV are recommended in patients with no previous treatment history, without cirrhosis or with compensated cirrhosis, and only when there is no access to IFN-free regimens with direct-acting antivirals (A1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  If there is no access to IFN-free regimens with direct-acting antivirals, regimens based on pegIFN/RBV or pegIFN/RBV/SMV are a therapeutic alternative, according to the 2015 Mexican Consensus on the Diagnosis and Management of Hepatitis C (A1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

There are different treatment options for patients with genotype 2 infection, two of which are first-line: the combination of sofosbuvir and velpatasvir (a combination not yet available in Mexico) and the combination of sofosbuvir and daclatasvir.9,46 Other treatment options can be evaluated with the following evidence:

• •

  Treatment-naïve patients with no cirrhosis or with compensated cirrhosis should receive the combination of sofosbuvir (400mg) plus daclatasvir (60mg) for 12 weeks (B2).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

Extending the 12-week combination treatment of daclatasvir plus sofosbuvir in treatment-naïve patients with compensated cirrhosis to 24 weeks has been associated with 100% SVR.67

• •

  Therapy should be extended from 16 to 24 weeks in patients with cirrhosis, especially if they are treatment-experienced (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

There are no data determining the extension of therapy that impacts SVR in patients with compensated cirrhosis, with or without previous treatment. Even though experience comes from a reduced number of patients enrolled in clinical studies on patients with cirrhosis infected with genotype 2, the data and results are in favor of extending therapy from 12 to 16 weeks.83,85

The FUSION study reported SVR above 60 to 78% when therapy was extended from 12 to 16 weeks.83 In contrast, the BALANCE study reported a higher SVR rate in patients treated only for 12 weeks (88%).84

• •

  Treatment-naïve or treatment-experienced patients with no cirrhosis or with compensated cirrhosis can be treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks with no ribavirin (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

In the ASTRAL 2 study, the 12-week regimens of sofosbuvir/velpatasvir vs sofosbuvir and ribavirin were compared, resulting in SVR of 99% vs 94%. The ASTRAL 1 study evaluated 104 treatment-naïve patients, with or without cirrhosis, observing 100% SVR.79,86

• •

  If resistance-associated variant (RAV) testing for NS5A is not performed, treatment-experienced patients with no cirrhosis, as well as treatment-naïve and treatment-experienced patients with compensated cirrhosis, should be treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks with ribavirin (1,000 or 1,200mg daily in patients < 75kg or ≥ 75kg, respectively) (A1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

• •

  If RAV testing for NS5A is performed, treatment-experienced patients with no cirrhosis, as well as treatment-naïve and treatment-experienced patients with compensated cirrhosis, with baseline detection of NS5A RAV Y93H should be treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks with ribavirin (1,000 or 1,200mg daily in patients < 75kg or ≥ 75kg, respectively). Patients with no baseline detection of NS5A RAV Y93H should receive a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks with no ribavirin (A1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  NS5A RAV testing for HCV genotype 3 can be a technical challenge, and thus a reliable result is not guaranteed in all cases (B2).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  Patients with a contraindication for ribavirin or with poor tolerance to treatment with ribavirin should receive the combination of sofosbuvir and velpatasvir for 24 weeks with no ribavirin (C1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

It was shown in the same ASTRAL-3 study that the SVR rate was higher (97%) in the group of patients that had no baseline NS5A RAVs (Y93H), compared with SVR in 88% of the patients in whom baseline NS5A RAVs were detected (present in 16% of the patients). Thus, treatment-experienced patients with no cirrhosis, as well as treatment-naïve and treatment-experienced patients with compensated cirrhosis, with detected baseline NS5A RAV Y93H, should be treated with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks plus ribavirin (1,000 or 1,200mg daily in patients < 75kg or ≥ 75kg, respectively). Patients with no baseline detection of NS5A RAV Y93H should receive the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks without ribavirin. If the patient has a contraindication for ribavirin use or does not tolerate treatment with ribavirin well, he or she should receive the combination of sofosbuvir and velpatasvir for 24 weeks with no ribavirin.86

• •

  Patients with genotype 4 infection can be treated with a combination of weekly pegIFN-α, a daily weight-based dose of ribavirin (1,000 or 1,200mg in patients < 75kg or 75kg, respectively) and simeprevir (150mg/24h) (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

That therapeutic regimen was evaluated in the RESTORE study by Moreno et al.92 It included 107 patients with genotype 4 infection, with an overall SVR of 65.4%. That combination is no longer among the most recently published recommendations of the EASL nor those in the 2016 AASLD/IDSA.9,46 In the 2015 EASL guidelines, that regimen was proposed with a B1 level of evidence.91 With the development and success of the interferon-free therapies, that combination is no longer recommended, and its use is left to the clinician's judgement, in accordance with his or her experience and with drug availability.

• •

  Simeprevir should be administered for 12 weeks in combination with pegIFN-α and ribavirin. After that, pegIFN-α and ribavirin should be administered for 12 weeks (total treatment duration of 24 weeks) in treatment-naïve patients and those with previous relapse (including patients with cirrhosis). The patients with a partial or null response, including cirrhotic patients, should have an additional 36 weeks of treatment (total treatment duration of 48 weeks) (B1).

Level of agreement: in complete agreement 77%.

In agreement with minor reservations: 23%.

In the study by Moreno et al.,92 that evaluated 107 patients, a 65.4% overall SVR was identified and in the analysis by groups there was 82.9% SVR in patients with no previous antiviral treatment, 86.4% in patients with relapse, 60% in partial responders, and 40% in previous nonresponders. In the patients with no previous antiviral treatment and those with relapse that had response-guided therapy, their SVR was 93.5% and 95%, respectively.

• •

  HCV RNA levels should be monitored during treatment. Treatment should be interrupted if the HCV RNA level is > 25 IU/ml at treatment week 4, week 12, or week 24 (A2).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

If that therapeutic regimen is prescribed,91 it is recommended to follow the initial evaluation criteria, follow-up, and suspension rules previously indicated in the 2015 Mexican Consensus on Hepatitis C.45

• •

  Patients with HCV genotype 4 infection with compensated cirrhosis should be treated with a fixed-dose combination of ombitasvir (12.5mg), paritaprevir (75mg), and ritonavir (50mg) in the same tablet (two tablets once-daily with meals) for 24 weeks with a daily weight-based dose of ribavirin (1,000 or 1,200mg in patients <75kg or 75kg, respectively), with no dasabuvir (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

Provisional results from the ongoing randomized, open, multicenter, phase III AGATE-I study94 on the treatment of genotype 4 hepatitis C with compensated cirrhosis using the combination of paritaprevir/ritonavir and ombitasvir (75/50/12.5) + ribavirin (RBV) for 12 or 16 weeks were presented this year. SVR in the individuals that received the 12-week regimen was 96% (52/54), whereas it was 100% (49/49) in those that received that regimen for 16 weeks. With respect to safety, no combination suspension due to adverse events was reported. However, there were 13 serious adverse events, none of which resulted in death.

• •

  Based on the data of patients with HCV genotype 1 infection, patients with compensated cirrhosis, including treatment-naïve and treatment-experienced patients, should receive that fixed-dose combination with a daily weight-based dose of ribavirin (1,000 or 1,200mg in patients < 75kg or 75kg, respectively) for 12 weeks (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

It is important to mention that in the study by Abergel et al.,100 in the genotype 4 cases, the patients with cirrhosis had a better relative response (10/10) than the patients with no cirrhosis (31/34). Additionally, in the studies on patients with genotype 1 with cirrhosis that were treated with the abovementioned combination (ION-2), the response was equivalent to that of the patients with no cirrhosis.70,71

• •

  Patients with compensated cirrhosis, in whom ribavirin is contraindicated or poorly tolerated, should receive a fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks with no ribavirin (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

That recommendation is based on the current focus of reducing potential toxicity attributable to ribavirin and supposing the availability of unrestricted access to treatment for 24 weeks. It is important to keep in mind that there are articles on the use of the combination of SOF-LDV plus RBV in patients with cirrhosis and genotype 4 in whom strict clinical surveillance is recommended.101

• •

  Based on data from patients with HCV genotype 1 infection, treatment with the fixed-dose combination of sofosbuvir and ledipasvir with ribavirin can be extended to 24 weeks in treatment-experienced patients with compensated cirrhosis and negative response predictors, such as a platelet count < 75 x 103/μl (B1).

Level of agreement: in complete agreement 86%.

In agreement with minor reservations: 14%.

In fact, those therapeutic regimens have been prescribed and well-tolerated, not only in patients with genotype 1 infection, but also in patients with genotype 4. However, strict clinical surveillance must always be carried out.

At present, the three treatment options for patients infected with the HCV genotypes 5 or 6 are the dose-fixed combination of sofosbuvir and daclatasvir, the dose-fixed combination of sofosbuvir and ledipasvir, and the combination of sofosbuvir and velpatasvir. In populations in which none of those options is available, the combination of pegIFN and ribavirin or the triple combination of pegIFN-α, ribavirin, and sofosbuvir continue to be acceptable.9

• •

  Patients with HCV genotype 5 or 6 infection that are treatment-naïve or that had previous treatment failure, without cirrhosis or with compensated cirrhosis, can be treated with a fixed-dose combination of sofosbuvir (400mg) and velpatasvir (100mg) in a single tablet, once-daily, with no ribavirin, for 12 weeks (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

That combination has been approved by the EASL9 and the AASLD/IDSA as an initial treatment option, with an A1 level of evidence.46 That therapeutic regimen demonstrated its efficacy in the ASTRAL-1 study that included 35 antiviral treatment-naïve patients with genotype 5 infection with or without cirrhosis of the liver. The patients received 12 weeks of the SOF/VEL combination, reaching 97% SVR, and 41 patients with genotype 6 infection had 100% SVR.79

• •

  All patients with recurrence of HCV infection after transplantation should be considered for antiviral treatment, ideally begun 3 months after liver transplantation (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

Several facts justify that recommendation: the natural history of post-transplantation HCV relapse is universal, given that graft reinfection is a dynamic process that begins with viral replication immediately after the post-transplantation anhepatic phase.105 In addition, faster progression time to fibrosis with the development of cirrhosis at 5 years has been demonstrated in 3 to 33% of post-transplantation patients.106–108 Those observations are explained through the study of the pathogenic mechanisms of accelerated damage in the graft with post-transplantation hepatitis C recurrence. It is known that the stellar liver cells are the greatest collagen producers and that the number of activated cells and TGFβ-1 expression are correlated with fibrosis stage and disease progression, with no influence from the type of immunosuppressant used.109,110 That explains the accelerated fibrosis in those patients and therefore they should be treated when there is virus C recurrence.

• •

  The clinical form of fibrosing cholestatic hepatitis, moderate-to-severe fibrosis, or portal hypertension that emerge during the course of the first post-transplantation year, predict rapid disease progression and graft loss and are indications for immediate antiviral treatment (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

Approximately 10% of the patients with post-transplantation HCV relapse develop fibrosing cholestatic hepatitis (FCH), which is characterized by severe jaundice with cholestatic liver dysfunction and a high level of viremia. From the histopathologic perspective, it is manifested by hydropic changes of hepatocytes, vacuolar degeneration, cholestasis, and periportal peritrabecular fibrosis, and a moderate inflammatory process that lead to acute liver failure and consequent loss of the graft. Thus, DAAs should be used as soon as possible.111 After treatment commencement, the laboratory values of INR, bilirubin, and albumin return to normal within a few weeks and are correlated with viral clearance at week 12. SVR in those patients has been reported at 70%, justifying the benefit of early treatment in severe manifestations of hepatitis C recurrence.112 The efficacy of the sofosbuvir and daclatasvir regimen has recently been shown in patients with post-transplantation FCH in a prospective cohort from 25 French and Belgian transplantation centers, in which 96% SVR was achieved at week 12 in 22 of the 23 study patients and the median time between transplantation and treatment commencement was 5 months.113 Regarding portal pressure, a study was conducted on 166 post-liver transplantation patients. Of the patients that had liver biopsy, the hepatic venous pressure gradient was measured to identify those cases at greater risk for post-transplantation HCV recurrence, and it was concluded that a hepatic venous pressure gradient equal to or greater than 6mmHg was a very accurate marker for identifying patients at greater risk for disease progression.114 That occurs because the established portal hypertension determines fibrosis irreversibility, with an endothelial inflammatory state and stellar cell activation, as well as the installation of fibrogenesis,115 making antiviral treatment a priority in those patients.

• •

  Patients with post-transplantation HCV recurrence should be treated with an IFN-free regimen of ribavirin for 12 or 24 weeks (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

The negative impact of hepatitis C infection on liver transplantation recipients is well known. The effect of HCV infection on patient survival and on the graft was studied in a cohort of 11,036 patients that underwent 11,791 liver transplants within the time frame of 1992 and 1998, according to the United Network for Organ Sharing (UNOS). Transplantation in HCV-positive recipients was found to increase the risk for death with an OR of 1.23 (95% CI: 1.12-1.35) and for graft failure with an OR of 1.30 (95% CI: 1.21-1.39).116 With the recently observed increase in donor age, the number of patients with severe forms of recurrence has increased, as well as the number of patients that require post-transplantation antiviral treatment.117,118 Hepatitis C recurrence causes graft loss and death, and achieving SVR with antiviral therapy improves post-transplantation survival.119 The difference between the reported SVR rates of 20 to 30% in treatment regimens with IFN and of 93 to 100% in IFN-free treatments makes the use of DAAs the best treatment option in those patients.

• •

  Post-transplantation patients with no cirrhosis or with compensated cirrhosis (Child-Pugh A) can be treated with any of the following combinations, depending on genotype: genotype 2 with sofosbuvir and ribavirin for 12 weeks (B1); genotypes 1, 4, 5, or 6 with sofosbuvir and ledipasvir or with sofosbuvir and daclatasvir for 12 weeks with ribavirin, or for 24 weeks with no ribavirin. Any genotype can be treated with sofosbuvir and daclatasvir with ribavirin for 24 weeks or sofosbuvir and velpatasvir for 12 weeks (A1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

The evidence supporting that recommendation comes from several studies. The sofosbuvir and ribavirin regimen was studied in a compassionate use program that included 104 patients with post-liver transplantation HCV relapse, in whom 57% SVR was achieved.112 The SOLAR-1 study was conducted on 233 patients with genotypes 1 to 4 and compensated cirrhosis of the liver. They were randomized to receive sofosbuvir 400mg and ledipasvir 90mg with 1,000 or 1,200mg of ribavirin, based on weight < 75kg or 75kg, respectively, for 12 or 24 weeks. SVR was achieved in 96% of the patients with compensated cirrhosis.120 In the ALLY-1 study, the combination of daily daclatasvir 60mg and sofosbuvir 400mg and ribavirin for 12 weeks was used in 53 patients with post-transplantation hepatitis C recurrence, resulting in 94% SVR.68 The daclatasvir and sofosbuvir combination in a cohort of 77 patients and daclatasvir with simeprevir in another 18 patients, both cohorts with virus C recurrence and treated for 24 weeks, were also reported on. The general SVR was 87%, and SVR was 91% with the daclatasvir and sofosbuvir combination with or without ribavirin, and 72% with the daclatasvir and simeprevir combination with or without ribavirin.121 At present, there are no reports on the safety and efficacy of the sofosbuvir and velpatasvir combination treatment regimen in liver transplantation recipients.

• •

  Post-transplantation patients with no cirrhosis or with compensated cirrhosis (Child-Pugh A) can be treated with the combination of paritaprevir potentiated by ritonavir, ombitasvir, and dasabuvir with ribavirin for 12 weeks (genotype 1b) or 24 weeks (genotype 1a with cirrhosis). In addition, the combination of paritaprevir potentiated by ritonavir and ombitasvir for 12 or 24 weeks with ribavirin can be used in patients with genotype 4 without or with cirrhosis, respectively, or with the combination of sofosbuvir and simeprevir with ribavirin for 12 weeks in genotypes 1 and 4, with the understanding that adjustments must be made in the doses of immunosuppressant drugs, and that with the combination of sofosbuvir and simeprevir, cyclosporine A must not be used (B1).

Level of agreement: In complete agreement 100%.

In agreement with minor reservations: 0%.

The combination of the so-called 3D regimen was analyzed in 34 patients that were liver transplantation recipients in the CORAL study. Patients were included that presented with no fibrosis, with moderate fibrosis, and with compensated cirrhosis in Child class A.122 Treatment was begun at one year after transplantation for 24 weeks, resulting in SVR in 33 of the 34 patients (97%). The side effects were mild, with fatigue, headache, and cough. Strict monitoring of the immunosuppressant medication was required, and the following had to be adjusted: tacrolimus was used at a dose of 0.5mg every 7 to 10 days and cyclosporine at one-fifth of the daily dose. The immunosuppressant levels were measured weekly at the discretion of the treating physician. Consequently, that regimen should only be used at specialized centers.

The combination of sofosbuvir and simeprevir with or without ribavirin for 12 or 24 weeks was evaluated in the longitudinal, real-life TARGET study. Twenty-one transplantation centers participated with a total of 151 patients, some of whom had undergone transplantation, with 88% SVR (133/151). There was a 4.81-fold increase in the simeprevir level in the patients treated with cyclosporine, and therefore the combination of simeprevir and cyclosporine is not recommended.123

• •

  Post-transplantation patients with decompensated cirrhosis (Child-Pugh B or C) can be treated with any of the following combinations: sofosbuvir and ribavirin for 12 weeks (genotype 2), with a fixed-dose of sofosbuvir/ledipasvir or sofosbuvir with daclatasvir, with ribavirin for 12 weeks (genotypes 1, 4,5, or 6), or with the combination of sofosbuvir plus daclatasvir or sofosbuvir/velpatasvir with ribavirin for 24 weeks (all genotypes). In those patients, ribavirin can be started at a daily dose of 600mg, adjusting the dose in accordance with tolerance (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

The patients with decompensated cirrhosis in the Child class B or C stages can be treated with the combination of sofosbuvir plus ribavirin, which was analyzed in a cohort of 51 patients with compensated cirrhosis or decompensated cirrhosis, with a minimum of one year since transplantation.112 They received that regimen as compassionate treatment, resulting in cirrhosis improvement in 23 patients (45%). The combination of sofosbuvir and ledipasvir in post-transplantation patients with decompensated cirrhosis showed an 86% SVR rate in the patients that had 12 weeks of treatment and an 88% rate in those with 24 weeks of treatment. The response rate in patients with Child class C was lower, with 60% SVR for the 12-week regimen and 75% for the 24-week treatment.124

The combination of daclatasvir and sofosbuvir has been analyzed in advanced cirrhosis in the so-called ALLY-1 phase III study. Forty-seven percent of the patients were associated with improvement in the Child and MELD scores, which was more evident in those with Child classes B and C. That improvement is attributable to a modest improvement in liver synthesis function, as well as in the Fibrotest, APRI, bilirubin, and ALT tests.124 There is evidence from the ASTRAL-4 study on the use of the sofosbuvir and velpatasvir combination in patients with decompensated cirrhosis. The study included all the genotypes in both naïve-treatment and experienced-treatment patients, with 3 treatment arms: SOF/VEL for 12 weeks, SOF/VEL for 24 weeks, and SOF/VEL+ RBV for 12 weeks, achieving an SVR rate of 83 to 94%.124 In those patients, ribavirin was started at a dose of 600mg per day, with later tolerance-dependent adjustments.

• •

  It is usually not necessary to adjust the dose of tacrolimus or cyclosporine with the sofosbuvir-ribavirin, sofosbuvir-ledipasvir, or sofosbuvir-daclatasvir regimens, but periodic surveillance is recommended (B2).

Level of agreement: in complete agreement 87%.

In agreement with minor reservations: 13%.

The dose of tacrolimus or cyclosporine does not require dosing adjustment with the use of sofosbuvir-ribavirin, which was demonstrated in the compassionate use program for patients with post-transplantation recurrent hepatitis C.112,124 It was also recently demonstrated in the preliminary results of the multicenter prospective study on ledipasvir/sofosbuvir with ribavirin in the treatment of post-transplantation hepatitis C virus recurrence, presented at the congress of the AASLD.120 Cyclosporine and tacrolimus increased the area under the curve 40 and 5%, respectively. However, those changes were not clinically significant. Daclatasvir did not cause significant changes of clinical importance with the calcineurin inhibitors, mTOR inhibitors, steroids, or mycophenolate mofetil,68 but periodic surveillance is nevertheless recommended.

• •

  Concomitant use of simeprevir and cyclosporine A is not recommended in liver transplantation recipients, due to the significant increase in plasma concentrations of simeprevir. No simeprevir dose modification is required with tacrolimus and sirolimus, but regular follow-up of its blood concentrations should be carried out (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

In healthy volunteers, the administration of a single dose of cyclosporine combined with simeprevir resulted in an increase in both cyclosporine and simeprevir concentration. Nevertheless, in a study on the simeprevir and daclatasvir plus ribavirin regimen, a 6-fold increase in simeprevir serum concentration was found, compared with simeprevir in the absence of cyclosporine. The interaction is thought to be caused by inhibition of the organic-anion-transporting polypeptide 1B1 (OATP1B1), glycoprotein p (P-gp), and the cytochrome P450 3A (CYP3A) by cyclosporine.123–125 In contrast, the concurrent administration of tacrolimus with simeprevir did not show notable changes in the serum concentrations.

• •

  When the combination of paritaprevir potentiated by ritonavir, ombitasvir, and dasabuvir is used, the tacrolimus dose should be adjusted to 0.5mg once-weekly, or 0.2mg every 3 days, whereas the cyclosporine A dose should be adjusted to one-fifth of the daily dose prior to HCV treatment, once-daily. Prednisone at a dose of ≤ 5mg/day is allowed, but mTOR inhibitors are not recommended (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

The use of a post-liver transplantation 3D regimen was reviewed in a multicenter study on patients with virus C recurrence that included 34 patients with F1-F2 mild fibrosis, 1 year after transplantation. Immunosuppressant drug adjustment was required in the patients that received 0.5mg of tacrolimus every 7-10 days, or 0.2mg every 3-5 days. Adjustments should be individualized, according to strict monitoring of the patient, determining tacrolimus levels every week until optimizing the dose. Said surveillance should be carried out in tertiary care centers that specialize in that type of management. In the patients that used cyclosporine, the dose was adjusted to one-fifth of the previous cyclosporine dose before virus C treatment. In addition, the use of prednisone was allowed at a dose of 5mg per day, obtaining 97% SVR (33 of 34 patients).122

• •

  HCV treatment, depending on individual patient characteristics, should be administered by health professionals with experience in HCV evaluation and treatment (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients with HCV infection should be made aware of the importance of treatment adherence to achieve SVR (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Programs for reducing injection drug use should be obligatory for persons with active parenteral drug consumption (A1).

Level of agreement: in complete agreement 88%.

In agreement with minor reservations: 12%.

• •

  Patients should be advised to abstain from alcohol ingestion during antiviral therapy. Patients with continuous alcohol consumption should receive additional support during antiviral therapy (A1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  HCV treatment can also be considered for patients with active parenteral drug use, as long as they wish to have the treatment, are capable of doing so, enroll in a rehabilitation program, and are willing to maintain their regular visits (A1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

Treatment monitoring includes the areas of follow-up, efficacy, safety, and side effects. The follow-up of treatment efficacy is based on the repeated measuring of HCV RNA levels. The decrease in HCV RNA is associated with SVR for the different treatment regimens and thus has been linked to treatment efficacy. A sensitive and specific test with a wide-ranging quantification dynamic, the same test, and the same laboratory should all be used. Test efficacy should be ensured by measuring HCV RNA levels in each patient at different points in time. At present, repeated follow-up of HCV RNA levels is recommended through real-time PCR at specific periods of time to evaluate patient treatment adherence138 with a sensitive and accurate molecular test.91 Currently, there are different types of tests with a lower limit of quantification ≤ 15 and a lower limit of detection of 10 a 15 IU/ml. A lower limit of detection < 10-15 IU/ml is considered adequate for decision-making.91–138

According to the results obtained, response-guided therapy can be carried out.91 Whether or not SVR has been achieved can be determined when those tests are performed upon treatment completion or during the later follow-up.91 In principle, all patients require HCV RNA determination before treatment commencement.138 When treatment based on pegIFN-α and ribavirin was developed, the strategy known as response-guided therapy was created to minimize drug exposure, which meant determining treatment duration based on viral load at a specific time of treatment.139 Patients with HCV treated with pegIFN + ribavirin are considered to have SVR when HCV RNA is undetectable at 24 weeks of follow-up.140 With the use of treatments that incorporate protease inhibitors in the regimens (telaprevir/boceprevir), conduct (to continue/discontinue) was able to be guided by the rapid virologic response (at 4 weeks of treatment), and therefore that evaluation has been adopted even for new drugs.138

The guidelines for pegIFN + ribavirin management recognize SVR at 24 weeks, but in the studies by Martinot-Peignoux et al.35 and Chen et al.,141 they found that carrying out an HCV RNA test at 12 weeks after treatment was as relevant as monitoring at 24 weeks, for predicting SVR and making patient management decisions. Combining that information with the findings of the ATOMIC study (SOF + pegIFN-α, ribavirin), in which the 12-week regimen was effective in genotypes 1, 4, and 6, and given the uniformity of the therapies, the response-guided regimen is not considered necessary and treatment response can be evaluated at 12 weeks.142

Essentially, all patients require HCV RNA testing before beginning treatment.138 In the QUEST-1 study, with treatment-naïve patients, 85% of the patients were candidates for shortening treatment, according to response-guided therapy, and 91% achieved SVR12. The primary aim was met in 80% of the patients, and so the HCV RNA evaluation at 12 weeks was considered important. It should be remembered that the study design shortened treatment to 24 weeks, and thus a viral load is required at that point, if treatment is response-guided.143 In the QUEST-2 study, 91% of the patients were candidates for suspending treatment at week 24, and 86% of those patients had SVR12.144 In the PROMISE study, for patients with relapse, treatment was shortened (24 weeks) in 93%, thus justifying monitoring at 12 and 24 weeks of treatment.145

The development of IFN-free therapy with high efficacy has changed the follow-up paradigm based on IFN, and so monitoring is adjusted to the consequent reduction, and depending on the response, treatment could be reduced.140 Monitoring associated with early response is maintained at week 4. The use of the 8, 12, or 24-week regimens, according to the population treated, enables HCV RNA monitoring to be adjusted to those times. However, SVR is defined by undetectable HCV RNA at 12 weeks after therapy completion. Those intervals have been accepted as goals in the United States and in Europe.91,146 Consequentially, that monitoring scheme only applies to treatments with INF, because there is no evidence on the effect of treatment with IFN-free DAA-based regimens on viral load for defining treatment duration or its interruption.

The findings of the QUEST-1 and QUEST-2 studies were commented on above, but it is important to remember the designs of those studies and the virologic rules utilized for discontinuing treatment. In those cases, simeprevir or placebo were discontinued if HCV RNA was > 1,000 IU/ml at week 4 and treatment was continued with pegIFN and RBV. In that scenario, in the QUEST-1 study,143 9% of the patients had lack of response and was associated with a mutation in NS3 (R155K / D168V) at the time of the evaluation in 92% of the patients. In the QUEST-2 study, 7% had treatment failure, and if the rule for failure is applied, it occurred in 4% of the patients treated with simeprevir.144

At present, the rules for treatment suspension have only been defined in relation to the triple combination of pegIFN-α, ribavirin, and simeprevir, and so the consensus recommends the suspension of that treatment if HCV RNA levels are equal to or greater than 25 IU/ml at week 4, 12, or 24 from treatment commencement. Those are the time intervals at which treatment monitoring of the viral load should be performed.91

Suspension rules have not been defined for the new direct-acting drugs. Therefore, treatment with those new drugs should not be suspended if the viral load is detectable during treatment and the null response definition is considered at treatment completion.

• •

  To determine HCV RNA levels during and after therapy, a real-time PCR test should be used with a lower limit of detection ≤ 15 IU/ml (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  HCV RNA should be measured at treatment commencement and at weeks 4 and 12 after therapy completion, in patients treated with the triple combination of pegIFN-α, ribavirin, and sofosbuvir for 12 weeks (A2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  RNA should be measured at the baseline and at treatment weeks 4, 12, and 24, in patients treated with the triple combination of pegIFN-α, ribavirin, and simeprevir that were treatment-naïve or had relapse (A2).

Level of agreement: in complete agreement 87%.

In agreement with minor reservations: 13%.

• •

  HCV RNA should be measured at treatment commencement, at week 4, at treatment completion, and at 12 weeks after treatment completion, in patients treated with an IFN-free regimen (A2).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  If the HCV RNA level is ≥ 25 IU/ml at treatment week 4 and detectable at treatment week 12 or 24 in patients receiving the triple combination of pegIFN-α, ribavirin, and simeprevir, treatment should be interrupted (A2).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

Current treatment regimens with DAAs offer SVR rates above 90% in the majority of patients, regardless of genotype and fibrosis grade. However, despite the success of those treatments, some patients do not respond. That small group of patients should be carefully evaluated, given that at present, studies and retreatment options are limited and it is important to know how to act (Table 6).

With regard to patients that are nonresponders to dual therapy with pegIFN plus ribavirin, different studies63,71,91 indicate that SVR is high and similar to that achieved in treatment-naïve patients with the new IFN-free DAA regimens. Thus, those patients should be treated as if they were treatment-naïve, in accordance with the recommendations of the present consensus regarding genotype, subtype, and fibrosis stage.

The patients with HCV genotype 1 infection that received the triple regimen of pegIFN, ribavirin, plus a protease inhibitor (PI) (telaprevir, boceprevir, simeprevir), and did not have SVR, can be retreated with sofosbuvir and an NS5A inhibitor.

The sofosbuvir/ledipasvir combination has been evaluated in the retreatment of patients that are nonresponders to the triple therapy, obtaining a high SVR rate. In the ION-2 study, the patients with no cirrhosis that received treatment with that combination for 12 weeks, with or without ribavirin, achieved 100 and 96% SVR, respectively. Another group received the same regimen for 24 weeks, with or without ribavirin, and also achieved 100 and 96% SVR, respectively.71 In the same study, the patients with cirrhosis received the same regimen for 12 weeks, with or without ribavirin, and SVR was 85 and 86%, respectively. In addition, it increased to 100%, with or without ribavirin, when treatment was extended to 24 weeks. In the SIRIUS study, a large number of patients with cirrhosis that did not respond to triple therapy were evaluated with the 12-week sofosbuvir/ledipasvir combination with ribavirin vs 24 weeks with no ribavirin, achieving 96 and 97% SVR, respectively.147 Based on those studies, the 2016 EASL91 treatment guidelines recommend giving that treatment regimen for 12 weeks with ribavirin in all patients (with and without cirrhosis), unlike the AASLD treatment guidelines46 that recommend various options: 12 weeks with no ribavirin in patients with no cirrhosis; and 12 weeks with ribavirin or 24 weeks with no ribavirin in patients with cirrhosis.

The ASTRAL-1 study evaluated the 12-week sofosbuvir/velpatasvir combination with no ribavirin in patients with and without cirrhosis with genotype 1, 2, 4, 5, or 6 that were treatment-naïve and treatment-experienced with triple therapy with a PI. The overall SVR rate obtained was 99%, and 100% SVR was achieved in the group of treatment-experienced patients with genotype 1.79

In patients with no cirrhosis that were nonresponders to triple therapy, the sofosbuvir/daclatasvir combination for 24 weeks, with or without ribavirin, achieved SVR rates of 100 and 95%, respectively.67

The newest DAA combination, elbasvir/grazoprevir, recently approved by the FDA and the EMA, and now available in Mexico, has been studied in patients that were nonresponders to the triple therapy of pegIFN/ribavirin plus a PI. SVR > 95% was achieved with that DAA combination for 12 weeks plus ribavirin.148

The resistance of HCV to DAAs can play an important role in patients with IFN-free DAA treatment failure. The presence of resistance-associated variants (RAVs) that are resistant to NS5A inhibitors is associated with a lower virologic cure rate in certain groups of patients, such as those with genotype 1a or 3 and with cirrhosis. The viruses that are resistant to the protease inhibitors and the viruses that are resistant to the non-nucleoside polymerase inhibitors progressively decrease until becoming undetectable in a few months or up to 2 years after treatment interruption. In contrast, the viruses that are resistant to NS5A inhibitors can remain detectable for many years.149

Despite the knowledge of the existence of RAVs, ordering resistance tests for making retreatment decisions is not indicated.2

The patients that have treatment failure with the IFN-free DAA regimens, with any genotype, should be treated with another IFN-free combination that includes drugs with a high barrier to resistance, plus one or two medicines that have no crossed-resistance with the drugs used.

Sofosbuvir is a DAA that has a high barrier to resistance. RAVs are exceptionally selected, and if present, they rapidly disappear upon treatment completion. Therefore, the current retreatment strategies should include sofosbuvir.

That group of patients should be retreated with a pegIFN-free regimen for 12 weeks plus weight-based ribavirin in cases of patients with little or no fibrosis (F0-F1). Extending treatment to 24 months can be considered, especially in patients with advanced liver disease (F3-F4) or that do not tolerate ribavirin.

Patients that had treatment failure with sofosbuvir alone, or sofosbuvir plus ribavirin, or sofosbuvir plus pegIFN-α and ribavirin, can be retreated with the combination of sofosbuvir plus simeprevir (genotype 1 or 4), sofosbuvir plus daclatasvir (all genotypes), or sofosbuvir plus ledipasvir (genotypes 1, 4, 5, or 6), with paritaprevir potentiated by ritonavir, ombitasvir, and dasabuvir (genotype 1), or with paritaprevir potentiated by ritonavir and ombitasvir (genotype 4).

Patients with genotype 1 and 4 that had treatment failure with a regimen that combined pegIFN-α, ribavirin, and simeprevir should be retreated with a combination of sofosbuvir with daclatasvir or ledipasvir. Patients with treatment failure that received a regimen combining pegIFN-α, ribavirin, and daclatasvir should be retreated with a sofosbuvir and simeprevir combination (genotype 1 and 4). Patients infected with genotype 1 or 4, that had treatment failure with a regimen that contained sofosbuvir and simeprevir, should be retreated with a combination of sofosbuvir with daclatasvir or ledipasvir, whereas patients that had treatment failure with a regimen that contained sofosbuvir and daclatasvir or ledipasvir should be retreated with a sofosbuvir and simeprevir combination (genotype 1 and 4).

A group of patients with genotype 1 that had treatment failures with sofosbuvir was retreated by Hezode et al.150 with a sofosbuvir/ledipasvir regimen plus ribavirin for 12 weeks, obtaining 98% SVR (50/51). In another study, 15 patients that did not achieve SVR after treatment that contained an NS5A inhibitor were retreated with sofosbuvir and simeprevir with no ribavirin for 12 weeks, achieving SVR12 in 8/10 patients with genotype 1a, 3/3 patients with genotype 1b, and 2/2 patients with genotype 4.151 Ten patients with F3 fibrosis or compensated cirrhosis that did not achieve SVR after an IFN-free regimen, were retreated with the triple combination of sofosbuvir, simeprevir, and daclatasvir with ribavirin for 24 weeks. Six of those patients achieved SVR12.152

In a study that utilized the combination of sofosbuvir and velpatasvir for 4 to 12 weeks, the patients that did not achieve SVR were retreated with the same combination with ribavirin for 24 weeks, achieving 97% SVR12 (33/34) in the patients infected with genotype 1, 91% (13/14) in the patients infected with genotype 2, and 76% (13/17) in the patients infected with genotype 3.153

In the QUARTZ-1 study, 20 patients with genotype 1 were included that had virologic failure to the previous DAA treatment. They were treated with a combination of sofosbuvir, paritaprevir potentiated by ritonavir, ombitasvir, and dasabuvir for 12 or 24 weeks, with or without ribavirin. SVR12 was achieved in 13/14 patients with genotype 1a with no cirrhosis treated for 12 weeks with ribavirin, in 6/6 patients infected with genotype 1a with cirrhosis treated for 24 weeks with ribavirin, and in 2/2 patients infected with genotype 1b treated for 12 weeks without ribavirin.154

In the C-SWIFT retreatment study, patients infected with genotype 1 were treated for 4, 6, or 8 weeks with the combination of sofosbuvir, grazoprevir, and elbasvir with no ribavirin. Another group was retreated with the same drug combination plus ribavirin for 12 weeks and all patients (23/23) achieved SVR.46

At present, there are few studies that support the recommendations for retreatment of therapeutic failures with DAA regimens without pegIFN, and they include a small number of patients. Those recommendations are based on scant evidence and are subject to changes when data become available. Specific algorithms to guide retreatment decisions cannot be derived from those observations. Therefore, retreatment should be based on knowledge of the drugs that are administered (Table 1).

Patients that have treatment failure with an IFN-free regimen, but do not require urgent retreatment (F0-F2), can wait until more data and/or alternative retreatment therapeutic options become available.

• •

  Patients that do not respond to the combination treatment of pegIFN and ribavirin should be considered treatment-experienced and treated with new direct-acting antivirals, according to genotype and fibrosis stage (A1).

Level of agreement: in complete agreement 90%.

In agreement with minor reservations: 10%.

• •

  Patients with HCV genotype 1 infection that had triple combination treatment failure with pegIFN, ribavirin, and telaprevir or boceprevir or simeprevir should be retreated with an INF-free combination based on sofosbuvir/velpatasvir, sofosbuvir/ledipasvir, grazoprevir/elbasvir, or sofosbuvir/daclatasvir for 12 weeks, with or without ribavirin (A1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  The retreatment recommendations after a second direct-acting antiviral (DAA) regimen are based on indirect evidence and subject to changes, as more information becomes available (A2).

Level of agreement: in complete agreement 88%.

In agreement with minor reservations: 12%.

• •

  Patients that have treatment failure with a DAA regimen, with or without pegIFN and with or without ribavirin, should be retreated with a pegIFN-free regimen for 12 weeks, plus a weight-adjusted dose of ribavirin (F0-F2). Treatment can be extended to 24 weeks, especially in patients with advanced liver disease (F3-F4) (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

• •

  Patients that have treatment failure with sofosbuvir alone, or combined with ribavirin or pegIFN and ribavirin, can be retreated with a combination of sofosbuvir and simeprevir (genotype 1 or 4), sofosbuvir and daclatasvir (all genotypes), sofosbuvir and ledipasvir (genotypes 1, 4, 5, or 6), or ritonavir + paritaprevir, ombitasvir, and dasabuvir (genotype 1), or with ritonavir + paritaprevir and ombitasvir (genotype 4), or grazoprevir/elbasvir (genotypes 1 and 4) (B2).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  Patients with HCV genotype 1 or 4 infection that had treatment failure with the combination of pegIFN, ribavirin, and simeprevir should be retreated with a combination of sofosbuvir with daclatasvir or ledipasvir or velpatasvir (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Patients with genotype 1 infection that have failure with a regimen containing an NS5A inhibitor (ledipasvir, velpatasvir, ombitasvir, elbasvir, or daclatasvir) can receive sofosbuvir plus ritonavir plus paritaprevir, ombitasvir, and dasabuvir; sofosbuvir plus grazoprevir plus elbasvir; or sofosbuvir plus daclatasvir plus simeprevir, all with ribavirin, for 12 or 24 weeks, depending on genotype 1a/1b or the grade of fibrosis (B1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  Patients with genotype 4 infection that have treatment failure with a regimen containing an NS5A inhibitor (ledipasvir, velpatasvir, ombitasvir, elbasvir, or daclatasvir) can receive sofosbuvir plus ritonavir + paritaprevir, ombitasvir, and dasabuvir; sofosbuvir plus grazoprevir plus elbasvir; or sofosbuvir plus daclatasvir plus simeprevir, all with ribavirin, for 12 or 24 weeks, depending on the grade of fibrosis (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  All patients with no urgent need for retreatment (F0-F2), regardless of genotype, can wait until there are better treatment options (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  The safety and efficacy of a triple regimen of sofosbuvir, an NS3 inhibitor, and an NS5A protease inhibitor in patients that had failed treatment with a DAA regimen are not known (B2).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  The usefulness of HCV resistance testing prior to retreatment in patients that had treatment failure with any regimen containing DAAs is not known (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Serum ALT and HCV RNA measurements 48 weeks after treatment completion are recommended in patients with F0 and F2 with SVR. If ALT is normal and HCV RNA is undetectable then the patient can be discharged as cured (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Surveillance for the appearance of hepatocellular carcinoma should be continued every 6 months through ultrasound imaging in patients that have cirrhosis or grade 3 fibrosis and SVR (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Patients that present with cirrhosis and SVR should have endoscopic follow-up for portal hypertension and varices in accordance with international guidelines (A2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Risk for reinfection should be explained to persons with high-risk behavior to positively modify that situation (B1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  After achieving SVR, persons at high risk for possible HCV reinfection should have follow-up through annual HCV RNA evaluation (B2).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Coinfected patients should be treated with the same regimens and following the same rules as patients with HCV monoinfection (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  If significant levels of HBV are replicated before, during, or after HCV clearance, concomitant therapy with nucleoside or nucleotide analogs should be indicated (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  IFN-free regimens should be used in the treatment of lymphoma associated with HCV, even though the effect of SVR on overall outcome is not yet known. Further study is needed on the effect of the new antiviral therapies, together with B-cell depletion, and a multidisciplinary approach with strict liver function monitoring is required in those patients (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Mixed cryoglobulinemia and kidney disease associated with chronic HCV infection should be treated (requiring multidisciplinary management). The role of rituximab in HCV-related kidney disease must be analyzed. HCV replication inhibition and SVR should be correlated with kidney lesion response and cryoglobulinemia. Strict monitoring of adverse effects is essential (B1).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  All patients undergoing renal replacement therapy are candidates for antiviral therapy (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients undergoing renal replacement therapy should receive an IFN-free regimen that is also ribavirin-free, if possible, for 12 weeks in patients with no cirrhosis and 24 weeks in patients with cirrhosis. If ribavirin is opted for, low doses are recommended (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  The recommended regimens in patients with genotype 1 infection with a low glomerular filtration rate (GFR < 30ml/min) are the combination of paritaprevir/ritonavir/ombitasvir plus dasabuvir, as well as grazoprevir/elbasvir. In patients with genotype 3, sofosbuvir plus daclatasvir or sofosbuvir/velpatasvir can be indicated, under strict surveillance (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  HCV treatment before kidney transplantation can prevent mortality related to a hepatic cause and prevent kidney graft dysfunction. Those patients should receive IFN-free treatment that is also ribavirin-free, if possible, for 12 weeks in patients with no cirrhosis and for 24 weeks in patients with compensated cirrhosis (Child-Pugh A), following the abovementioned recommendations. The use of those medications must be accompanied by strict surveillance (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  In non-liver solid organ transplantation recipients, patients indicated for antiviral therapy should receive an IFN-free regimen, following the recommendations described above, with adequate surveillance of pharmacologic interactions with immunosuppressants (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients with decompensated cirrhosis (Child-Pugh B and C, up to 12 points) that are not on the liver transplant waiting list and have no concomitant comorbidities that could affect their survival should receive immediate treatment with any of the following regimens: sofosbuvir and ribavirin for 16 to 20 weeks (genotype 2), a fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5, and 6), or the combination of sofosbuvir and daclatasvir or sofosbuvir/velpatasvir (all genotypes) with a weight-based ribavirin dose, for 12 weeks (B1).

Level of agreement: in complete agreement 86%.

In agreement with minor reservations: 14%.

• •

  Patients with decompensated cirrhosis, in whom ribavirin is contraindicated or poorly tolerated, should receive the combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5, or 6), or the combination of sofosbuvir and daclatasvir, or sofosbuvir/velpatasvir (all genotypes) for 24 weeks, with no ribavirin (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients that underwent resection or ablation due to HCV-associated HCC should receive adequate antiviral treatment for their liver disease, in accordance with the previously mentioned recommendations (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  HCV in patients on the liver transplant waiting list should be treated if the waiting period exceeds 6 months, to prevent post-transplantation recurrence (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Treatment should be started as soon as possible, so it can be completed before transplantation and the effect of elimination of the virus (SVR) on liver function can be evaluated. Liver function could significantly improve, resulting in the patient's removal from the waiting list (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients waiting for a liver transplant should be treated with an IFN-free regimen, and the addition of ribavirin, for 12 or 24 weeks, or alternatively, after the transplantation (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients with conserved liver function (Child-Pugh A) that are indicated for transplantation due to HCC can be treated with the combination of sofosbuvir and ribavirin for 16-20 weeks (genotype 2); the fixed-dose combination of sofosbuvir/ledipasvir with ribavirin for 12 weeks (genotypes 1, 4, 5, or 6); the combination of paritaprevir potentiated by ritonavir, ombitasvir, and dasabuvir, with ribavirin, for 12 weeks (genotype 1b) or 24 weeks (genotype 1a); the combination of paritaprevir potentiated by ritonavir and ombitasvir, with ribavirin, for 12 weeks (genotype 4); the combination of sofosbuvir and simeprevir, with ribavirin, for 12 weeks (genotypes 1 and 4); or with the combination of sofosbuvir and daclatasvir or sofosbuvir/velpatasvir, with ribavirin, for 24 weeks (all genotypes) (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Treatment with pegIFN-α, ribavirin, and sofosbuvir for 12 weeks is acceptable in patients with compensated cirrhosis (Child-Pugh A) that are waiting for a liver transplant, if the IFN-free combinations are not available. However, it should be specified that there is less efficacy and a lower safety profile in that patient population (B2).

Level of agreement: in complete agreement 92%.

In agreement with minor reservations: 8%.

• •

  Patients with decompensated cirrhosis (Child-Pugh B or C) that are waiting for a liver transplant can be treated with the combination of sofosbuvir and ribavirin for 16-20 weeks (genotype 2); with the fixed-dose combination of sofosbuvir and ledipasvir, with ribavirin, for 12 weeks (genotypes 1, 4, 5, or 6); or with the combination of sofosbuvir and daclatasvir or sofosbuvir/velpatasvir, with ribavirin, for 24 weeks (all genotypes). However, there are limited data on patients with cirrhosis that have Child-Pugh C > 12 points or a MELD score > 20 (A1).

Level of agreement: in complete agreement 78%.

In agreement with minor reservations: 22%.

• •

  The ideal time for treating patients before or after transplantation continues to be a subject of debate and requires individual evaluation (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Considering the limited treatment safety data available in relation to patients with decompensated cirrhosis that are on the waiting list for a liver transplant, their evaluation and management should be carried out at a medical center with a transplantation program (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  In patients with decompensated cirrhosis, ribavirin can be started at a dose of 600mg daily, with later tolerance-related dosing adjustments (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Patients in whom ribavirin is contraindicated or poorly tolerated during treatment, should receive the fixed-dose combination of sofosbuvir and ledipasvir (genotypes 1, 4, 5, or 6); the fixed-dose combination of sofosbuvir and velpatasvir (all genotypes); or the combination of sofosbuvir and daclatasvir (all genotypes) for 24 weeks, with no ribavirin (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

There is a high prevalence of chronic hepatitis C virus infection in the population of subjects with injection drug addiction and it is the main known risk factor for that infection in some countries. An example is the cohort from the United Kingdom in which 90% of HCV infections were due to injection drug use.203 Mexico is no exception. In a study conducted in the cities of Tijuana and Juárez, where the prevalence of injection drug addicts is high, it was found that 85% of the addicts had HCV infection after 2 years of injection drug use and 100% of the study subjects with more than 6 years of addiction were infected with hepatitis C.204

Given the high prevalence of hepatitis C virus infection in that population, it is important to include harm reduction programs to reduce infection transmission.205 Such programs include needle and syringe provision, through which a reduction in new infections has been demonstrated.206 However, it is important for Public Safety policies or programs to be linked to those of the Public Health Sector, otherwise harm reduction programs, such as those of needle and syringe provision, will not work and can become deleterious factors. That was demonstrated in a study conducted in Tijuana and Juárez, in which public safety policies became a deleterious factor in the sterile needle and syringe provision program. Despite the fact that it is not illegal to buy or carry syringes, it was common for drug users carrying syringes to be arrested, favoring consequent needle sharing with other drug users.207

Injection drug users should be counselled to moderate marijuana consumption or abstain from it if there is evidence of liver disease. Its use has been clearly shown to promote the progression of inflammation, fibrosis, and liver steatosis. In addition, it is considered an independent fibrosis progression factor in hepatitis C.208,209 Research studies have shown that inhibition of cannabinoid CB1 receptors in the liver reduces fibrosis progression.210,211

Numerous studies have shown that alcohol consumption in persons with hepatitis C results in greater liver damage and more rapid disease progression.212–214 Thus it is essential to counsel injection drug users, as well as the rest of the population with hepatitis C infection, to moderate or abstain from alcohol consumption if there is evidence of liver damage.

Abstinence from alcohol is extremely important for maintaining or prolonging liver health. Studies on injection drug users with hepatitis C and alcohol consumption have demonstrated liver function benefit in the patients that were able to abstain from alcohol consumption.215

Injection drug users face more barriers to having access to treatment, compared with other persons,216,217 and for a long time, patients with active addiction to injection drugs were excluded from treatment. However, there is no information in the literature or evidence of greater risk for virologic failure in the population with a history of injection drug use or with active injection drug use. Studies on populations with chronic hepatitis C virus infection secondary to injection drug use have shown that it is not a risk factor for virologic failure. In fact, studies from the era of interferon and ribavirin showed 95% SVR (100% for genotype 3 and 86% for genotype 1), which was most likely associated with a lower fibrosis grade and younger study populations.218 Studies on addict populations have shown a similar response to that of the non-addict population. A study on a Swiss cohort included patients with active addiction, compared with controls (199 addicts and 301 controls), and results were similar in the two groups.219 Therefore, today, active injection drug addiction is not considered a contraindication for treatment and the decision to treat or not to treat should be an individualized one.

Patients with active addiction behave the same as those with a history of injection drug addiction and those in a replacement program, with similar SVR. However, greater patient loss was demonstrated in the subjects that received replacement therapy and IFN, due to side effects (36%) and abandonment (46%).220 Therefore, injection drug users undergoing opioid replacement therapy should receive an IFN-free regimen.

Considering that hepatitis C virus infection prevalence and incidence are high in injection drug addicts, counselling that includes risk factors for infection and reinfection, disease progression, treatment regimens, and potential harm-reducing strategies is essential. Studies have shown that the addict population faces many barriers that promote poor adherence to treatment and treatment failure. Other factors associated with the chaotic lifestyle can also result in a poor perception of medical treatment, creating obstacles to communication that favor inferior treatment adherence and abandonment due to inadequate doctor-patient communication. Practical strategies in treating injection drug users involve multidisciplinary management, adequate adverse effect management, education, and counselling.221 In addition, it is necessary to include programs dedicated to the pharmacologic management of addiction or to needle and syringe provision to prevent reinfection.222

Subjects with injection drug addictions are a high-risk group for infection with and an elevated prevalence of hepatitis C. That population group also faces the greatest barrier to having access to treatment and clinical research trials. There is evidence, albeit scant, that the therapeutic response to the new direct acting antivirals is similar to that of the pegIFN and ribavirin regimens in injection drug users, when compared with the general population, with the only difference being better treatment adherence. Nevertheless, the studies have small samples and no statistical power for generalizing or extrapolating their results, thus more research on the injection drug-using population is needed. 218,223

The current most common indication for liver transplantation is liver disease due to hepatitis C virus infection and one of the main risk factors for that infection is injection drug use. Comparative population group studies have shown that persons with a past history of injection drug use that required liver transplantation due to cirrhosis of the liver did not have substance use relapse. The retransplantation risk was the same as that in the rest of the population, with similar post-transplantation progression to fibrosis, and patient and graft survival. Therefore, a history of drug addiction should not be an exclusion criterion and transplantation should be considered a therapeutic option in that population.224

There are liver transplantation centers in which, out of fear of or as a precautionary measure against addiction relapse and consequent failure of the liver transplant, one of the pre-transplantation requisites is that subjects are not actively using methadone or receiving another opioid replacement therapy. However, a review conducted by researchers at the Mount Sinai Medical Center included 36 subjects using methadone at the time of liver transplantation and found that only one of the patients had drug use relapse, and graft survival was similar to that of the national average. Based on those data, there is no contraindication for transplantation in patients with active methadone use.225

In another 4-year case series that included 33 patients with liver transplantation and stable methadone use, 4 patients (11%) had heroin use relapse. However, that did not affect survival or graft complications, thus permitting the recommendation that, until there is evidence to the contrary, the stable use of methadone should not be a contraindication for liver transplantation.226

• •

  Anti-HCV antibody determination should be carried out in active injection drug users (IDUs), and if negative, repeated every 6-12 months (A1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  IDUs should receive sterile injection material and have access to opioid replacement therapy as part of the integrated harm reduction programs, even in prisons (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  All patients should be offered pre-treatment education and counseling that includes: HCV transmission routes, risk factors for fibrosis progression, treatment regimens, risk for reinfection, and potential strategies for harm reduction (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  IDUs should be counseled to abstain from alcohol consumption (A1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  IDUs should be counseled to abstain from marijuana consumption (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  HCV treatment should be considered in an individualized manner for IDUs and administered by a multidisciplinary team (A1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  A history of injection drug use and recent drug use at the start of treatment are not associated with reduced SVR and the decision to treat or not to treat should be made in an individualized manner (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Drug and alcohol users or other patients with social problems and/or a history of psychiatric disease, and those that consume drugs during treatment, are at risk for lower treatment adherence and less probability of achieving SVR. Thus, they should be closely supervised during treatment and receive multidisciplinary support (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  An evaluation of the safety and efficacy of the new antiviral regimens in IDUs is necessary (C1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

• •

  IDUs undergoing opioid replacement therapy should receive an IFN-free regimen (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Antiviral regimens for IDUs are the same as those for the rest of the infected population. Dosing adjustments for methadone or buprenorphine are not necessary, but signs of toxicity or opioid withdrawal should be monitored. More data on the regimens that include daclatasvir are needed in that group of patients (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  If indicated, liver transplantation should be considered as a therapeutic option in patients with a history of injection drug use (B1).

Level of agreement: in complete agreement 91%.

In agreement with minor reservations: 9%.

• •

  Opioid replacement therapy is not a contraindication for liver transplantation and does not need to be adjusted (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  Indications for HCV therapy are the same in patients with or without hemoglobinopathies (A1).

Level of agreement: in complete agreement 95%.

In agreement with minor reservations: 5%.

• •

  Patients with hemoglobinopathies should be treated with an IFN-free regimen, with no ribavirin (B1).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.

• •

  Antiviral regimens are the same in patients with or without hemoglobinopathies (B1).

Level of agreement: in complete agreement 96%.

In agreement with minor reservations: 4%.

• •

  When ribavirin use is indispensable, close surveillance is recommended (B2).

Level of agreement: in complete agreement 100%.

In agreement with minor reservations: 0%.