Secondary Logo

Challenges and opportunities for hepatitis C drug development in HIVhepatitis C virus-co-infected patients

Soriano, Vincenta; Sherman, Kenneth E.b; Rockstroh, Juergenc; Dieterich, Douglasd; Back, Davide; Sulkowski, Markf; Peters, Mariong

doi: 10.1097/QAD.0b013e32834bbb90
EDITORIAL REVIEW
Free

The approval of the first direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) has been eagerly expected for treating chronic hepatitis C in HIV individuals given that progression to cirrhosis and end-stage liver disease occurs faster in the co-infected population. The appropriate and judicious use of DAAs may provide cure to a large number of HIV–HCV patients. On the contrary, the widespread use of DAAs will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance in HCV. As a result of using first-generation DAAs in HIV–HCV-co-infected patients, a growing proportion of the remaining hepatitis C individuals will be those harboring non-HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will accumulate in resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.

aDepartment of Infectious Diseases, Hospital Carlos III, Madrid, Spain

bDepartment of Gastroenterology, University of Cincinnati, Cincinnati, Ohio, USA

cDepartment of Internal Medicine, University of Bonn, Bonn, Germany

dDivision of Liver Diseases, The Mount Sinai Medical Center, New York, New York, USA

eDepartment of Pharmacology, University of Liverpool, Liverpool, UK

fDivision of Infectious Diseases, The John Hopkins University, Baltimore, Maryland

gDepartment of Hepatology Research, University of California, San Francisco, California, USA.

Correspondence to Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III, Hospital Carlos III, calle Sinesio Delgado 10, Madrid 28029, Spain. Tel: +34 91 453 2500; fax: +34 91 733 6614; e-mail: vsoriano@dragonet.es

Received 19 June, 2011

Revised 23 July, 2011

Accepted 8 August, 2011

Back to Top | Article Outline

Introduction

The clinical burden of HIV and hepatitis C virus co-infection

Liver disease is one of the leading causes of hospitalization and death in HIV-infected persons in the western world [1,2] where HAART is widely available and halts progression of HIV-associated immunodeficiency in most infected individuals. AIDS-related opportunistic infections and cancers steadily became less common, being currently diagnosed mainly in individuals unaware of their HIV status and/or recent immigrants coming from highly HIV endemic developing regions where antiretroviral therapy is not easily affordable. For the vast majority of HIV-infected persons in the western world, who regularly attend HIV outpatient clinics, hepatic complications mainly result from chronic viral hepatitis (B, C, D), drug-related hepatotoxicity (antiretroviral drugs and other meds), alcohol abuse and liver involvement as part of other systemic conditions (i.e. tuberculosis) [3,4].

Chronic hepatitis C is by far the most frequent cause of liver complications in HIV patients infected parenterally, as intravenous drug users or recipients of contaminated blood or blood products (i.e. hemophiliac patients). More than two-thirds of intravenous drug users with HIV infection in Europe and North America have chronic hepatitis C [5,6]. In the absence of successful hepatitis C virus (HCV) therapy, one third may progress to cirrhosis within 25 years of infection [5]. This faster liver disease progression in the HIV setting may be improved with the use of HAART [7], which has led to recommendations for earlier antiretroviral treatment initiation in all HIV–HCV-co-infected individuals [8]. However, accumulated toxicity from antiretroviral drugs, HIV itself or comorbidities (i.e. metabolic abnormalities) may help explain why progression of HCV-related liver disease remains accelerated in most co-infected patients on HAART [9].

Underlying chronic hepatitis C enhances the risk of elevations in liver enzymes in patients using HAART [10,11], and the tolerance of antiretroviral therapy improves following clearance of HCV with successful therapy [12]. Thus, in the absence of contraindications, treatment of chronic hepatitis C should be provided as early as possible to co-infected persons. Ideally, it might be considered before beginning antiretroviral therapy in patients with CD4 cell counts higher than 500 cells/μl and relatively low plasma HIV-RNA (i.e. <50 000 copies/ml). If plasma HIV-RNA is higher, concerns have been raised about a detrimental impact of uncontrolled HIV replication on the efficacy of hepatitis C therapy [13].

In places where interferon α (IFNα)-based HCV therapy has been widely used in HIV–HCV-co-infected patients, those who were not cured often show a difficult-to-treat phenotype, characterized by high HCV-RNA levels, infection by HCV genotypes 1 or 4 [14], unfavorable IL28B alleles and/or advanced liver fibrosis [15]. Therapeutic options for this population are limited and many co-infected patients with advanced liver fibrosis have already died and/or entered liver transplant lists, although only a few have been transplanted [16]. Moreover, liver transplantation is not the ultimate solution for HIV–HCV-co-infected patients, given that HCV re-infection of the allograft is almost universal and progression to cirrhosis is further accelerated in HIV–HCV-co-infected transplanted patients, with survival rates below 50% at 5 years after transplantation [17]. Novel anti-HCV therapies are urgently needed in this population [18].

Back to Top | Article Outline

Lessons from using direct-acting antiviral in hepatitis C virus mono-infection

The treatment of HCV infection is expected to evolve rapidly following the recent approval of the first HCV protease inhibitors. Telaprevir and boceprevir were approved by the US Food and Drug Administration (FDA) in May 2011 for the treatment of chronic hepatitis C. They have to be used in combination with pegylated (peg)IFNα and ribavirin (RBV) in patients infected with HCV genotype 1.

For treatment-naive patients and prior relapsers, telaprevir is given orally 750 mg (two pills) per 8 h for the initial 12 weeks of therapy, continuing with pegIFNα–RBV for an additional 12 weeks (total length of therapy 24 weeks) or 36 weeks (total length of therapy 48 weeks) based on achievement of undetectable HCV-RNA at week 4 of therapy (rapid virologic response) [19]. The sustained virologic response (SVR) rate observed in treatment-naive HCV-mono-infected patients ranged from 44% in pegIFNα–RBV controls to 75% in telaprevir triple arms [20]. Prior partial responders and null responders should receive 12 weeks of telaprevir along with pegIFNα–RBV followed by 36 weeks of pegIFN–RBV. SVR rates were higher when retreating with telaprevir–pegIFNα/RBV patients who previously had failed pegIFNα–RBV therapy compared with retreatment with pegIFNα–RBV alone (86 vs. 24% in relapsers; 57 vs. 15% in partial responders; and 31 vs. 5% in null responders) [21]. However, in all these studies, telaprevir was associated with a higher treatment discontinuation rate due to adverse effects of which rash is the most common and can be severe in up to 4% of patients. Interestingly, it tends to develop as time passes by affecting more than 25% of treated patients by completion of week 12 of therapy. Other frequent adverse events are gastrointestinal side-effects (nausea, vomiting, diarrhea), pruritus and anemia [22,23]. Given the challenge represented by the need for dosing the drug thrice daily, the results of a recent study supporting twice-daily dosing of telaprevir [24] are especially welcome for the co-infected population.

Boceprevir is another linear serine HCV protease inhibitor that has also received approval for use in combination with pegIFNα–RBV in patients infected with HCV genotype 1. In a phase 2 study, IFNα-naive HCV-mono-infected patients were treated with pegIFNα–RBV for 4 weeks (‘lead-in’ phase), followed by the addition of oral boceprevir 800 mg per 8 h until completion of triple therapy for an additional 24 weeks (total 28 weeks) or 44 weeks (total 48 weeks). The SVR rates were significantly higher in patients randomized to receive boceprevir (56–75%) compared with those who took placebo (40%) [25]. In phase 3 trials, SVR rates of 67–68% were obtained in boceprevir arms compared with 40% in pegIFN–RBV controls in IFNα-naive white patients [26]. These figures were 69–75 vs. 29% in prior relapsers and 40–52 vs. 7% in prior nonresponders [27]. In all boceprevir treatment arms, however, there was a significantly increased risk of anemia compared with pegIFNα–RBV, and erythropoetin was used by 40% of patients. No severe rash has been reported with boceprevir. Similar to telaprevir, boceprevir patients with viral breakthrough and viral relapse were found to have selected viruses with drug resistance mutations. As with telaprevir, relapses are seen in less than 10% of patients completing a course of boceprevir therapy with undetectable viremia, although it is around 25% in patients only treated with pegIFNα–RBV.

Other molecules with potent antiviral activity, improved safety profile and more convenient dosing are being tested in clinical trials and will hopefully come to market soon. Most direct-acting antivirals (DAAs) target specific HCV enzymes, such as the polymerase, protease or NS5A protein. Other future medications may include novel IFN-type preparations, such as IFNλ, or cyclophilin inhibitors, such as alisporivir [18]. To date, only some phase I studies have been performed with these newer agents in HIV-infected patients and further investigations must be encouraged.

Back to Top | Article Outline

Evaluation of direct-acting antivirals in the HIV setting

Drug interactions with antiretroviral drugs [28,29], increased and overlapping toxicities, and rapid selection of drug-resistant HCV mutants are among the most challenging issues with the use of DAAs in HIV–HCV-co-infected patients. It is further complicated because other recently identified prognostic factors also play a role in the outcome of HCV treatment in HIV–HCV-co-infected patients. The data on IL28B status in HIV patients closely parallels that in HCV-mono-infected patients [30,31]. Vitamin D is a relatively new factor to consider in treatment success and is emerging as particularly important in the HIV-seropositive patient [32,33]. Insulin resistance is another variable to consider, as it seems to be quite common in co-infected patients [34,35] and may be related to the underlying antiretroviral regimen. In addition, CD4 cell count and HIV replication are unique to the co-infected patient and need to be considered in any trial design of HCV therapy in this population.

In HIV–HCV-co-infected patients, clinical trials evaluating the safety and efficacy of HCV protease inhibitors are underway. The first data with telaprevir were released early this year [36]. Vertex study 110 is an ongoing phase II trial that examines the safety and efficacy of telaprevir in combination with pegIFNα–RBV in HIV–HCV-co-infected patients, most of whom were on antiretroviral therapy. Preliminary results at weeks 4 and 12 were recently presented (Fig. 1) [36], with responses similar to those seen in HCV-mono-infected patients. No serious adverse events were recorded, including rashes. Given the induction of telaprevir metabolism by efavirenz, higher telaprevir dosing (1125 mg every 8 h) was used in individuals receiving efavirenz. Other antiretroviral drugs allowed in the trial were tenofovir, emtricitabine, lamivudine and ritonavir-boosted atazanavir for all of which information on drug interactions is available.

Fig. 1

Fig. 1

Because HIV and HCV share some biological similarities [37], concern have been raised that HIV drugs might induce changes in the HCV polymerase and/or protease [38], or vice versa. However, in a study of 28 HIV–HCV-co-infected patients in whom the HCV NS5B gene was sequenced before and during antiretroviral drug use, there was no evidence of selection of drug resistance mutations in the HCV polymerase [39]. It should be highlighted that the HCV polymerase is a RNA-dependent RNA polymerase distinct from the HIV reverse transcriptase, which is a RNA-dependent DNA polymerase and that no cross-activity has been observed in vitro. Likewise, the HCV protease is serine protease, whereas the HIV protease is a structurally different aspartate protease [40].

The dosing schedule of first-generation HCV protease inhibitors lacks convenience, as telaprevir has to be given as two pills (three pills with efavirenz) and boceprevir as four pills, both drugs every 8 h with food. In HIV patients, this complex dosing must be integrated into the antiretroviral therapy requirement; for example, efavirenz should be taken on an empty stomach. Further, polypharmacy may be associated with poor drug adherence and this will be a major challenge in the treatment of chronic hepatitis C in HIV-co-infected individuals, as most patients are often taking other medications in addition to antiretroviral drugs. Poor treatment adherence may lead to selection of drug resistance in HCV. Although the use of pegIFNα as part of hepatitis C therapy may suppress HIV replication (approximately 1 log on average), poor drug compliance may particularly impact on the risk of failure to HCV protease inhibitors. Unexpected drug interactions and/or overlapping toxicities between HCV and HIV drugs (i.e. rash, anemia) may further impact negatively on the efficacy of HCV protease inhibitors in this population.

Back to Top | Article Outline

Drug interactions between direct-acting antivirals and HIV medications

New challenges are ahead in relation to understanding the pharmacokinetics and potential drug interactions of the new DAAs. Specifically, most HIV-infected patients with chronic hepatitis C are receiving antiretroviral drugs and are at a high risk for drug interactions. As combination HCV treatment evolves, it is essential to consider the increased potential for drug interactions in this population.

Back to Top | Article Outline

Potential interactions using current hepatitis C virus treatment and antiretrovirals

Interactions between pegIFNα–RBV and antiretroviral drugs are relatively limited, with the main concern being RBV and zidovudine (severe anemia); RBV and didanosine (increased risk of mitochondrial toxicity attributed to increased exposure to the intracellular metabolite dideoxy-ATP) [41,42]; RBV and stavudine (increased risk of mitochondrial toxicity, including exacerbated weight loss) [43,44]; RBV and abacavir (reduced response to anti-HCV treatment in some studies, probably due to competition for intracellular phosphorylation) [45,46]; RBV and atazanavir (hyperbilirubinemia may be more pronounced) [47]; and pegIFNα and efavirenz (potentiation of insomnia, depressive symptoms and other mood disorders). For up-to-date information on HCV drug interactions, the reader may access the website http://www.hep-druginteractions.org and/or http://medicine.iupui.edu/clinpharm/ddis/.

Back to Top | Article Outline

Interactions between hepatitis C virus protease inhibitors and HIV drugs

Although there are limited data available at present, there is clear evidence of interactions between HCV protease inhibitors and some antiretroviral drugs (Table 1).

Table 1

Table 1

Telaprevir is a substrate and inhibitor of CYP3A4 and the transporter P-gp. On the basis of prior knowledge, it was assumed that telaprevir exposure would increase when co-administered with ritonavir-boosted HIV protease inhibitors [28]. Contrary to expectations, there is a reduction in telaprevir exposure, slightly with atazanavir/r but significant with darunavir/r or fosamprenavir/r and very pronounced with lopinavir/r. The mechanism involved in the decreased exposure is yet to be determined. Efavirenz also reduces telaprevir exposure significantly, and an increased dose of telaprevir is recommended [48]. The use of tenofovir does not modify telaprevir exposure; however, telaprevir increases significantly tenofovir exposure and close monitoring of kidney function is warranted when both drugs are used concomitantly [49]. The effect of telaprevir on HIV protease inhibitors is variable, with reduced exposure of darunavir/r and fosamprenavir/r, no change of lopinavir/r with an increase in atazanavir/r trough concentrations. Although appropriate doses have not been well established for telaprevir with ritonavir-boosted HIV protease inhibitors, a dose of 1125 mg per 8 h has recently been successfully tested with efavirenz [36]. Other interactions highlighted in Table 1 show that telaprevir causes a decrease in the CYP2C9-metabolised antidepressant escitalopram [50]. The interactions of telaprevir with methadone [51] do not appear to be clinically relevant, as despite a decrease in the total R-methadone concentration, the unbound drug remains unaltered.

Boceprevir is principally metabolized by the enzyme aldo-keto reductase with a minor contribution from CYP3A4; however, it inhibits CYP3A4 [52]. The interaction studies of boceprevir were conducted in HIV-negative individuals using medications likely to be co-administered in chronic hepatitis C patients [53]. The information recorded in Table 1 suggests that CYP3A4 and P-gp do not contribute substantially to boceprevir metabolism and/or elimination. There is no significant increase in boceprevir exposure when given with multiple doses of low-dose ritonavir (indeed there is a small decrease possibly due to induction). The findings with ketoconazole suggest involvement of another non-CYP3A4-mediated pathway. The aldo-keto reductase inhibitor diflusinal causes a small increase in boceprevir trough concentration. The increase in midazolam supports boceprevir as a strong, reversible inhibitor of CYP3A4. No dosage adjustment for boceprevir is needed when co-administered with tenofovir. The clinical implications of a reduced boceprevir trough concentration when co-administered with efavirenz are as yet unclear. Boceprevir significantly affected the exposure of the oral contraceptive drospirenone (increased) and ethinyloestradiol (decreased), and accordingly the use of these drugs along with boceprevir is contraindicated. The significance of the increase in the progestogen is unclear. To date, no information is available about interactions between boceprevir and raltegravir or methadone, although it is expected that they will not be clinically relevant.

Given the findings currently with telaprevir and boceprevir, it seems quite difficult to make predictions of interactions with drugs commonly used by HIV–HCV-co-infected patients. Also, there are HCV protease inhibitors that are boosted by ritonavir due to inhibition of CYP3A4 metabolism. This is the case for danoprevir, which is currently in clinical development boosted by ritonavir [54]. Despite being metabolized by CYP3A4, TMC435 is not boosted and is in clinical trials as a once-daily drug. Clearly, there are differences in the disposition of HCV protease inhibitors, which is reflected in the effect of ritonavir to either boost or reduce plasma exposure. This probably means that we will need interaction studies for all HCV protease inhibitors and their ritonavir-boosted HIV counterparts in order to realistically assess the direction and magnitude of an interaction.

What about the impact of the HIV nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, etravirine and rilpivirine? These are drugs that have an induction effect on certain enzymes and transport proteins. Although we have some data in relation to efavirenz and telaprevir (as previously discussed), we will need additional information to have confidence in treating the co-infected individual.

Back to Top | Article Outline

Potential interactions between hepatitis C virus polymerase inhibitors and antiretrovirals

On the basis of their metabolic profile, the potential for pharmacokinetic interactions between HCV polymerase inhibitors and antiretroviral drugs is very much less. However, pharmacodynamic interactions may be more problematic, especially as result of inhibitory competitive phenomena in the phosphorylation pathways, for example, between mericitabine and other cytidine analogues, such as lamivudine or emtricitabine [55].

Back to Top | Article Outline

Implications of viral kinetics in HIVhepatitis C virus-co-infected patients

Viral kinetic modeling is a powerful mathematical technique that permits analysis, interpretation and extrapolation of data derived from perturbation of the steady state of viral replication and clearance by an intervention. Prior to introduction of a perturbation, levels of chronic viral infections, including HCV, hepatitis B virus and HIV tend to exist in a relatively steady state with stable viral titers observed over serial sequential measurements. Although this appears to be a static condition, it in fact represents a complex equilibrium between viral production and viral clearance [56]. In HIV, a high and stable viral load is associated with disease progression. In contrast, for HCV, high viral load does not predict degree of hepatic injury or liver fibrosis progression, but is associated with a poorer response to IFNα-based therapy [37].

Any intervention that affects either viral production or clearance perturbs the system and affects the steady state. A change in viral production may be observed with addition of IFNα, RBV, DAAs or potentially with immune modulators. The ‘perfect drug’ would completely abrogate the replicative process, resulting in a rapid block to viral production. In reality, perfect drugs do not exist, and this is reflected in the observed rates of viral decline following administration of one or more antiviral agents [56]. In Fig. 2, several key features are apparent. First, there is a lag period with no change in viral load following administration of an antiviral agent. This reflects both absorption and the time needed for a biological effect to occur. Next, there is a rapid decline in viral load, which has been termed ‘phase 1’ response [56]. This reflects a relative but less than complete block to viral production, with the decline driven by intrinsic mechanisms of viral clearance. As production block is incomplete, rapid decline does not continue and we enter a ‘phase 2’ decline, characterized by a lesser slope [57]. During this phase, less new cells are infected, and infected cells continue to produce virus until they undergo natural host cell death and turnover, which ultimately leads to complete viral clearance. It is important to note that even when viral titers are undetectable in serum, several logs of virus may still be present in the body and the viral decline continues along its predetermined path, ultimately ending in total host clearance.

Fig. 2

Fig. 2

The more potent the antiviral agent, the greater the level of first phase decline. Even very minor differences in viral efficacy at stopping viral production (e.g. 99% block vs. 99.9%) can have a dramatic effect on the degree of first-phase decline. The faster the first-phase decline, the more rapid is the time to predicted viral clearance. Early sampling can predict the time to serum/plasma viral clearance with a high degree of accuracy with almost complete blocking of HCV replication and nearly perfect drug adherence, HCV clearance would require 8–12 weeks of treatment [57]. An added advantage of early clearance is the more rapid loss of preexisting variants with reduced affinity in the catalytic site for DAAs, which reduces the risk of emergence of drug-resistant viral strains [58].

Use of viral kinetic modeling permits rapid evaluation of different drugs, different doses or formulations of the same drug and combinations of antiviral agents in terms of efficacy in viral clearance. It also permits comparison of host effects on antiviral therapies, including sex, race, body weight, steatosis, host genetic polymorphisms (e.g. IL28B) and other characteristics. The utility of the technique has limitations as well. Patients must agree to undergo frequent sampling under controlled conditions during the first 2–3 days of antiviral drug administration. Multiple viral loads must be obtained. The mathematical techniques are complex and require special skills in calculation and interpretation. Short-term response predictions can be modified by issues of tolerability and adherence that cannot be predicted in the first days of therapeutic intervention. With these caveats, kinetic modeling remains a powerful tool in DAA research.

In the HIV setting, a singular viral kinetic behavior has been noticed, attributed initially to a slower viral decay associated with the underlying immunodeficiency [59], and thereafter being shown to mainly depend on the greater levels of viremia (approximately 1 log on average) seen in HIV–HCV-co-infected patients with respect to HCV-mono-infected individuals (Fig. 2) [60]. Exposure to RBV seems to particularly influence viral kinetics in this population [61,62], as well as IL28B alleles [63].

Back to Top | Article Outline

Hepatitis C virus drug resistance in the HIV setting

One of the major challenges with the use of DAAs is selection of drug resistance, a concern that did not exist for pegIFNα nor RBV. No doubt the knowledge about drug resistance in HIV is helpful for understanding resistance in HCV. However, biological differences between these viruses may account for significant distinct clinical implications [37]. At least four aspects have raised particular attention. First, the speed of selection of drug resistance in HCV is faster than in HIV for most drugs (with the notable exception of nucleos(t)ide analogues inhibiting the active site of the HCV polymerase), displaying most compounds low barrier to resistance [64,65]. The consequences are that there is no room for monotherapy (real or ‘virtual’) and that very early viral kinetics (days to a few weeks) predicts the likelihood of HCV treatment success.

Second, like in HIV, broad cross-resistance between HCV drugs belonging to the same family exists [66], being the only exception nonnucleoside polymerase inhibitors, which may be split out in four to five distinct classes [18], which may allow their additive/synergistic combination. The major positions associated with resistance to current HCV drugs are recorded in Fig. 3. Given the high HCV variability, resistance patterns may depend on both drugs considered and HCV subtypes. For instance, the most frequent resistance mutations selected failing boceprevir and telaprevir are at codons 36 and 155 in HCV-1a and at codons 54, 156 and 170 in HCV-1b.

Fig. 3

Fig. 3

Third, transmission of drug-resistant viruses is relevant for antiretroviral therapy in drug-naive HIV patients, but may be less a concern for HCV depending upon whether chronic hepatitis C patients exposed to DAAs but who have failed therapy and selected drug resistance remain engaged in high-risk behaviors and become the source of new incident HCV cases. In contrast with HIV, natural polymorphisms across distinct HCV genotypes/subtypes may be a huge challenge, driving differences in susceptibility to distinct DAAs and barrier to resistance, and for this reason eventually justify baseline resistance testing. Table 2[67–73] summarizes the results of studies that have examined the frequency of changes at positions associated with resistance to DAAs in treatment-naive HCV individuals [67–73]. Using population sequencing, around 7% of HCV-mono-infected individuals may harbor resistance-associated mutations to HCV protease inhibitors; however, their presence does not seem to compromise the virologic response to these agents when they are used along with pegIFNα–RBV triple combination therapy. Although the rate of minority variants increases using more sensitive techniques, the reproducibility of results tend to be limited when present at rates less than 1% of the quasispecies population.

Table 2

Table 2

Lastly, although concern has been raised about a potential harmful effect of HIV-associated immunodeficiency on the risk of selection of drug resistance in HCV, as result of increased variability due to loss of immune control or to interference with the concomitant use of antiretroviral agents, recent data do not support these concerns. As previously highlighted, viral enzyme targets for antivirals are quite different in HIV and HCV, and significant structural differences between these molecules preclude that treatment with their respective inhibitors may select drug resistance changes in the other virus [39]. On the contrary, viral diversity for HCV in the presence of immunosuppression does not seem to be associated with an increased rate of HCV resistance-associated mutations [74].

Back to Top | Article Outline

Design of clinical trials in HIVhepatitis C virus-co-infected patients

A simple categorization of the HIV–HCV-co-infected population can be made based on treatment experience for each virus. Due to recent recommendation for more aggressive treatment of HIV infection in persons with high CD4 cell counts, the largest number of co-infected patient candidates for DAAs will be on antiretroviral therapy. In this subset of patients, HCV therapy must focus on the risk for drug interactions and plan in advance which antiretroviral drugs must be used concomitantly. Before beginning HCV therapy, patients should be on a stable, well tolerated, antiretroviral regimen for at least 1 month and have undetectable plasma HIV-RNA. In these patients, the major concern will be for failing HCV therapy, given that HIV suppression will be further enhanced by pegIFNα, which exerts some antiretroviral activity [75].

In situations where hepatitis C therapy has actively being given to co-infected individuals, a substantial proportion of the current co-infected population will have been exposed to pegIFNα and/or RBV, and become failures, relapsers or intolerant to HCV medications [14]. This accumulation of the most difficult-to-treat patients, which are those with more advanced stages of liver fibrosis, will be the most challenging population in most urgent need of therapy [15].

As prioritization of DAAs will most likely be mandated upon approval, co-infected patients with advanced liver fibrosis should be those with easier access to triple combination therapy [76]. However, HCV-mono-infected individuals with advanced liver fibrosis are more likely to fail to respond to hepatitis C therapy. Once these demands are covered, DAAs should be considered for a wider number of co-infected individuals. Given the good responses using triple therapy in prior relapsers, treatment should also be prioritized in this subset of patients.

Back to Top | Article Outline

Special HIVhepatitis C virus-co-infected patient populations

There are groups of co-infected individuals with particular medical needs (Table 3). The highest need is in HIV–HCV-co-infected patients undergoing liver transplantation, prior nonresponders to pegIFNα–RBV, individuals intolerant to pegIFNα and/or RBV and patients with advanced liver disease with thrombocytopenia.

Table 3

Table 3

Back to Top | Article Outline

Liver transplantation

The outcome of liver transplantation in HIV-infected patients is poorer than in HIV-negative individuals [17], with 5-year survival rates of 48 vs. 75%, respectively [77]. The main reason for this unfavorable prognosis is the accelerated course of the almost universal HCV re-infection of the allograft. Indeed, the SVR to pegIFNα–RBV is as low as 22% in HIV–HCV-co-infected liver transplant recipients. Clearly, better HCV treatment options are needed for this population in whom a major challenge will be drug interactions between HIV and HCV drugs in the presence of immunosuppressants. In a phase I study, large increases in cyclosporine or tacrolimus exposure were seen when co-administered with telaprevir [78].

Back to Top | Article Outline

Prior interferon-α nonresponders

In HIV–HCV-co-infected patients who failed a previous course of suboptimal hepatitis C therapy, retreatment with adequate doses and duration of pegIFNα–RBV is advisable in the presence of advanced liver fibrosis. However, even with improved drug dosing, duration and optimal adverse event management, the overall response rates in HCV genotype 1 patients is below 20%. Successful treatment becomes even less likely if patients were previous null responders (<1 log drop in HCV-RNA on pegIFNα–RBV therapy). Most of these individuals harbor unfavorable IL28B alleles [63], and new therapeutic options beyond IFNα are clearly needed for them.

Back to Top | Article Outline

Advanced liver disease with thrombocytopenia

Low platelet count in HIV–HCV-co-infected patients may be related to HIV or HCV. Thrombocytopenia associated with HIV infection is generally occurs following suppression of viral replication with antiretroviral therapy. Low platelet count due to HCV-related cirrhosis with portal hypertension and hypersplenism is more challenging, because pegIFNα may enhance thrombocytopenia and increase the risk of bleeding. Clearly, other therapeutic options are eagerly awaited for this particularly difficult-to-treat population.

Back to Top | Article Outline

Regulatory aspects

For label approval of new DAA and specific acknowledgment of its potential use in HIV-infected persons, a minimum of experience in 300 HIV–HCV -co-infected patients in development trials is required according to the published FDA guidelines. The European Medical Agency (EMA) has suggested that fewer patients (approximately 100) will be needed for labeling in the co-infected population.

Following the approval of the first HCV protease inhibitors, the inclusion of control arms providing only pegIFNα–RBV will generally no longer be required in the design of trials that assess new DAAs. Moreover, immediate roll-over plans adding more potent therapeutic options for patients failing virologically will be required. Given the high risk of selection of drug resistance, exposure to single agents as monotherapy is currently considered only for very short periods and generally not over 3 days.

Back to Top | Article Outline

Future prospects of direct-acting antivirals in HIVhepatitis C virus co-infection

Contraindications to the use of either pegIFNα and/or RBV are quite common in HIV–HCV-co-infected individuals and have discouraged the treatment of many patients until now. As DAAs will initially be provided along with pegIFNα–RBV, the benefit of triple therapy will still exclude certain populations, such as patients with serious neuropsychiatric conditions, decompensated cirrhosis, severe anemia, alcohol abuse and renal disease. Unfortunately, all these situations are more frequently seen in co-infected than in HCV-mono-infected patients. Therefore, combination DAA regimens, sparing IFNα and/or RBV, are eagerly awaited for the treatment of chronic hepatitis C in the HIV population.

Combination DAA trials are already being tested in HCV-mono-infected individuals [79]. Several caveats, however, should be taken into consideration before moving ahead in the HIV population. Combinations have to be synergistic or at least additive in terms of antiviral activity to avoid antagonistic effects. Combinations of DAA agents belonging to the same family should generally be avoided, given the large overlap in cross-resistance profiles with most of the current molecules. Likewise, drugs with overlapping toxicities must be used with caution, and particular attention must be focused on the potential risk for drug interactions with antiretroviral drugs.

Given that the antiviral activity of DAA agents may differ according to HCV genotypes/subtypes and that the benefit of pegIFNα seems to be largely influenced by IL28B genotypes, it is reasonable to envisage that personalized regimens will be utilized.

Following the approval of the first DAAs, a widespread use of these agents should be expected. Their use will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance. On the contrary, the appropriate and judicious use of DAAs may provide cure to a large number of patients. As a consequence, a growing proportion of the remaining infected patients will harbor non–HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will concentrate in developing and resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.

Back to Top | Article Outline

Acknowledgements

V.S. and M.S. chaired the panel. All authors participated in face-to-face meetings and teleconferences. Each author wrote one to two sections of the manuscript. V.S. wrote the consensus draft, which was circulated electronically and revised by all authors. The final submission recorded the suggestions of all authors.

Back to Top | Article Outline

Conflicts of interest

Vertex Pharmaceuticals Inc. provided support for the meetings that the members of the expert panel attended. Vertex was not involved in the discussions neither in the writing of this manuscript.

Back to Top | Article Outline

References

1. Weber R, Sabin C, Friis-Møller N, Reiss P, El-Sadr W, Kirk O, et al. Liver-related deaths in persons infected with the HIV: the D:A:D study. Arch Intern Med 2006; 166:1632–1641.
2. Ruppik M, Ledergerber B, Rickenbach M, Furrer H, Battegay M, Cavassini M, et al.Changing patterns of causes of death: SCCS, 2005 to 2009 [abstract 789]. In: CROI 2011; 27 February to 2 March 2011; Boston, Massachusetts, USA.
3. Merwat S, Vierling J. HIV infection and the liver: the importance of HCV-HIV coinfection and drug-induced liver injury. Clin Liver Dis 2011; 15:131–152.
4. Peters M, Soriano V. HIV and the liver. In: Dooley J, Lok A, Burroughs A, Heathcote J, editors. Sherlock's diseases of the liver and biliary system. 12th ed. Oxford: Blackwell Publishing Ltd; 2011. pp. 438–451.
5. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007; 21:1073–1089.
6. Rockstroh J, Bhagani S, Benhamou Y, Bruno R, Mauss S, Peters L, et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 2008; 9:82–88.
7. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 2003; 362:1708–1713.
8. Shafran S. Early initiation of antiretroviral therapy: the current best way to reduce liver-related deaths in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2007; 44:551–556.
9. Blanco F, Barreiro P, Ryan P, Vispo E, Martín-Carbonero L, Tuma P, et al. Risk factors for advanced liver fibrosis in HIV-infected individuals: role of antiretroviral drugs and insulin resistance. J Viral Hepat 2011; 18:11–16.
10. Soriano V, Puoti M, Garcia-Gascó P, Rockstroh J, Benhamou Y, Barreiro P, et al. Antiretroviral drugs and liver injury. AIDS 2008; 22:1–13.
11. Nuñez M. Clinical syndromes and consequences of antiretroviral-related hepatotoxicity. Hepatology 2010; 52:1143–1155.
12. Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007; 196:670–676.
13. Dore G, Torriani F, Rodriguez-Torres M, Brau N, Sulkowski M, Sola R, et al. Baseline factors prognostic of sustained virological response in patients with HIV-hepatitis C virus co-infection. AIDS 2007; 21:1555–1559.
14. Medrano J, Resino S, Vispo E, Madejon A, Labarga P, Tuma P, et al. HCV treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV-coinfected patients. J Viral Hepat 2011; 18:325–330.
15. Poveda E, Vispo E, Barreiro P, de Mendoza C, Labarga P, Fernandez-Montero JV, et al.Predicted challenges using direct acting antivirals in the current HIV-HCV coinfected population in Spain. Antivir Ther (in press).
16. Maida I, Núñez M, González-Lahoz J, Soriano V. Liver transplantation in HIV-HCV coinfected candidates: what is the most appropriate time for evaluation?. AIDS Res Hum Retroviruses 2005; 21:599–601.
17. Tan-Tam C, Frassetto L, Stock P. Liver and kidney transplantation in HIV-infected patients. AIDS Rev 2009; 11:190–204.
18. Soriano V, Peters M, Zeuzem S. New therapies for hepatitis C virus infection. Clin Infect Dis 2009; 48:313–320.
19. Sherman K, Flamm S, Afdhal N, for the ILLUMINATE Team. Telaprevir combination with peginterferon alfa-2a and ribavirin for 24 or 48 weeks in treatment-naive genotype 1 HCV patients who achieved an extended rapid virological response: final results of phase 3 ILLUMINATE study [abstract LB-2]. In: 61th American Association for the Study of Liver Diseases (AASLD); 29 October to 2 November 2010; Boston, Massachusetts, USA.
20. Jacobson I, McHutchison J, Dusheiko G, di Bisceglie A, Reddy K, Bzowej N, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405–2416.
21. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428.
22. Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839–1850.
23. McHutchison J, Manns M, Muir A, Terrault N, Jacobson I, Afdhal N, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362:1292–1303.
24. Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, et al. Telaprevir is effective given every 8 or 12 h with ribavirin and peginterferon alfa-2a or 2b to patients with chronic hepatitis C. Gastroenterology 2011; 140:459–468.
25. Kwo P, Lawitz E, McCone J, Schiff E, Vierling J, Pound D, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 HCV (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376:705–716.
26. Poordad F, McCone J, Bacon B, Bruno S, Manns M, Sulkowski M, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.
27. Bacon B, Gordon S, Lawitz E, Marcellin P, Vierling J, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217.
28. Seden K, Back D, Shoo S. New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals. J Antimicrob Chemother 2010; 65:1079–1085.
29. Jiménez-Nácher I, Alvarez E, Morello J, Rodriguez-Nóvoa S, de Andrés S, Soriano V. Approaches for understanding and predicting drug interactions in HIV-infected patients. Expert Opin Drug Metab Toxicol 2011; 7:457–477.
30. Rallón NI, Naggie S, Benito JM, Medrano J, Restrepo C, Goldstein D, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS 2010; 24:F23–F29.
31. Nattermann J, Vogel M, Nischalke H, Danta M, Mauss S, Stellbrink H, et al. Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C. J Infect Dis 2011; 203:595–601.
32. Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, Bono A, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010; 51:1158–1167.
33. Lange C, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011; 54:887–893.
34. Ryan P, Berenguer J, Michelaud D, Miralles P, Bellón JM, Alvarez E, et al. Insulin resistance is associated with advanced liver fibrosis and high body mass index in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr 2009; 50:109–110.
35. Cacoub P, Carrat F, Bedossa P, Lambert J, Pénaranda G, Pol S, et al. Insulin resistance impairs sustained virological response rate to pegylated interferon plus ribavirin in HIV-hepatitis C virus-coinfected patients: HOMAVIC-ANRS HC02 Study. Antivir Ther 2009; 14:839–845.
36. Sulkowski M, Dietrich D, Sherman K, Rockstroh J, Adda N, Mahnke L, et al.Interim analysis of a phase 2a double-blind study of TVR in combination with pegIFN-α2a and RBV in HIV/HCV co-infected patients [abstract 146LB]. In: 18th CROI; 2011; Boston, Massachusetts, USA.
37. Soriano V, Perelson A, Zoulim F. Why different dynamics of selection of drug resistance in HIV, hepatitis B and C viruses?. J Antimicrob Chemother 2008; 62:1–4.
38. Morsica G, Bagaglio S, Uberti-Foppa C, Galli L, Lazzarin A. Detection of hepatitis C mutants with natural resistance to NS3/4A protease inhibitors in HIV/HCV-coinfected individuals treated with antiretroviral therapy. J Acquir Immune Defic Syndr 2009; 51:106–108.
39. Plaza Z, Soriano V, Bar-Magen T, González MM, Di Lello F, Macías J, et al.Impact of antiretroviral therapy on the variability of the HCV NS5B polymerase in HIV-HCV coinfected patients. J Antimicrob Chemother (in press).
40. Soriano V, Vispo E, Labarga P, Medrano J, Barreiro P. Viral hepatitis and HIV co-infection. Antivir Res 2010; 85:303–315.
41. Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet 2001; 357:280–281.
42. Mauss S, Valenti W, De Pamphilis J, Duff F, Cupelli L, Passe S, et al. Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy. AIDS 2004; 38:F21–F25.
43. Garcia-Benayas T, Blanco F, Soriano V. Weight loss in HIV-infected patients. N Engl J Med 2002; 347:1287–1288.
44. Fleischer R, Boxwell D, Sherman K. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004; 38:e79–e80.
45. Vispo E, Barreiro P, Pineda JA, Mira JA, Maida I, Martín-Carbonero L, et al. Low response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C treated with abacavir. Antivir Ther 2008; 13:429–437.
46. Mira JA, López-Cortés L, Barreiro P, Tural C, Torres-Tortosa M, de Los Santos Gil I, et al. Efficacy of pegylated interferon plus ribavirin treatment in HIV/hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone. J Antimicrob Chemother 2008; 62:1365–1373.
47. Rodríguez-Nóvoa S, Morello J, González M, Vispo E, Barreiro P, González-Pardo G, et al. Increase in serum bilirubin in HIV/hepatitis C virus-coinfected patients on atazanavir therapy following initiation of pegylated interferon and ribavirin. AIDS 2008; 22:2535–2537.
48. Van Heeswijk R, Vandervoorde A, Boogaerts G, Vangeneugden T, de Paepe E, Polo R, et al.Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers [abstract 119]. In: 18th CROI; 2011; Boston, Massachusetts, USA.
49. Van Heeswijk R, Gysen V, Boogaerts G, de Paepe E, Vangeneugden T, De Becker K, et al.The pharmacokinetic interaction between tenofovir disoproxil fumarate and the investigational HCV protease inhibitor telaprevir. In: 48th ICAAC; 13–17 September 2008; San Francisco, California, USA. A-966.
50. Van Heeswijk R, Boogaerts G, de Paepe E, De Becker K, van Solingen-Ristea R, Garg V, et al.The pharmacokinetic interaction between escitalopram or esomeprazole and telaprevir [abstract 76]. In: 11th International Workshop on Clinical Pharmacology of HCV; 4–6 November 2010; Boston, Massachusetts, USA.
51. Van Heeswijk R, Vandevoorde A, Verboven P, Boogaerts G, de Paepe E, van Solingen-Ristea R, et al.The pharmacokinetic interaction between methadone and the investigational HCV protease inhibitor telaprevir [abstract 1244]. In: EASL; 30 March to 3 April 2011; Berlin, Germany. J Hepatol 2011; 54 (Suppl):S491–S492.
52. Ghosal A, Yuan Y, Tong W, Su A-D, Gu C, Chowdhury S, et al. Characterisation of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos 2011; 39:510–521.
53. Kasserra C, Hughes E, Treitel M, Gupta S, O’Mara E. Clinical pharmacology of BOC: metabolism, excretion and drug-drug interactions [abstract 118]. In: 18th CROI; 27 February to 2 March 2011; Boston, Massachusetts, USA.
54. Rouzier R, Larrey D, Gane E, Wiercinska-Drapalo A, Chang L, Zhang Y, et al.Activity of danoprevir plus low-dose ritonavir (DNV/R) in combination with peginterferon alfa-2A (40KD) plus ribavirin (PEGIFNα-2A/RBV) in previous null responders [abstract 62]. In: 46th EASL; 2011; Berlin, Germany.
55. Soriano V, Vispo E, Barreiro P. New 2011 updated DHHS antiretroviral treatment guidelines and chronic hepatitis B. AIDS 2011; 25:1013–1014.
56. Neumann A, Lam N, Dahari H, Gretch D, Wiley T, Layden T, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 1998; 282:103–107.
57. Guedj J, Perelson A. Second-phase HCV RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration. Hepatology 2011; 53:1801–1808.
58. Rong L, Dahari H, Ribeiro R, Perelson A. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2010; 2:30–32.
59. Torriani F, Ribeiro R, Gilbert T, Schrenk U, Clauson M, Pacheco D, Perelson A. Hepatitis C virus (HCV) and HIV dynamics during HCV treatment in HCV/HIV coinfection. J Infect Dis 2003; 188:1498–1507.
60. Sherman K, Shire N, Rouster S, Peters M, James Koziel M, Chung R, et al. Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients. Gastroenterology 2005; 128:313–327.
61. Dixit N, Layden-Almer J, Layden T, Perelson A. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 2004; 432:922–924.
62. Ramos B, Núñez M, Rendón A, Berdún MA, Losada E, Santos I, et al. Critical role of ribavirin for the achievement of early virological response to HCV therapy in HCV/HIV-coinfected patients. J Viral Hepat 2007; 14:387–391.
63. Rallón NI, Soriano V, Naggie S, Restrepo C, Goldstein D, Vispo E, et al. IL28B gene polymorphisms and viral kinetics in HIV/hepatitis C virus-coinfected patients treated with pegylated interferon and ribavirin. AIDS 2011; 25:1025–1033.
64. Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138:447–462.
65. Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55:192–206.
66. Kieffer T, Kwong A, Picchio G. Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 2010; 65:202–212.
67. Bartels D, Zhou Y, Zhang E, Marcial M, Byrn R, Pfeiffer T, et al. Natural prevalence of HCV variants with decreased sensitivity to NS3-4A protease inhibitors in treatment-naive subjects. J Infect Dis 2008; 198:800–807.
68. Kuntzen T, Timm J, Berical A, Lennon N, Berlin A, Young S, et al. Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naive patients. Hepatology 2008; 48:1769–1778.
69. Gaudieri S, Rauch A, Pfafferott K, Barnes E, Cheng W, McCaughan G, et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 2009; 49:1069–1082.
70. Sun S, Bae A, Qi X, Harris J, Wong K, Miller M, et al.Natural variation in drug susceptibility to HCV polymerase inhibitors in treatment-naive HCV patient isolates. J Viral Hepat (in press).
71. Bae A, Sun S, Qi X, Chen X, Ku K, Worth A, et al. Susceptibility of treatment-naive HCV clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 2010; 54:5288–5297.
72. Treviño A, de Mendoza C, Parra P, Rodriguez C, Madejon A, Plaza Z, et al. Natural polymorphisms associated with resistance to new antivirals against hepatitis C virus (HCV) in newly diagnosed HIV/HCV-coinfected patients in Spain. Antivir Ther 2011; 16:413–416.
73. Trimoulet P, Belzunce C, Faure M, Wittkop L, Reigadas S, Dupon M, et al.HCV protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients. HIV Med 2011; 12:506–509.
74. Blackward J, Ma G, Limketkai B, Welge J, Dryer P, Martin C, et al. Variability of the polymerase gene (NS5B) in HCV-infected women. J Clin Microbiol 2010; 48:4256–4259.
75. Torriani F, Rodriguez-Torres M, Rockstroh J, Lissen E, Gonzalez J, Lazzarin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–450.
76. Aronsohn A, Jensen D. Distributive justice and the arrival of direct acting antivirals: who should be first in line?. Hepatology 2001; 53:1789–1791.
77. Miro JM, Castells L, Valdivieso A, Torre-Cisneros J, Abradelo M, Fernandez J, et al.Treatment with pegIFN+RBV of 67 HIV+ patients with recurrent HCV infection after liver transplantation [abstract 964]. In: CROI 2011; 27 February to 2 March 2011; Boston, Massachusetts, USA.
78. Garg V, van Heeswiijk R, Eun-Lee J, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54:20–27.
79. Gane E. Future hepatitis C virus treatment: interferon-sparing combinations. Liver Int 2011; 4:62–67.
Keywords:

boceprevir; co-infection; direct-acting antivirals; drug resistance; hepatitis C; HIV; liver; telaprevir

© 2011 Lippincott Williams & Wilkins, Inc.