Continued improvements in combination antiretroviral therapy (ART) have resulted in sustained gains in projected life expectancy for HIV-infected individuals [
Grading system for recommendations.
Classification description | |
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Class of evidence | |
Class 1 | Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective |
Class 2 | Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment |
Class 2a | Weight of evidence/opinion is in favour of usefulness/efficacy |
Class 2b | Usefulness/efficacy is less well established by evidence/opinion |
Class 3 | Conditions for which there is evidence and/or general agreement that a diagnostic evaluation and procedure/treatment is not useful/effective and in some cases may be harmful |
|
|
Grade of evidence | |
Level A | Data derived from multiple randomized clinical trials or meta-analyses |
Level B | Data derived from a single randomized trial or nonrandomized studies |
Level C | Only consensus opinions of experts, case studies, or standard-of-care |
Adapted from [
In the three decades since HIV was identified, tremendous progress has been made in its treatment. Once universally fatal, characterized by AIDS-related opportunistic infections and malignancies, HIV infection now has been rendered a manageable chronic condition in developed countries through effective combination therapies [
HCV infection is recognized as one of the fastest growing health problems facing both developed industrialised countries and developing regions with an estimated 170 million persons [
Aboriginals, women, and youth who injected drugs are at particular risk for HIV and HCV infection [
Another important population at risk is persons incarcerated in correctional facilities. The elevated prevalence of HIV and HCV infections amongst inmates has been closely linked to IDU and the sharing of injection equipment. Reports have shown that 30%–50% of Canadian inmates have a history of IDU. Overall, 24% of Federal and 23% of provincial prisoners were HCV positive in 2011 [
Acquisition of HCV often occurs rapidly following initiation of injection drug use, either from the needle itself or the injecting paraphernalia [
Given the risk of HCV morbidity and the high costs of treating HCV amongst PWID (see economic impact below), evidence-based harm reduction strategies should be implemented for all populations at risk [
Counselling regarding risk of acquiring HIV in HCV monoinfected individuals should be undertaken at time of original diagnosis, as subsequent HIV infection may occur if risk behaviours continue [
Sexual transmission of HCV amongst heterosexuals is rare, estimated at 1 in 190,000 episodes of intercourse [
Historically, the most important predictor of treatment response has been HCV genotype, with more favourable responses to pegylated interferon and ribavirin seen amongst genotypes 2 and 3 and lower response rates in genotypes 1 and 4. In Canada, 62% of HCV infections are of genotype 1. Amongst PWID genotypes 1 and 3 are most common. Genotype 2a is more frequent in patients previously exposed to multiple injections, surgery, or transfusions, and genotype 4 more common in African immigrants while genotype 6 is seen more commonly in immigrants from Asia. Some recent global outbreaks of HCV amongst HIV+ MSM have been attributed to genotype 4 infections [
In HCV monoinfection without concurrent excess alcohol consumption, a minimum of 20–30 years is typically required for HCV to cause significant liver disease such as cirrhosis or hepatocellular carcinoma (HCC) [
A recent study of 435 liver biopsy pairs from a prospective cohort of 282 coinfected individuals without cirrhosis suggests that many have rapid and progressive fibrosis [
In a large prospective cohort of 638 adults coinfected with HIV and HCV who received a baseline liver biopsy, hepatic fibrosis stage was independently associated with a composite outcome that included end-stage liver disease (ESLD), hepatocellular carcinoma, and death [
The rapid progression of liver fibrosis seen in coinfected individuals drives high rates of liver-related mortality observed worldwide in developed countries in the post-ART era. A Euro-SIDA analysis found that liver-related death accounted for 21.6% of deaths in a cohort of 3941 HCV antibody positive HIV patients [
Coinfected individuals are more likely to develop HCC at a young age in comparison to monoinfected individuals. In a retrospective study of 63 coinfected individuals with hepatocellular carcinoma, HIV-positive individuals were younger and developed HCC more quickly than HIV-negative controls [
In the Ontario Burden of Infectious Disease Study, HCV had the highest burden of disease as measured by years of life lost due to premature mortality and year-equivalents of reduced functioning, outranking all other infectious pathogens including HIV and
All HIV+ persons should undergo screening for HCV antibodies when first evaluated. Screening should be repeated periodically at least annually, particularly for high risk individuals found to be initially negative (such as active injection drug users, Aboriginal peoples living in poverty or in marginalized circumstances, and persons who are/have been incarcerated) (Class 1, Level C). HIV+ MSM should undergo screening for HCV antibodies annually in combination with liver enzymes every 6 months if sexually active with high risk behaviours, and repeat HCV antibody (with consideration of additional HCV RNA testing) should be performed whenever unexplained elevations in liver enzymes are noted (Class 2a, Level C). Screening for HCV in HIV-infected individuals provides opportunities for prevention of transmission, risk-reduction, counselling, and linkage to care and harm reduction services (Class 1, Level C).
The management of HIV infection in coinfection requires consideration of a number of factors: Effect of antiretroviral therapy on the natural history of liver disease. Timing of initiation of antiretroviral therapy. Risk of hepatotoxicity when antiretroviral therapy is initiated. Potential for drug-drug interactions when undertaking HCV therapy. Adherence to ART and HCV therapy, particularly in those with active addictions concerns.
Coinfected individuals experience faster progression of HCV disease, with higher risk of ESLD, particularly when both HIV and HCV remain untreated [
Initiation of ART has also been shown to reduce liver-related mortality in coinfected patients. In a cohort of 285 coinfected patients initiating either limited antiretroviral therapy (
These data have been incorporated into current IAS-USA and US Department of Health and Human Services (DHHS), European and British treatment guidelines for HIV-infected individuals, where underlying hepatitis C coinfection is recognized as further justification to initiate ART irrespective of CD4 cell count [
In certain circumstances with CD4 cell counts >500 cells/
Hepatotoxicity is usually defined using the AIDS Clinical Trial Group (ACTG) grading system with grade 3 (ALT elevations greater than five times the upper limit of normal (ULN) range in individuals with normal values at baseline) considered a standard for more severe disease. Some experts have proposed an additional classification with grade 3 elevation considered as >3.5 × ULN when baseline values were abnormal [
Tolerability of current first and second line NNRTI, PI, and integrase inhibitor agents in coinfected patients has been assessed in post hoc analysis of phases II and III randomized clinical trials including newer agents such as raltegravir [
Risk of antiretroviral-related hepatotoxicity has been associated with degree of underlying liver fibrosis. In a prospective study of 107 patients with biopsy-confirmed fibrosis ranging from F0 to F4, the overall incidence of hepatotoxicity was 5.1 events/100 person-years. However the incidence amongst those with F3 or F4 fibrosis was 38% compared to 15% in those with F1 or F2 fibrosis (RR 2.75; 95% CI 1.08–6.97) [
Successful HCV therapy has been associated with potential decrease in risk for subsequent antiretroviral-related hepatotoxicity [
At present, no specific antiretroviral regimen can be preferentially recommended for use in coinfected patients. However, certain regimens may need to be used cautiously in the setting of advanced liver disease. Close monitoring is required, and dosage adjustments or alterations of combination antiretroviral therapy may be required if hepatic decompensation occurs [
ART regimens should be initiated as per current guidelines as they are effective and well-tolerated in coinfected patients (Class 1, Level A). Initiation of ART may serve to slow progression of liver disease in coinfected patients. Early initiation of ART is recommended for all individuals with CD4 >500 cells/ All individuals being considered for therapy with the paritaprevir/ritonavir-based regimen should initiate ART prior to HCV therapy (Class 1, Level B).
Baseline evaluation and monitoring of coinfected patients is similar to that of monoinfected patients and should focus on determination of genotype and degree of liver disease/hepatic fibrosis as a prelude to consideration of HCV therapy (Table
Baseline assessment of coinfected patients.
Test | Comment | |
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Viral hepatitis screens | HCV antibody | |
Quantitative HCV RNA | ||
HCV genotype | ||
Hepatitis B surface antigen | Chronic HBV infection | |
Hepatitis B surface antibody | Immunity to HBV | |
Hepatitis B core antibody | ||
Hepatitis A IgG | If negative, indicates need for HAV vaccine | |
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Liver-related | Complete blood count | Thrombocytopenia may indicate advanced liver disease |
ALT, AST | ||
ALP, GGT | ||
Albumin, INR, and total bilirubin | Abnormalities suggest advanced liver disease | |
Ultrasound | ||
Fibroscan | ||
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Screens for other chronic conditions of liver disease | Alpha-1-antitrypsin | Alpha-1 antitrypsin deficiency |
Antinuclear antibody, anti-smooth muscle antibody | Autoimmune hepatitis | |
Anti-mitochondrial antibody | Primary biliary cholangitis | |
Ceruloplasmin | Wilson’s disease | |
Iron saturation | Hemochromatosis | |
Lipid Profile | Fatty liver disease | |
TSH | Autoimmune thyroiditis | |
Immunoglobulins A, G, and M | Autoimmune hepatitis, primary biliary cholangitis, and alcoholic liver disease |
In Canada, as many as 25%–30% of HIV-HCV coinfected persons are estimated to be unaware of their infection, highlighting the clear need for more HCV screening and testing [
All HIV-infected patients should be screened for HCV coinfection by serologic testing. Similarly, all HCV-infected patients should be evaluated for HIV coinfection. In individuals with significant immune compromise, HCV antibodies may occasionally be falsely negative, and consideration should be given to directly testing for presence of HCV RNA [
The frequency of HCV antibody testing should depend on ongoing risk behaviours (Section
Individuals with positive HCV RNA should undergo determination of HCV genotype as an initial step of determining HCV therapy (Section
Individuals with baseline negative HCV RNA should be considered for repeat testing to confirm the absence of chronic infection at least once, especially if ALT is elevated.
Patients with confirmed HCV antibody should be evaluated with HCV RNA PCR (Class 1, Level C). Those with positive HCV RNA should undergo HCV genotyping (Class 1, Level C). Those with negative HCV RNA should undergo repeat testing at least once to confirm spontaneous clearance if liver enzymes are elevated (Class 1, Level C).
All individuals should also undergo screening for hepatitis A immunity (hepatitis A IgG) and for hepatitis B (HBsAg, anti-HBs, and anti-HBc) and should be vaccinated if nonimmune. If chronically infected with hepatitis B, they should be assessed for therapy.
All patients should undergo screening for hepatitides A and B and should be offered vaccination if nonimmune (Class 1, Level C).
A detailed history and physical examination focused on signs and symptoms of liver disease is required. Features of advanced liver disease may include ascites, bulging flanks, peripheral edema, history of gastrointestinal bleeding, and jaundice. Examination includes assessment for splenomegaly, ascites, gynecomastia, spider nevi, and other manifestations of end-stage liver disease.
Monitoring of complete blood count (CBC), liver enzyme panel including ALT and AST, and markers of synthetic function (INR, albumin, and bilirubin) should be performed at baseline and can be monitored as a component of routine (every 6 months) laboratory testing in individuals undergoing ART therapy.
Thrombocytopenia may be a marker of hypersplenism and advanced liver disease. Derangements in synthetic function also suggest advanced disease. Caution should be used when interpreting elevated bilirubin levels in patients receiving atazanavir-based regimens as atazanavir is associated with unconjugated (indirect) hyperbilirubinemia, but elevated conjugated (direct) bilirubin levels indicate liver disease. Similarly, discordance between the absolute CD4 cell count and CD4 percentage (higher CD4 percentage than expected for the corresponding absolute value) in coinfected individuals may also suggest advanced disease. Amongst individuals enrolled in the CCC, 31% had evidence of high discordance, which was associated with markers of end-stage liver disease [
Additional baseline screen for other causes of chronic liver disease can be considered, including investigations for hemochromatosis (iron binding capacity with genetic testing if iron saturation exceeds 0.60), autoimmune hepatitis (including primary biliary cholangitis where appropriate, ANA, anti-smooth muscle antibody, anti-mitochondrial antibody, and immunoglobulin levels), Wilson’s Disease (ceruloplasmin), and alpha-1-antitrypsin deficiency. Attention to alcohol consumption is essential given the negative influence alcohol has on fibrosis progression. Referral to alcohol cessation programs is a critical component to preserving liver health. Recognizing the diagnostic limitations, a workup for steatosis should be considered by performing a metabolic syndrome workup (lipid profile, glucose, and hemoglobin A1C), radiological evaluation (ultrasound, transient elastography-controlled attenuation parameter measurement), and potentially liver biopsy.
Patients should be evaluated for other conditions which may result in or exacerbate chronic liver disease (Table All patients should be counselled regarding alcohol reduction/abstinence and engaged in cessation programs when necessary (Class 1, Level C).
Ultrasound of the liver at baseline should also be considered and should be performed whenever there is thrombocytopenia. In cirrhotics, it should be conducted every 6 months for hepatocellular carcinoma screening [
Criteria for interpretation of transient elastography in HIV-HCV coinfected patients [
Score (kilo Pascals, kPa) | Metavir equivalent | Interpretation |
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≤7.2 | F0/1 | Mild fibrosis |
7.2–9.5 | F2 | Moderate fibrosis |
9.5–12.5 | F3 | Advanced fibrosis |
>12.5 | F4 | Severe fibrosis/cirrhosis |
Although liver enzyme elevations have traditionally been thought to reflect disease activity, it is now evident that HCV-infected individuals may develop fibrosis and even cirrhosis without significant liver enzyme elevations. In a retrospective review of 326 liver biopsies performed in coinfected individuals between 1997 and 2003 at a European centre, approximately 25% of individuals with persistently normal ALT values were found to have at least stage 2 fibrosis [
Liver biopsy has traditionally been regarded as the gold standard of investigation for HCV-related disease progression in North America [
Transient elastography (TE, Fibroscan
TE has been validated in coinfected patients. In an analysis of 183 patients undergoing simultaneous liver biopsy, a cutoff of 7.2 kPa for significant fibrosis (>F2) had an area under the receiver-operator curve (ROC) of 0.83, while a cutoff of 12.5 kPa (ROC 0.95) was indicative of cirrhosis [
Fibroscan may be limited by body habitus (obesity may impair the ability of the probe to accurately assess the liver) and may be falsely elevated in circumstances of significant hepatic inflammation [
Use of noninvasive laboratory markers may aid in the assessment of fibrosis in coinfected patients. Use of the AST to platelet index (APRI) calculated as [(AST/ULN)/platelet count × 109/L] × 100 has been validated in a Canadian cohort of coinfected patients [
Other formulae for assessing fibrosis include the Fib-4 score (age [years] × AST [IU/L]/platelet count [expressed as platelets × 109/L] × (ALT1/2 [IU/L]) [
Patients with confirmed cirrhosis should undergo additional monitoring for the development of complications such as hepatocellular carcinoma (HCC). Surveillance screening with regular ultrasounds (every 6 months) with or without use of serum alpha fetoprotein should be undertaken as is the case in HIV-negative individuals with cirrhosis. Referral to a gastroenterologist for consideration of endoscopy in order to screen and/or monitor esophageal varices may also be indicated.
Ongoing monitoring for HCC is also advised in patients with cirrhosis who have achieved SVR with HCV therapy, as the risk related to underlying cirrhosis may persist albeit diminished.
ALT criteria alone should not be used to determine the need for treatment initiation in coinfected patients (Class 2a, Level C). Baseline abdominal ultrasound with Doppler should be considered in all patients (Class 2a, Level B). Baseline evaluation of liver fibrosis (e.g., Fibroscan, FibroTest, and APRI) to determine degree of hepatic fibrosis is advised (Class 2a, Level B). Evaluation of liver fibrosis with liver biopsy can be considered if noninvasive methods of determining fibrosis are not available, or if alternate diagnoses are being considered (Class 2a, Level C). Patients with evidence of underlying cirrhosis should be screened every 6 months for hepatocellular carcinoma using ultrasound (Class 1, Level B). Patients with underlying cirrhosis should be considered for gastroscopy for screening for esophageal varices (Class 1, Level B).
Baseline laboratory determination of HCV status as outlined is necessary in order to evaluate HCV genotype and degree of hepatic fibrosis/disease.
Given the burden of comorbid conditions in the setting of coinfection, evaluation of factors such as substance use/addictions, mental health, and housing and food security is vital when preparing for HCV therapy. Substance use, lack of housing, or adequate food supply may limit the adherence to HCV therapy with deleterious effect on treatment outcome. However, if stabilized, these issues do not represent contraindications to treatment. In fact, HCV therapy can be successfully initiated and completed in active injection drug users [
Individuals considering HCV therapy should be assessed for potential contraindications. Contraindications include the following: Pregnancy (absolute contraindication based on either known teratogenicity of pegylated interferon/ribavirin or lack of data with DAA regimens). Decompensated liver disease (relative contraindication, particularly with pegylated interferon/ribavirin based regimens).
Individuals >50 years of age with history of hypertension, diabetes, or prior retinopathy should undergo baseline ophthalmology assessment if interferon-based therapy is considered, as it has been associated with exacerbation/new onset of retinopathy [
When considering HCV therapy in PWID, concomitant use of harm reduction strategies is necessary given the risk of potential reinfection if injection drug use resumes after successful therapy [
Adherence is crucial to the success of treatment of HCV infection. In the era of interferon and ribavirin therapy, the consumption of 80% of each of the prescribed medications for a minimum of 80% of the target treatment duration was set as a “gold standard” [
Data on adherence in the DAA era are limited, but results from the NIAID SYNERGY trial in which “real-world” patients received combinations of 1–3 pills/day taken for 6–12 weeks suggest high levels of adherence in coinfected patients [
Peer-driven support programs and multidisciplinary primary-care models have been used successfully for inner city populations of PWID [
All coinfected patients should undergo evaluation for HCV therapy (Class 1, Level A). Evaluation and management of factors such as substance use/addictions, mental health, and housing and food security are vital when preparing for HCV therapy (Class 1, Level B). Assuming appropriate supports are provided, addiction is not an exclusion criterion for HCV therapy (Class 1, Level B). Multidisciplinary care is recommended to optimally support patients as they progress through HCV workup and treatment (Class 1, Level B). If interferon will be used, detailed assessment for interferon-related contraindications is essential (Class 1, Level C). Appropriate levels of funding for HCV treatment programs and removal of barriers to HCV antiviral therapy are necessary to optimize engagement in care and treatment outcomes (Class 1, Level C). An adherence plan should be developed for all patients initiating HCV antiviral therapy (Class 1, Level C).
There is clear evidence that successful HCV treatment leads to reduced disease burden from HCV infection. Successful treatment is the achievement of a sustained virological response (SVR), although historically this was defined as HCV RNA negativity at least 24 weeks after completion of antiviral therapy (SVR24); this is now defined as HCV RNA negativity at least 12 weeks after completion of antiviral therapy (SVR12) based on an FDA analysis [
All coinfected patients should be assessed for HCV therapy. From 2001 until 2011, anti-HCV therapy consisted of pegylated interferon plus ribavirin (PR) for all HCV genotypes. The year 2011 heralded the availability of the first direct acting antiviral agents (DAAs) for HCV, boceprevir and telaprevir, both of which are HCV NS3 protease inhibitors. Boceprevir and telaprevir were approved only for genotype 1 in combination with PR. In late 2013, simeprevir, another NS3 protease inhibitor, was approved for use in combination with PR only in genotype 1. Then in December 2013, the uridine nucleotide NS5B polymerase inhibitor sofosbuvir was approved, leading to significant changes in recommended therapies, such that triple therapy with PR plus a NS3 protease inhibitor was no longer recommended as preferred therapy in genotype 1 and PR dual therapy was no longer recommended as preferred therapy in genotypes 2, 3, or 4. Additional new DAAs were approved in 2014 and 2015, and others are expected over the next two years.
At present, therapy for HCV is determined by HCV genotype. When treatment consisted of dual therapy with PR, SVR rates in the coinfected were significantly lower than in the HCV monoinfected, especially in genotype 1 [
A fixed dose combination tablet containing sofosbuvir 400 mg and 90 mg of the NS5A inhibitor ledipasvir was approved in October 2014 for genotype 1, on the basis of three large clinical trials in the HCV monoinfected [
A 12-week regimen of sofosbuvir-ledipasvir was evaluated in 335 HIV-infected patients with HCV genotypes 1 and 4, of whom 20% had cirrhosis and 55% failed prior HCV therapy (ION-4) [
The combination of the NS3 protease inhibitor paritaprevir boosted by the CYP3A4 inhibitor ritonavir, the NS5A inhibitor ombitasvir, and the NS5B nonnucleoside polymerase inhibitor dasabuvir, with ribavirin given for 12 weeks, results in SVR rates of 93 to 99% in HCV genotype-1 monoinfected patients, including PR treatment-experienced patients and those with compensated cirrhosis in multiple clinical trials [
This regimen (including ribavirin) was evaluated in 63 patients coinfected with HIV and HCV genotype 1 [
The presence of multiple CYP3A4 metabolized medications, including ritonavir, limits antiretroviral treatment options in HIV coinfected patients considered for this regimen. Specifically, it is not recommended to administer efavirenz, rilpivirine, etravirine, or lopinavir/ritonavir, darunavir/cobicistat with this regimen. Darunavir Cmin is reduced by approximately 50% with this regimen. The clinical significance of this reduction in darunavir exposure is unknown, but caution should be exercised. This regimen is not recommended for patients who failed PR plus a NS3 protease inhibitor because of the concern that NS3 protease resistance mutations will compromise the activity of paritaprevir and the absence of clinical data in this patient population.
Due to concern regarding hepatotoxicity this regimen in contraindicated in those with decompensated liver disease [Holkira PM] [
In the COSMOS study, 167 HCV genotype 1 monoinfected, treatment-naïve, and prior PR null responders (i.e., failure to achieve a 2 log reduction in HCV RNA by week 12 of PR treatment) received once daily sofosbuvir plus simeprevir (a NS3 protease inhibitor), with (
Daclatasvir was the first NS5A inhibitor to be studied in combination with sofosbuvir. In a phase 2 study in the HCV monoinfected, SVR rates after 24 weeks of treatment with sofosbuvir plus daclatasvir with or without ribavirin were 98% in genotype 1 (
A phase 3 study of sofosbuvir plus daclatasvir without ribavirin was recently completed in 203 HIV coinfected participants of which 168 were genotype 1 infected [
Grazoprevir is a protease inhibitor and elbasvir is an NS5a inhibitor. This once daily regimen combination received regulatory approval in early 2016. In the C-EDGE COINFECTION study, 218 HIV-HCV coinfected study participants with genotype 1, 4, or 6 infection naïve to HCV treatment received this regimen for 12 weeks [
sofosbuvir 400 mg coformulated with ledipasvir 90 mg daily for 12 weeks of therapy (Class 1, Level B), or ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin for 12 weeks or grazaprevir-elbasvir for 12 weeks (Class 1, Level C).
sofosbuvir 400 mg daily coformulated with ledipasvir 90 mg daily for 12 weeks (Class 1, Level B). Cirrhotic patients should be treated for 24 weeks, based on data in the HCV monoinfected (Class 1, Level C), or ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin for 12 weeks (Class 1, Level B) (this regimen may be used in patients who failed dual PR therapy but is not recommended for patients who have failed a regimen including a NS3 protease inhibitor).
Triple therapy with PR plus any DAA for HCV genotype 1 is no longer recommended for use given the improved efficacy, safety, and tolerability profiles of all oral therapy. Sofosbuvir plus simeprevir for genotype 1 for reasons of cost and minimal data in the coinfected.
Sofosbuvir plus ribavirin has been evaluated for use in genotypes 2 and 3 in a large noninferiority trial with standard pegylated interferon/ribavirin as the comparator [
Sofosbuvir plus ribavirin has also been evaluated in treatment-experienced genotypes 2 and 3 participants. In the FUSION trial, individuals were randomized to receive 12 or 16 weeks of therapy with sofosbuvir and ribavirin. Those with genotype 2 achieved an SVR rate of 86% after 12 weeks and 94% after 16 weeks. SVR rates were much lower for genotype 3, with an SVR rate of 30% in those receiving 12 weeks versus 62% in those who received 16 weeks of therapy [
In the LONESTAR-2 phase II trial, the addition of pegylated interferon to a 12-week course of sofosbuvir/ribavirin resulted in SVR rates of 83% for genotype 3, with or without cirrhosis [
A 12-week regimen of sofosbuvir plus daclatasvir was highly efficacious in HCV genotype 3 monoinfected patients without cirrhosis, whether HCV treatment-naïve (SVR 97%) or experienced (SVR 94%), but was much less effective in the presence of cirrhosis (SVR 58% in the treatment-naïve and 69% in the treatment-experienced) [
Sofosbuvir was evaluated in HIV coinfected patients in the phase 2 Study P7977-1910 trial [
In the phase III PHOTON-1 study, three cohorts of coinfected patients (genotype 1 treatment-naïve patients
PHOTON-2 was a multicentre phase 3 study of sofosbuvir and ribavirin in HIV/HCV coinfected patients [
Ledipasvir has little genotype 2 activity and is not recommended for use in coinfected patients. Data from 51 treatment-naïve, mostly noncirrhotic patients in the phase 2 ELECTRON-II study, suggests there may be a role for sofosbuvir, ledipasvir, and ribavirin for 12 weeks in HCV genotype 3 treatment-naïve, noncirrhotic, and HCV monoinfected individuals [
Overall, while the number of treated patients is low in the dedicated coinfected studies, these data do suggest that genotypes 2 and 3 can be treated with high cure rates with sofosbuvir and ribavirin, in some circumstances combined with ledipasvir (HCV GT3) or pegylated interferon. However, it is worth noting that other potent, all oral combinations may soon be available for HCV genotypes 2 and 3 treatment and that delay of treatment in those who do not have an urgent need for treatment is reasonable.
A phase 3 study of sofosbuvir plus daclatasvir (without ribavirin) in the HIV coinfected included mainly genotype 1 infected participants (83%) but also included a small number with nongenotype 1 infection (ALLY-2 trial) [
sofosbuvir 400 mg daily with weight-based ribavirin for 12 weeks with consideration for 16 weeks in cirrhotics (Class 1, Level B). sofosbuvir 400 mg daily and Daclatasvir 60 mg daily for 12 weeks (Class 1, Level B).
sofosbuvir 400 mg daily with weight-based ribavirin for 12 weeks, or 16 weeks in cirrhotics (Class 1, Level B). sofosbuvir 400 mg daily with weight-based ribavirin and pegylated interferon 180 sofosbuvir 400 mg daily and Daclatasvir 60 mg daily for 12 weeks (Class 1, Level B).
sofosbuvir 400 mg daily with weight-based ribavirin and pegylated interferon 180 sofosbuvir 400 mg daily with weight-based ribavirin for 24 weeks (noncirrhotics) (Class 1, Level B), or sofosbuvir 400 mg daily and Daclatasvir 60 mg daily for 12 weeks (noncirrhotics) and sofosbuvir 400 mg daily and Daclatasvir 60 mg daily with weight-based ribavirin for 12 weeks (Cirrhotics) (Class 1, Level B).
sofosbuvir 400 mg daily with pegylated interferon alpha 2a 180 sofosbuvir 400 mg daily with weight-based ribavirin for 24 weeks (Class 1, Level B), or sofosbuvir 400 mg daily and Daclatasvir 60 mg daily for 12 weeks (noncirrhotics) and sofosbuvir 400 mg daily and Daclatasvir 60 mg daily with weight-based ribavirin for 12 weeks (cirrhotics) (Class 1, Level B).
There are limited data on direct acting antiviral therapy in HCV genotypes 4, 5, and 6 infected patients as few studies, dedicated or otherwise, have included them, and when permitted were conducted in countries with a low prevalence of genotypes 4–6 infection. Data in these genotypes are even rarer in the context of HIV/HCV coinfected individuals.
Eight HIV-HCV coinfected, genotype 4 patients received sofosbuvir 400 mg daily coformulated with ledipasvir 90 mg daily for 12 weeks in the ION-4 study [
The all oral, 12-week regimen ombitasvir, paritaprevir, ritonavir, with or without ribavirin was assessed in 135 treatment-naïve and experienced, noncirrhotic HCV genotype 4 monoinfected patients in the PEARL-I study [
The NEUTRINO study treated HCV monoinfected patients with sofosbuvir, pegylated interferon, and ribavirin for 12 weeks and included a small number of genotype 4 (30 patients) and genotype 5 or 6 (7 patients). 96% of genotype 4 patients and all of the 7 genotype 5 or 6 patients achieved SVR12 in this study [
The PHOTON-2 trial also included 31 HCV genotype 4, treatment-naïve patients treated for 24 weeks with sofosbuvir and weight-based ribavirin with 84% of patients achieving SVR12 [
The SYNERGY trial treated 21 individuals with genotype 4 with 12 weeks of sofosbuvir and ledipasvir, 33% of whom had compensated cirrhosis, with an SVR12 in 95% of those treated [
sofosbuvir 400 mg daily and ledipasvir 90 mg daily for 12 weeks (Class 1, Level B), or paritaprevir 150 mg daily, ritonavir 100 mg daily, ombitasvir 25 mg daily, and weight-based ribavirin for 12 weeks (Class 1, Level C), or sofosbuvir 400 mg daily with pegylated interferon and ribavirin for 12 weeks (NB-based on HCV monoinfection studies) (Class 1, Level C), or sofosbuvir 400 mg daily and weight-based ribavirin daily for 24 weeks.
There are currently insufficient data in HIV-HCV coinfection with genotypes 4–6 to comment on the efficacy of sofosbuvir-simeprevir or sofosbuvir-daclatasvir. Likewise, there are currently insufficient data in HIV-HCV coinfection with genotypes 5-6 to comment on the efficacy of sofosbuvir with pegylated interferon and ribavirin.
Studies of triple therapy with peginterferon plus ribavirin plus a NS3 protease inhibitor demonstrate that over 80% of failures are associated with treatment-emergent resistance mutations in the NS3 region [
As noted earlier, the ION-2 study of sofosbuvir/ledipasvir with or without ribavirin in 440 patients with genotype 1 monoinfection who failed prior therapy included 231 patients (52.5% of the study population) who failed prior therapy with peginterferon plus ribavirin plus a NS3 protease inhibitor and 209 who failed prior dual therapy with peginterferon plus ribavirin. SVR rates were over 93% and virtually identical in both groups of patients, and the addition of ribavirin did not improve SVR rates [
As noted earlier, a 12-week regimen of sofosbuvir/ledipasvir was evaluated in 335 HIV coinfected patients of whom 98% had HCV genotype 1 infection and 2% had HCV genotype 4 infection [
The regimen of paritaprevir/ombitasvir/ritonavir plus dasabuvir with or without ribavirin has not been evaluated in patients who failed therapy including a NS3 protease inhibitor. Indeed, studies of this regimen that included prior treatment failures specifically excluded patients who had received NS3 protease inhibitors because of concerns that NS3 resistance mutations might compromise the efficacy of paritaprevir [
In an open-label “real life” cohort study of patients treated with sofosbuvir plus simeprevir, patients who failed prior therapy with boceprevir or telaprevir had a lower SVR rate (76%; 35/46) than those with no prior NS3 protease inhibitor exposure (SVR rate 93%; 118/129), suggesting that prior NS3 protease inhibitor exposure compromises the activity of simeprevir [
Twenty patients with HCV genotype 1 monoinfection who failed treatment with sofosbuvir plus ribavirin were treated with a 12-week course of sofosbuvir/ledipasvir plus ribavirin and all achieved SVR [
Twenty-five patients with HCV genotype 1 monoinfection who failed treatment with peginterferon plus ribavirin plus sofosbuvir were treated with a 12-week course of sofosbuvir/ledipasvir plus ribavirin and all achieved SVR [
Virological failure is very uncommon in HCV genotype 1 infection treated with sofosbuvir/ledipasvir. In a combined analysis of 2144 patients from the ION 1–3, LONESTAR and ELECTRON studies, virological failure occurred in only 2.4% (51/2144) of patients [
Limited data are available regarding retreatment of patients who failed sofosbuvir/ledipasvir therapy. The single patient noted above whose virus developed the S282T NS5B RAV was retreated with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and achieved SVR.
Forty-one patients with HCV genotype 1 infection who failed 8- or 12-week courses of sofosbuvir/ledipasvir were retreated with a 24-week course of sofosbuvir and ledipasvir and SVR was achieved in 71% (29/41) [
When patients fail treatment with sofosbuvir/ledipasvir, most will have NS5A RAVs and almost none will have NS5B RAVs [
There are no data yet available on retreatment of patients failing sofosbuvir plus simeprevir. Nevertheless, data indicate that patients failing this regimen generally have viruses with treatment-emergent NS3A RAVs but no NS5B RAVs [
There are no data yet available on retreatment of patients failing paritaprevir/ombitasvir/ritonavir plus dasabuvir with or without ribavirin, which occurs very infrequently. Pooled phases 2 and 3 data of 1083 patients treated with the recommended regimen identified 19 cases of virological failure (1.8%), of which 18 were of genotype 1a. At virological failure, 83% had NS3A RAVs, 78% had NS5A RAVs, and 78% had NS5B RAVs [
The potential for interactions between HCV directly acting antiviral agents and other drug classes is high due to the pharmacological characteristics of these HCV agents, particularly in the context of earlier ART initiation, the aging HIV population, and need for management of comorbidities [
HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and the integrase inhibitor elvitegravir are substrates and inhibitors or inducers of numerous cytochrome P 450 (CYP450) hepatic enzymes and transporters. The integrase inhibitor raltegravir is not a P450 substrate, whereas for dolutegravir it represents only a minor pathway. Neither raltegravir nor dolutegravir are inducers or inhibitors of these enzymes and therefore may be used with HCV DAAs without dosage adjustment [
Similarly, the newer HCV agents are also substrates and inhibitors or inducers of various P450 enzymes and transporters. The NS5A inhibitor ledipasvir (which is coformulated with sofosbuvir) is a substrate and weak inhibitor of P-glycoprotein (P-gp). It is also a weak inhibitor of transporters including BCRP (breast cancer resistance protein) and OATP (organic anion transporter protein) 1B1/1B3.
Ledipasvir/sofosbuvir may be coadministered with most antiretrovirals, but special attention is required for tenofovir-containing regimens. Tenofovir exposures are increased 40–98% in the presence of ledipasvir/sofosbuvir, regardless of the type of antiretroviral combination used. This effect is postulated to be secondary to inhibition of P-gp and BCRP-mediated efflux of tenofovir by ledipasvir. There is no evidence to suggest that clinical relevant negative consequences result from this interaction. Nonetheless, patients continuing on tenofovir treatment during ledipasvir/sofosbuvir therapy should be monitored for tenofovir-associated adverse events. Use of an alternate NRTI backbone may be considered, particularly in patients with additional risk factors for renal dysfunction including use of other potentially nephrotoxic agents (including NSAID use), or when prolonged ledipasvir/sofosbuvir treatment (i.e., greater than 12 weeks) is required.
The combination of paritaprevir and ombitasvir, both of which are substrates of CYP3A4, P-glycoprotein, and BCRP, is combined also with dasabuvir, a substrate of CYP2C8, 3A4, P-glycoprotein, and BCRP. Paritaprevir and ombitasvir are coformulated with ritonavir since paritaprevir requires pharmacokinetic boosting for optimal exposures. This coformulated regimen should not be given with NNRTIs or certain boosted antiretrovirals due to risk of altered DAA exposures and/or increased risk of adverse events.
The NS5A inhibitor daclatasvir is a substrate of CYP3A4 and P-gp and is an inhibitor of P-gp, OATP1B1, OCT1, and BCRP. Daclatasvir requires dose adjustment with certain boosters and enzyme inducers.
The investigational combination of grazoprevir and elbasvir has recently been filed for evaluation by the FDA and Health Canada and is anticipated to be available as a fixed dose, once daily combination product in early 2016. Grazoprevir is an NS3/4A protease inhibitor and a substrate of CYP3A4, P-gp, and OATP1B1. Elbasvir is an NS5A inhibitor and is a substrate of CYP3A4, P-gp, and OATP. Grazoprevir inhibits CYP2C8 and is a weak inhibitor of 3A4 and UGT (uridine glucuronosyltransferase) 1A1. Both grazoprevir and elbasvir inhibit the BCRP transporter. From a practical standpoint, grazoprevir/elbasvir are mainly susceptible as victims of drug-drug interactions (DDIs) rather than perpetrators. Grazoprevir/elbasvir should not be coadministered with boosted protease inhibitors or efavirenz due to significant increases or decreases in DAA concentrations [
Therefore, there is a high potential for drug interactions in the coinfected population, particularly if simultaneous treatment of HCV and HIV is required.
Negative consequences of drug interactions include HIV and HCV viral breakthrough and development of resistance, suboptimal disease/symptom management, or drug toxicities and possible nonadherence [
Drug-drug interactions between antiretroviral agents and directly acting antivirals for hepatitis C.
Usual doses | 90 mg/400 mg daily | 150/100/25 mg daily + 250 mg BID with food | 150 mg daily and 400 mg daily with food | 60 mg daily plus 400 mg daily |
|
||||
Nucleoside/nucleotide reverse transcriptase inhibitors | ||||
Abacavir/lamivudine | 18% ↑ AUC, 10%, ↑ |
Coadministration has not been studied but no clinically significant drug interaction expected. |
Coadministration has not been studied but no clinically significant drug interaction is expected. |
Coadministration has not been studied but no clinically significant drug interaction is expected. |
Tenofovir disoproxil fumarate (TDF)/emtricitabine | TDF exposures are increased (AUC 40–98%, |
No clinically significant changes. No dose adjustment required (Holkira Pak PM) |
No clinically significant changes in pharmacokinetics of TDF, simeprevir, or sofosbuvir noted. No dose adjustment is required (Galexos PM, Harvoni PM). |
No clinically significant changes in pharmacokinetics of TDF, daclatasvir, or sofosbuvir noted. No dose adjustment is required (Galexos PM, Harvoni PM). |
|
||||
Integrase strand transfer inhibitors | ||||
Dolutegravir | TDF exposures were 65–115% higher when ledipasvir/sofosbuvir was coadministered with dolutegravir plus TDF DF/emtricitabine. Ledipasvir/sofosbuvir may be coadministered with dolutegravir. If TDF DF/emtricitabine is included as an NRTI backbone, appropriate monitoring for TDF-associated toxicities is recommended [ |
Dolutegravir exposures increased 22–38% while paritaprevir |
Coadministration has not been studied but no clinically significant drug interaction is expected. |
No clinically significant changes in pharmacokinetics of dolutegravir or daclatasvir noted. No dose adjustment is required [ |
Elvitegravir/cobicistat | Increased TDF exposures anticipated with coadministration; appropriate monitoring for TDF-associated toxicities is recommended [ |
Coadministration has not been studied but cobicistat is expected to increase paritaprevir and ritonavir concentrations (Holkira Pak PM). Coadministration |
|
Potential for increased daclatasvir exposures due to CYP3A4 inhibition by cobicistat. Reduce daclatasvir dose to 30 mg once daily when coadministering with cobicistat-based regimens (Daklinza PM). |
Raltegravir | No clinically significant changes noted with coadministration. No dose adjustment required (Harvoni PM). |
No clinically significant changes noted with coadministration. No dose adjustment required (Holkira Pak PM). |
No clinically significant changes noted with coadministration. No dose adjustment is required [ |
Coadministration has not been studied but no clinically significant drug interaction is expected (Daklinza PM). |
|
||||
Nonnucleoside reverse transcriptase inhibitors | ||||
Efavirenz | In combination with TDF/FTC, no clinically significant changes in sofosbuvir or efavirenz pharmacokinetics were noted, while tenofovir AUC ↑ 98% and |
Coadministration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir is |
91% ↓ |
Daclatasvir exposures are decreased with coadministration. Increase daclatasvir to 90 mg once daily with efavirenz (Daklinza PM). |
Etravirine | Coadministration has not been studied. |
|
|
Coadministration has not been studied. Potential for decreased daclatasvir concentrations; |
Rilpivirine | In combination with TDF/FTC, no clinically significant changes in sofosbuvir or rilpivirine pharmacokinetics were noted, while tenofovir AUC ↑ 40% and |
3.25-fold ↑ AUC, 2.55-fold ↑ |
No clinically significant changes noted with coadministration. No dose adjustment required [ |
Coadministration has not been studied but no clinically significant drug interaction expected (Daklinza PM). |
|
||||
Protease inhibitors | ||||
Atazanavir/ritonavir | 75% ↑ |
Atazanavir should be taken without additional ritonavir with the 3D regimen (Holkira Pak PM). |
|
Reduce dose of daclatasvir to 30 mg once daily when coadministering with atazanavir/ritonavir (Daklinza PM). |
Atazanavir/cobicistat | Combination is not studied. In combination with elvitegravir/cobicistat, cobicistat exposure is increased. Clinical significance is unknown but likely not clinically relevant [ |
Atazanavir plus cobicistat is |
|
Reduce dose of daclatasvir to 30 mg once daily when coadministering with cobicistat (Daklinza PM). |
Darunavir/ritonavir | No changes in darunavir pharmacokinetic parameters; 39% ↑ AUC, 45% ↑ |
24% ↓ AUC, 8% ↓ |
2.59-fold ↑ AUC, 1.79-fold ↑ |
Daclatasvir AUC increased 41%, |
Darunavir/cobicistat | Coadministration has not been studied but no clinically significant drug interaction expected. In combination with elvitegravir/cobicistat, cobicistat exposure is increased. Clinical significance is unknown but likely not clinically relevant [ |
Darunavir plus cobicistat is |
|
Coadministration has not been studied but no clinically significant drug interaction is expected. |
Lopinavir/ritonavir | Coadministration has not been studied. Significant drug interaction not anticipated. |
|
|
No clinically significant changes noted with coadministration. No dose adjustment required [ |
|
||||
CCR5 antagonist | ||||
Maraviroc | Coadministration has not been studied but no clinically significant drug interaction expected. |
Coadministration has not been studied but maraviroc exposure is expected to be increased by ritonavir. Reduce maraviroc to 150 mg BID or 300 mg daily. |
Coadministration has not been studied but no clinically significant drug interaction is expected (Galexos PM). |
Coadministration has not been studied but no clinically significant drug interaction is expected (Daklinza PM). |
Key:
AUC: area under the curve;
Summary of antiretroviral regimen recommendations for patients who require concomitant HIV and hepatitis C treatment.
Recommended | Alternative | Not recommended | |
---|---|---|---|
Sofosbuvir 400 mg/ledipasvir 90 mg once daily | No restrictions with first or second line ART regimens | In patients with preexisting renal dysfunction or significant risk factors for nephrotoxicity: may wish to avoid tenofovir-containing regimens due to potential for ↑ tenofovir concentrations | |
|
|||
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg once daily + dasabuvir 250 mg BID with food | Atazanavir (without additional ritonavir), raltegravir, and Dolutegravir | Darunavir (without additional ritonavir) | Ritonavir- or cobicistat-boosted regimens; efavirenz, etravirine, and rilpivirine |
|
|||
Simeprevir |
Dolutegravir, raltegravir, or rilpivirine-based regimens | Ritonavir- or cobicistat-boosted regimens; efavirenz, etravirine, and nevirapine | |
|
|||
Daclatasvir 60 mg daily plus sofosbuvir 400 mg daily | Atazanavir (requires decrease in daclatasvir dose to 30 mg daily), darunavir, dolutegravir, raltegravir, or rilpivirine-based regimens | Efavirenz (requires increase in daclatasvir dose to 90 mg daily) | Etravirine and nevirapine |
BID: twice daily.
Careful attention to drug-drug interactions between HCV antivirals and concurrently administered HIV and non-HIV medications is critical to avoid viral breakthrough of either HIV or HCV, development of resistance, suboptimal disease/symptom management, and drug toxicities (Class 1, Level C). For individuals with genotype 1 infection initiating therapy with sofosbuvir/ledipasvir, traditional first line antiretrovirals may be used. If a tenofovir-based regimen is used, close monitoring of renal function is recommended due to potential for increased tenofovir exposures (Class 2b, Level B). For individuals with genotype 1 infection initiating HCV therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir, atazanavir (without additional booster), raltegravir, or dolutegravir may be used (Class 2b, Level B). For individuals with genotype 1 infection initiating HCV therapy, switch from alternate regimens to an acceptable regimen as listed above can be considered if HIV treatment history and resistance profile permits such a switch. For patients with HIV multidrug resistance who are well controlled on nonpreferred ART regimens, initiation of triple therapy including DAAs may be considered in consultation with an expert physician and pharmacist with experience in managing HIV and HCV drug interactions.
Many common drugs from multiple different classes are at risk of drug interactions with DAAs. The product monographs of direct acting agents provide a list of drugs with known or potential CYP interactions. In addition to CYP450 isoenzymes, drug transporters including OATP1B1/3, P-gp, and BCRP are responsible for changes in drug disposition. Drugs altering gastric pH may also lead to clinically relevant drug interactions. For instance, ledipasvir requires an acidic environment for optimal absorption. Examples of interacting drug classes include acid-reducing agents, benzodiazepines (e.g., midazolam), HMG coenzyme A reductase inhibitors (statins), macrolides, rifamycins (e.g., rifampin), anticonvulsants, antiarrhythmics, psychotropics, azole antifungals, erectile dysfunction drugs, antipsychotics, inhaled corticosteroids, calcium channel blockers, immunosuppressants, and more. Herbals and over-the-counter drugs are not exempt of potential significant interactions. St-John’s wort (
The management of these complex medication combinations requires expert knowledge. Substitution or safe discontinuation of the interacting drug can be attempted after careful evaluation of the benefit-risk ratio.
Assessment and monitoring of drug-drug interactions between direct acting agents and commonly prescribed medications should occur at baseline and at frequent intervals during HCV therapy (Class 1, Level C). Ensuring that medication records are up to date, use of a systematic approach to identify combinations of potential concern, consulting pertinent HIV and/or HCV drug interaction resources (e.g., Nonessential medications should be discontinued for the duration of HCV treatment, particularly when HCV DAAs are used (Class 1, Level C).
The recognition that sexual transmission is a risk factor for acute HCV-infected in HIV-infected MSM populations has increased the need for periodic screening and consideration of rapid initiation of HCV antiviral treatment [
Historically, acute HCV infection was managed with interferon-based antiviral treatment [
Patients participating in high risk activities for HCV infection or presenting with signs and symptoms of acute infection should be screened for HCV (Grade I, level C).
In cohorts of greater than 3000 pregnant patients, HCV seroprevalence has been found to range from 0.1% to 2.4% [
HCV vertical transmission risk has been reported to be approximately 1.7% in HCV seropositive women and 4.3% in HCV viremic women. The risk of vertical transmission is much higher in HIV-HCV coinfection (estimated to be as high as 19.4%) [
Although HCV virus is detected in breast milk, the risk of transmission with breast feeding is low unless the nursing mother has cracked or bleeding nipples. Breast feeding is not contraindicated in women with HCV. However, breast feeding is not routinely recommended in HIV-HCV coinfection due to the potential risk of HIV transmission.
HCV treatment options for pregnant patients are limited. Pegylated interferon is poorly tolerated in pregnancy and ribavirin is contraindicated due to teratogenicity. It is recommended that ribavirin be avoided for 6 months prior to conception in both females and their male partners. Women of childbearing potential and nonvasectomized HCV-infected men with female partners of childbearing potential are advised to utilize two forms of contraception while ribavirin is used. DAA safety and efficacy data in pregnancy are lacking.
Pegylated interferon and ribavirin are contraindicated during pregnancy and 6 months prior to conception (Class 1, Level C). Women of childbearing potential and nonvasectomized HCV positive men with female partners of childbearing potential on ribavirin therapy should use 2 forms of contraception during treatment and for 6 months after treatment (Class 1, Level C). HCV positive women can safely breast feed. In HIV-HCV coinfection, breast feeding is contraindicated given HIV transmission risk (Class 2A, Level C). HCV positive pregnant women should not be offered HCV DAA therapy at present given the absence of safety and efficacy data and the fact that short-term deferral of therapy is rarely harmful (Class 2A, Level C).
Globally there are an estimated 11 million viremic pediatric cases of HCV infection (defined as <15 years of age) [
Screening for HIV and HCV is recommended for children with potential risk factors for exposure to these viruses (e.g., born to parents with HIV and/or HCV). All HIV-HCV coinfected infants should have HCV viremia testing done at ages 1, 2, and 3 given the high rate of spontaneous clearance before the age of 3 (Class 1, Level B). Current standard of treatment for HCV in pediatrics is weight-based pegylated interferon and ribavirin for those with advanced fibrosis. Consultation with a HCV pediatric specialist is recommended for patients with cirrhosis (Class 1, Level B). Children with minimal fibrosis should delay treatment for approval of interferon-free DAA regimens (Class 1, Level C).
Historically, treatment regimens for HCV containing pegylated interferon and ribavirin had numerous side effects, many of which overlapped with side effects from HIV antiretrovirals. An extensive review of the side effects of interferon-based therapy and their management is beyond the scope of this paper but can be found elsewhere [
Ledipasvir-sofosbuvir was well-tolerated in a large open-label phase III study involving 335 coinfected patients (ION-4) treated for HCV genotype 1 [
Ledipasvir-sofosbuvir when coadministrated with tenofovir disoproxil fumarate (TDF) causes an increase in tenofovir levels, but the clinical significance of these increased levels remains unclear. In ION-4, 4 patients (1%) developed an increase in serum creatinine greater than 35
Ombitasvir-paritaprevir-ritonavir plus dasabuvir with ribavirin was studied in coinfected individuals in an open-label study that included 63 patients (TURQUOISE-1) [
Treatment with sofosbuvir combined with weight-based ribavirin was examined in treatment-naïve and treatment-experienced individuals with HIV and HCV coinfection in the PHOTON-1 and PHOTON-2 studies [
Ribavirin is well-described to cause predictable effects in HIV-positive individuals, including lymphopenia and transient hyperbilirubinemia secondary to ribavirin-induced hemolysis, particularly in patients receiving atazanavir [
ALLY-2 investigated the combination of daclatasvir and sofosbuvir in treatment-naïve and treatment-experienced patients with HCV genotypes 1–4 coinfected with HIV [
There are no dedication sofosbuvir-simeprevir studies in HIV-HCV coinfection to provide insights into side effect profile. In the COSMOS study of HCV monoinfected participants, common side effects included fatigue (25%), headache (21%), nausea (17%), insomnia (14%), and pruritus (11%). Other noteworthy side effects with sofosbuvir-simeprevir for 12 weeks included rash (11%) and photosensitivity reactions (7%) [
Close monitoring for side effects during HCV therapy is required (Class 1, Level C). Anemia related to HCV treatment either with pegylated interferon/ribavirin or a DAA with ribavirin should be primarily managed with ribavirin dose reduction. Erythropoietin use is not recommended for first line anemia management (Class 2b, Level B).
The management of end-stage liver disease includes orthotopic liver transplantation. Guidelines for liver transplant have been developed in both Europe and the United States [
HCV antiviral treatment following transplant is complex but far more feasible with interferon-free DAA regimens [
Liver transplant patients on immunosuppressive drugs are at particular risk for serious drug interactions since cyclosporine and tacrolimus metabolism are highly dependent on CYP3A4 [
HIV-HCV coinfected patients should be considered for liver transplantation assuming all necessary criteria are met (Class 2a, Level C). HCV antiviral therapy should be considered in post-liver transplant recipients (Class 1, Level C).
Access to standard of care antiviral therapy when clinically indicated has long been recommended in Canada by experts involved in the care of patients living with HCV [
Additional considerations of patient readiness and consideration of possible onward HCV transmission risk for individuals in a core transmitter group (IDU and certain MSM populations) compared to those without high risk for transmission (e.g., many baby boomers (born approximately 1945–1970)) may influence a decision to consider delaying therapy.
Circumstances may exist in which first line regimens are not accessible to patients (e.g., restricted funding). The above second line regimens could be considered as treatment options. However, the patient must be fully aware of the diminished likelihood for cure and/or increased likelihood for adverse events compared to first line regimens. Furthermore, lack of provincial availability of some DAAs may preclude use.
HIV-HCV coinfection is common in Canada and associated with a heavy burden of concurrent comorbid conditions which affect health status and outcomes. As such, harm reduction strategies should be implemented to decrease risk of infection amongst high risk populations such as injection drug users and incarcerated individuals.
Coinfection is associated with increased risk of progression of liver disease. End-stage liver disease is a chief cause of morbidity and mortality amongst coinfected individuals.
All HIV-HCV coinfected individuals should be assessed for HCV therapy. ART initiation, irrespective of CD4 count, is an effective strategy to slow liver disease progression and is consistent with current HIV treatment guideline recommendations. However, HCV antiviral treatment initiation prior to HIV ARV therapy in patients with high CD4 cell counts (>500 cells/
DAA treatment has revolutionized HCV treatment in the HIV-HCV coinfected population providing highly effective, short duration, well-tolerated, and safe treatment options. In fact, SVR rates achieved in HIV-HCV coinfection are similar to HCV monoinfection. Current standard of care for genotype 1-infected patients consists of interferon-free, combination DAA regimens. Careful assessment of drug-drug interactions with ART and other common medications is necessary when using these agents.
Current standard of care for genotypes 2 and 3 infected patients remains dual therapy with sofosbuvir and ribavirin as well as daclatasvir with sofosbuvir. When included in DAA regimens, weight-based dosing of ribavirin is recommended. In individuals with mild liver disease, conservative monitoring with deferral of therapy may be necessary given current HCV DAA funding restrictions. Due to current reimbursement restrictions in some jurisdictions, pegylated interferon and ribavirin may represent the only treatment option available for nongenotype 1 infection. This is not acceptable and should be changed immediately to allow for the provision of optimal patient care.
Mark Hull, MD, is affiliated to University of British Columbia, British Columbia Centre, for Excellent in HIV/AIDS. Grant support is from National Institute on Drug Abuse (NIDA R01DA031043-01). Honoraria was received from (speaking engagements and/or consultancy) AbbVie, Bristol Myers Squibb, Gilead, Merck, Ortho-Janssen, and ViiV. Stephen Shafran, MD, is affiliated to University of Alberta. Research funding and Honoraria are from AbbVie, BI, BMS, Gilead, Janssen, Merck, Pfizer, Roche, and Vertex. Alex Wong is affiliated to Regina Qu’Appelle Health Region, Regina. Consulting and Honoraria are received from Merck, Gilead Sciences, Bristol Myers Squibb, Pfizer, Janssen, Boehringer-Ingelheim, and AbbVie. Funding for regional and provincial programming was received from Merck, Gilead Sciences, Bristol Myers Squibb, ViiV, Janssen, and AbbVie. Clinical trials funding is from Gilead Sciences, ViiV, Merck, and AbbVie. Alice Tseng, B.Sc.Phm., Pharm.D., is affiliated to Toronto General Hospital. Speaking honoraria is received from AbbVie, Gilead, and Merck. Unrestricted educational grants are received AbbVie, Gilead, Janssen, Merck, and ViiV. Pierre Giguère, B.Pharm., M.S., is affiliated to The Ottawa Hospital. Education support, research grants, and consultation fees are received from Bristol Myers Squib, Gilead Sciences, Merck, ViiV, Janssen, and AbbVie. Lisa Barrett, MD, is affiliated to Dalhousie University. Advisory or consultancy is from Merck, Gilead, AbbVie, and BMS. Research funding is from AbbVie and Gilead. Shariq Haider is affiliated to McMaster University, Hamilton. Advisory Boards are Viiv, BMS, Gilead, Merck, and AbbVie. Speaker honorarium is from AbbVie and Merck. Clinical Trials are received from AbbVie, BMS, and Brian Conway, Vancouver Infectious Diseases Centre. Grants, honoraria, and consultancies are received from Jannsen, Merck, Gilead, and AbbVie. Marina Klein, MD, is affiliated to McGill University. Grants are received form CIHR, Fonds de recherche Santé-Québec (FRQ-S), and CIHR Canadian HIV Trials Network (CTN); “Chercheurs nationaux” career award from the FRQ-S; research support from Merck, Bristol Myers Squibb, Gilead, and ViiV. Consulting fees are from ViiV, AbbVie, BMS, and Gilead. Speaker honorarium is from AbbVie and Merck. Curtis Cooper, MD, is affiliated to University of Ottawa. Grants are received from Ontario HIV Treatment Network Applied HIV Research Chair. Clinical Trials are from Gilead, AbbVie, and Merck. Advisory Boards are BMS, Gilead, Merck, and AbbVie. Speaker honorarium is from AbbVie, Gilead, and Merck.
The authors declare that they have no competing interests.
The authors are grateful for the opinions and suggestion offered by patients, health care providers, and other HCV stakeholders which guided the development of this document. Special thanks are due to David Mackie, Erin Love, Andrew Matejcic, and Heiko Decosas for their assistance in the development and publication of these guidelines. Support for the development of these guidelines was provided from The Canadian Institutes for Health Research Canadian HIV Trials Network, CIHR Dissemination Grant Program, and the Canadian Association for HIV Research. Unrestricted funding from Gilead Canada, Merck, Abbvie, and BMS is gratefully acknowledged.