Current Opinion in Infectious Diseases:
HIV INFECTIONS AND AIDS: Edited by David Dockrell
Focus on drug interactions: the challenge of treating hepatitis C virus infection with direct-acting antiviral drugs in the HIV-positive patient
aFundación de Investigación, San Juan
bPonce School of Medicine, Ponce, Puerto Rico
Correspondence to Maribel Rodríguez-Torres, MD, CPI, Fundación de Investigación, Ave. Muñoz Rivera #998, Río Piedras, San Juan 00927, Puerto Rico. Tel: +787 722 1248; fax: +787 721 6098; e-mail: firstname.lastname@example.org
Purpose of review: Successful treatment of hepatitis C virus (HCV) infection is necessary for the survival of HIV-infected patients. This review covers the outcomes of current therapy, first-generation HCV direct-acting antivirals (DAAs) and their drug-to-drug interactions (DDIs). Understanding DDIs between HIV antiretroviral therapy (ART) and the DAAs in development is important to assure the best management of the HIV/HCV coinfected individuals.
Recent findings: The two first-in-class DAAs were approved for clinical use in 2011. The first trials with boceprevir or telaprevir added to standard therapy in HIV/HCV coinfected patients revealed triple therapy to be efficacious with significantly improved sustained virological response rates. However, these DAAs were associated with more and worse adverse effects, as well as with significant DDIs with multiple drugs, including ART. Early data on DAAs in development suggest improved efficacy and safety and the potential for lesser DDIs.
Summary: Anti-HCV therapy is fundamental in coinfected patients, but the approved therapies are suboptimal. The first-generation of approved HCV DAAs improved efficacy of therapy in coinfected patients, but have multiple safety concerns, including potentially serious drug interactions with ART. Early results from newer DAAs are promising.
People with HIV infection have now an improved prognosis [1,2]. However, a significant number of these individuals also have hepatitis C virus (HCV) infection. As both viruses share similar modes of transmission, they are common coinfections. Worldwide, HIV-infected persons are estimated to number 40 million; of these, an estimated 4–5 million have HCV coinfection, yielding a global HCV prevalence of 10–12.5% in the HIV-infected population . In the United States, about 25–35% of patients with HIV are infected with HCV , and even higher rates have been reported in certain populations. The highest rates were among those acquiring it from IDU, specifically, 72–95%, as compared with other forms of acquiring it .
Of relevance and most importantly, HCV infection has emerged as a significant factor influencing the survival of HIV patients . Patients with HIV/HCV coinfection have a higher HCV viral load and a faster rate of fibrosis progression, resulting in more frequent occurrences of cirrhosis, end-stage liver disease and hepatocellular carcinoma .
Although the importance of treating the HCV infection is known, the actual treatment of the HCV/HIV coinfected patient poses serious challenges. Approximately two-thirds of coinfected patients do not receive anti-HCV treatment because of poor compliance with antiretroviral therapy (ART), decompensated liver disease, comorbidities, active substance or alcohol abuse, and/or advanced HIV disease . In addition, the approved therapies for HCV infection in the coinfected patient have a suboptimal efficacy and safety profile, resulting in a minority of coinfected patients actually being treated for chronic hepatitis C (CHC) . Truly, better therapies and strategies are needed to improve the outcomes for HCV/HIV coinfected patients.
HEPATITIS C VIRUS INFECTION THERAPY IS FUNDAMENTAL IN COINFECTED PATIENTS
Due to the lack of critical CD4 T cell responses upon acquiring HCV [8,9], the HIV patients have lower spontaneous resolution rates  and higher viral loads , resulting in chronic infection in over 90% of HIV patients. Furthermore, coinfected patients have a faster fibrosis progression leading to a higher frequency of liver complications, as compared with HCV monoinfected patients [6,12]. As the likelihood of developing cirrhosis is higher and more rapid, and as liver failure occurs more often [12–14], there is also a higher incidence of hepatocellular carcinoma in coinfected patients [15,16▪], which more frequently tends to present at an advanced stage, with an infiltrative pattern, and more frequently, extra-nodal metastasis [16▪].
In addition to the reports that have established that treatment for HCV infection in coinfected patients is necessary due to their more rapid progression to liver failure, there have been studies that report a worse outcome for patients who receive no HCV therapy at all [17,18]. On the other hand, the benefit of successful HCV treatment in HIV/HCV coinfected patients has also been shown. Obtaining HCV clearance/cure has been associated with liver fibrosis regression, decreased liver-related complications and decreased mortality . Moreover, a recent study  found that HCV eradication in HIV/HCV coinfected patients is also associated with a reduction in HIV progression and mortality not related to liver disease.
CHRONIC HEPATITIS C THERAPY IN COINFECTED PATIENTS
Pegylated-interferon-alpha along with ribavirin (Peg-IFN/RBV) is the approved therapy for the coinfected patient [21–24]; however, it leads to a sustained virological response (SVR; defined as nondetectable HCV RNA 6 months after the end of therapy) in only 14–36% of patients with HCV genotype 1 infection [21–23,25,26,27▪,28,29▪], and higher rates (∼64%) for genotype 2 and 3 infection . The lowest SVR rates (∼15%) are seen in African-Americans and coinfected patients with HCV genotype 1 . The toxicity of this regimen is problematic in this population, as it is associated with significant weight loss, neutropenia and anaemia [29▪]. In addition to having a much lower response to Peg-IFN/RBV and more common and severe side effects, the drug components for the HIV treatment raise even more complexities to the management of the HIV/HCV coinfected patient. As the combination of ART and Peg-IFN/RBV has increased adverse effects , the treatment regimens must be individualized. For patients with HCV coinfection, the safest drugs to combine are emtricitabine, lamivudine and tenofovir. Efavirenz and raltegravir should be monitored for hepatoxicity when combined with Peg-IFN/RBV, and nevirapine and maraviroc should be avoided or used with extreme caution in patients with liver disease. Zidovudine, didanosine, zalcitabine and stavudine are not recommended at all. Peg-IFN/RBV with zidovudine is associated with higher anaemia rates , and didanosine and zalcitabin are associated with increased mitochondrial DNA toxicity and worsening steatosis and fibrosis when used with RBV . Finally, the decision to treat CHC needs to consider any conditions that may limit life expectancy or increase therapeutic side effects such as HIV disease stability (having CD4 cell count levels >150–200 cells/ml), psychiatric diseases and ongoing substance abuse . Ultimately, the treatment for HCV in patients with HIV poses many obstacles; however, the benefits of viral eradication warrant the challenge of considering and offering therapy.
THE ERA OF DIRECT-ACTING ANTIVIRAL DRUGS
The direct-acting antivirals (DAAs) are drugs that target HCV enzymes essential for viral replication and do not significantly activate host defenses that affect the hepatic cell, contrasting to the IFN-based therapy, which leads to apoptosis and death of the infected hepatocyte. Because of this viral-based mechanism of action, it is anticipated that DAA drugs could be administered to patients with more advanced hepatic damage without the risk of hepatic decompensation. DAAs under development include NS3/4A protease inhibitors, nucleoside/nucleotide analogues and nonnucleoside inhibitors of the RNA-dependent RNA polymerase, NS5A inhibitors, cyclophilin inhibitors and messenger RNAs, such as miravirsen, an antisense oligonucleotide inhibitor of the liver-expressed micro RNA-122 (miR-122) [32,33].
The two first-in-class HCV NS3/4A serine protease inhibitors were approved for clinical use in 2011. Compared with Peg-IFN/RBV therapy alone, the addition of boceprevir (BOC, Victrelis) or telaprevir (TVR, Incivek) increased SVR rates among patients with HCV genotype 1 infection who were previously untreated, as well as those who had previously failed to respond to Peg-IFN/RBV [34–37]. These results changed the optimal treatment of genotype 1 CHC . In addition to the naive patients, the benefits of triple therapy was also observed in populations considered to be poor responders to Peg-IFN/RBV, such as those with unfavourable IL28B polymorphisms, African-Americans, Latinos, patients with advanced fibrosis or cirrhosis, and those with high baseline levels of HCV RNA levels [39–42]. The addition of BOC or TVR introduced the concept of response-guided therapy, wherein patients with good early viral response could shorten the total duration of therapy to 24 or 28 weeks, and wherein early viral response was defined as nondetectable HCV RNA at weeks 4 and 12 for TVR, and at weeks 8 and 24 for BOC. Unfortunately, both drugs added new adverse effects or worsened those adverse effects previously known to occur with Peg-IFN/RBV, such as increased rates of anaemia and neutropenia, skin rash and pruritus, anorectal symptoms and dysgeusia. Moreover, the triple therapy increased the pill burden and treatment complexity, potentially impacting on patient compliance and adherence. In addition, both DAAs have significant drug-to-drug interactions (DDIs) with many other frequently used drugs, including ARTs.
EFFICACY AND SAFETY OF BOCEPREVIR AND TELAPREVIR-BASED THERAPIES FOR HIV/HEPATITIS C VIRUS COINFECTED PATIENTS
Not having robust safety and efficacy data to support its clinical use, BOC or TVR-based therapy is not approved for use in coinfected patients at this moment. There is available early and preliminary information from a small number of patients in clinical trials in the coinfected population. A phase IIa study investigating the safety and efficacy of BOC-based therapy versus placebo in HIV/HCV coinfected patients evaluated 98 patients [43,44]. Most patients were on a ritonavir-boosted HIV protease inhibitor (91% in the placebo arm and 84% in the BOC arm), which included lopinavir, atazanavir and darunavir. A few patients (four in the placebo arm, 11 in the BOC arm) received raltegravir, and one patient in each of the arms was on a maraviroc-based ART. Zidovudine, didanosine or efavirenz was not permitted in this trial. The proportion of patients achieving undetectable HCV RNA was substantially greater with BOC-based therapy than with placebo at 8 weeks (42 versus 15%), at 24 weeks (73 versus 34%) and at 12 weeks after the end of therapy (SVR12) (61 versus 27%). Although adverse effects were common in both study arms, patients on BOC were more likely to have anorexia, pyrexia, dysgeusia, vomiting, asthenia, anaemia and neutropenia. Data on drug interactions, not available at the start of the trial, highlighted that DDIs between HIV-boosted protease inhibitors and BOC could decrease the exposure of ART drugs. In summary, this small first trial of BOC-based therapy in HIV/HCV coinfected patients demonstrated the triple therapy (BOC/Peg-IFN/RBV) to be efficacious, resulting in significantly higher SVR12 rates. However, the safety profile of BOC/Peg-IFN/RBV caused more adverse effects and the multiple and significant DDIs between BOC and ART drugs are extremely worrisome, as will be discussed in more detail later on.
A phase IIa study investigating the safety and efficacy of TVR-based therapy versus placebo in HIV/HCV coinfected patients evaluated 60 patients [45–47], of which 13 patients (22%) were not taking ART, and those on ART were using tenofovir/emtricitabine with either efavirenz (24 patients, 40%) or ritonavir-boosted atazanavir (23 patients, 38%). The proportion of patients with undetectable HCV RNA at 4 weeks, defined as rapid virologic response (RVR), was substantially greater with TVR-based therapy than with placebo (68 versus 4.5%), as well as at 24 weeks (74 versus 55%) and at 12 weeks after the end of therapy or SVR12 (74 versus 45%). In this small number of patients, there was no difference in virologic outcomes among patients with or without ART. Adverse effects such as pruritus, skin rash, headache, nausea, dizziness, pyrexia and depression were more common in patients on TVR-based therapy.
DRUG-TO-DRUG INTERACTIONS OF BOCEPREVIR AND TELAPREVIR-BASED THERAPIES FOR HIV/HEPATITIS C VIRUS COINFECTED PATIENTS
There have been many reports on the pharmacokinetics and DDIs of both BOC and TVR with multiple drugs, including ARTs. Table 1 summarizes their pharmacology and DDIs. TVR is a substrate and inhibitor of the cytochrome P450 (CYP)3A4 enzyme and P-glycoprotein transporter, and also it has a low potential to induce CYP2C, CYP3A or CYP1A . BOC is a primary substrate of aldoketoreductases 1C2 and 1C3 and, to a lesser extent, a substrate and potent inhibitor of the CYP3A4 enzyme and P-glycoprotein transporter [49,50]. As both BOC and TVR inhibit CYP3A4/CYP3A5, they are contraindicated when combined with drugs that are highly dependent on CYP3A for clearance (elevating plasma concentrations and provoking serious events) and when combined with drugs that strongly induce CYP3A (leading to lower exposure and loss of efficacy). Due to this CYP3A4/5 inhibition, both interact with ritonavir, lopinavir, darunavir, efavirenz, nevirapine, etravirine and rilpivirine.
TVR has been studied in combination with efavirenz, tenofovir, multiple HIV protease inhibitors and raltegravir [51,52], revealing several ARTs that appear well tolerated for coadministration. Although efavirenz reduces the blood concentrations of TVR, this effect can be partially offset by using a higher TVR dose (1125 mg every 8 h) ; this was the strategy utilized in the phase IIa trial reported before, in which potent anti-HCV activity and no effect on HIV suppression were observed [45–47]. However, further investigations are needed to establish appropriate dose adjustments. By contrast, raltegravir is not metabolized by CYP3A, and a pharmacokinetic study in healthy volunteers indicated that no dose adjustment is needed when TVR and raltegravir are coadministered . Other ART agents that could be used in combination with TVR are tenofovir and emtricitabine. DDIs between TVR and the ritonavir-boosted protease inhibitors were also evaluated in healthy volunteers . TVR use significantly reduces the concentrations of darunavir and fosamprenavir; on the other hand, TVR concentrations are reduced by the use of ritonavir-boosted fosamprenavir, darunavir, lopinavir and, to a lesser extent, atazanavir. Combining TVR with the ritonavir-boosted HIV protease inhibitors lopinavir, darunavir and fosamprenavir could reduce exposure of the ART agents or TVR, so they should not be used in combination. In healthy volunteers, coadministration of etravirine and TVR showed no change in etravirine pharmacokinetics, but a mild reduction in the TVR concentrations, which was deemed unlikely to adversely affect HCV control response. So, this coadministration was considered possible, but it should be confirmed in patients . Coadministration of rilpivirine and TVR in healthy volunteers showed slightly reduced TVR concentrations, but significantly increased rilpivirine concentrations that, given interpatient variability, in some patients could reach levels that prolong the QTc interval and cause cardiac conduction abnormalities. Therefore, this combination would have to be studied with extreme caution and definitely not be used with any other drug known to increase rilpivirine concentrations or prolong the QTc interval, or in patients at risk for torsade de pointes .
More extensive pharmacokinetic and DDI studies between BOC and ART drugs were conducted in healthy volunteers after the clinical trial in coinfected patients was started. One pharmacokinetic study with BOC  revealed that efavirenz reduced the mean trough BOC concentrations by 44%, requiring further studies in order to determine the clinical implications. The study also revealed that low-dose ritonavir decreased BOC concentrations by 19%, and that it should not be used with efavirenz, etravirine or nevirapine, pending further research. A study between BOC and ritonavir-boosted atazanavir, lopinavir and darunavir found the following: first, that BOC reduces the concentrations of all HIV protease inhibitors from 34 to 44%; second, that BOC reduces the concentration of ritonavir; third, that lopinavir and darunavir decrease BOC concentrations by 32–45%; and fourth, atazanavir does not affect BOC concentrations . On the basis of these data, a letter from Merck Inc. [followed by a U.S. Food and Drug Administration FDA safety announcement, http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm291144.htm, and an EMA press release] recommended that BOC not be coadministered with these HIV protease inhibitors, as it could reduce the drug's effectiveness and, potentially, permit the HCV or HIV virus levels to increase. On the contrary, DDI data between raltegravir and BOC revealed no significant effect; thus, this is the only ART drug that could, theoretically, be used in combination with BOC . With regard to the coadministration of etravirine and BOC in healthy volunteers, it was found that BOC concentrations were increased and etravirine concentrations were decreased, with great interpatient variability that actually became clinically relevant. So, this coadministration should not be considered either unless additional information is obtained .
THE FUTURE OF HEPATITIS C VIRUS INFECTION THERAPY IN THE COINFECTED PATIENT
There are currently more than 50 investigational agents in human studies for HCV infection, with seven different mechanisms of action directed towards the virus and the host [57–59]. Novel anti-HCV drugs include second-generation protease inhibitors, the polymerase inhibitors (nucleoside and nonnucleoside) and the NS5A inhibitors, the great majority of which are being evaluated in clinical trials for naive or relapser HCV monoinfected patients. Of great interest and clinical relevance to the coinfected population are the combinations of DAAs without Peg-IFN due to the known challenges of combining IFN with ART. Early data show increased efficacy, reduced resistance to HCV and an excellent safety profile [60–67], and some have demonstrated antiviral efficacy in a difficult-to-treat population (null responders). Ideally, clinical trials of these IFN-free DAA combination therapies should be initiated as early as possible in the coinfected population.
Although there are many potential DDIs between ART and the HCV DAAs in development, studies of DAAs in patients on select ART regimens will be less complex. For example, HCV NS3A/4 protease inhibitors and NS5A inhibitors, which are metabolized by the liver, could be studied in combination with raltegravir and tenofovir/emtricitabine, which are metabolized by the kidneys. Daclatasvir (BMS-790052) is a highly selective, first in-class HCV NS5A replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro, which is being developed for the treatment of CHC in combination with other DAAs and/or Peg-IFN/RBV. Although metabolized by the liver, daclatasvir was found to be well tolerated in individuals with hepatic impairment . Other pharmacokinetic assessments of daclatasvir reported no clinically significant DDIs with the ART drug: tenofovir, efavirenz and atazanavir/r , or with the oral contraceptives (ethinyl estradiol/norestimate) in healthy volunteers . Another DDA in development, the HCV protease inhibitor TMC435, also reported a DDI study with ART drugs in healthy volunteers. The combination of TMC435 and rilpivirine, tenofovir, raltegravir or efavirenz revealed only an adverse interaction with efavirenz and no significant DDIs with the others . Asunaprevir (BMS-650032) is a selective inhibitor of the HCV NS3 protease with antiviral activity against genotype 1 HCV , and a weak to moderate inhibitor/inductor of CYP2D6, CYP3A4 and P-glycoprotein, as found in a study on healthy volunteers . However, the results suggested a substantially lesser effect of asunaprevir on CYP3A4 activity than BOC or TVR. so presumably the DDIs are expected to be of lesser magnitude. The uridine nucleotide analogue GS-7977 (sofosbuvir), another DDA in development, is a potent and selective inhibitor of NS5B-directed HCV RNA replication, and it has shown that it does not appreciably inhibit CYP450. As it has unlikely interactions with metabolically based drugs, it will not interfere with the efficacy of the HIV nucleoside analogues, suggesting that sofosbuvir may be efficacious and well tolerated to be used in HIV/HCV coinfected patients on ART. Evaluating this is an ongoing DDI study of sofosbuvir with ART combinations of efavirenz, tenofovir and emtricitabine; efavirenz, zidovudine and lamivudine; atazanavir/r, tenofovir and emtricitabine, darunavir/r, tenofovir and emtricitabine, and raltegravir, tenofovir and emtricitabine in HIV/HCV coinfected patients (ClinicalTrials.gov identifier: NCT01565889).
Other ongoing clinical trials involving coinfected patients include the following: first, a phase III trial of BI-201335 in treatment-naive and relapsed HIV/HCV coinfected patients, where the aim is to evaluate the efficacy and the safety of BI-201335 given for 12 or 24 weeks in combination with Peg-IFN/RBV given for 24–48 weeks. According to early treatment success, patients at 24 weeks are re-randomized to stop Peg-IFN/RBV or continue until week 48 (ClinicalTrials.gov identifier: NCT01399619); second, a safety and efficacy study of BMS-790052 (daclatasvir) along with Peg-IFN/RBV in untreated HIV/HCV coinfected patients, where the purpose of this open-label study is to evaluate the safety and efficacy of this regimen compared with historic controls (ClinicalTrials.gov identifier: NCT01471574); and third, a trial of TMC435 in HCV (genotype 1)/HIV coinfected patients, where the purpose of this study is to investigate the safety, tolerability and efficacy of TMC435 along with Peg-IFN/RBV in the coinfected population (ClinicalTrials.gov identifier: NCT01479868).
The documented interactions between BOC and the ritonavir-boosted HIV protease inhibitors illustrate the challenge of understanding and managing concomitant therapy with ART and the new HCV DAAs. It is quite difficult to confidently predict these interactions, as all are substrates, inhibitors and inducers of drug metabolizing enzymes and membrane transporters. The potential interaction between the approved HCV NS3/4A protease inhibitors and ART is complex and, so far, incompletely characterized. It is prudent to wait for sufficient pharmacokinetic data that would support the use of any of these combinations. Currently, data may support the use of BOC or TVR in coinfected patients with high CD4+ T-cell counts who are not taking ART or those on select ART regimens for which sufficient safety data have been provided. At this moment, the off-label use of TVR may be considered in theory, in patients using atazanavir boosted with ritonavir, raltegravir or efavirenz (using higher TVR dose) based therapies in combination with tenofovir and emtricitabine. On the other hand, it is evident that BOC should not be combined with nonnucleoside reverse transcriptase inhibitors, or ritonavir-boosted HIV protease inhibitors. Furthermore, before a patient is given either BOC or TVR, it is also important that any single medication that a patient uses for concomitant medical conditions be carefully assessed for potential drug interactions. One available web resource is the University of Liverpool's hepatitis tools (www.hep-druginteractions.org). At the present time, having HIV/HCV coinfected patients participate in clinical trials as their first therapeutic option would better serve to guarantee their safety, as well as advance the knowledge in managing this difficult-to-treat population. Development of new therapies is ongoing. Second-generation protease inhibitors and new classes of DAAs are in clinical trials and preliminary results show improved efficacy and safety, and some even have pan-genotypic activity. This rapid progress strongly suggests that in the near future, IFN-free, shorter duration DAA combinations will make possible the cure of CHC for the majority of patients, including the coinfected population. Hope lies within the different treatment options for HCV that are currently under investigation.
The author wishes to acknowledge the writing assistance of Deana Hallman at the Fundaciön de Investigaciön in the production of this article.
Conflicts of interest
Maribel Rodríguez-Torres has received grants/research support from Vertex, Hoffman la Roche, Glaxo Smith Kline, Novartis, Bristol-Myers Squibb, Vertex Pharm., Idera, Pharmasset, Sanofi-Aventis, Merck, Abbott Labs, Pfizer, Human Genome Sciences, Gilead, Johnson & Johnson, Zymogenetics, Akros, Pfizer, Scynexis, Santaris, Mochida, Boehringer, Inhibitex, Idenix and Siemens. The author is also a consultant for Hoffman La Roche, Akros, Genentech, Bristol-Myers Squibb and Vertex Pharm.
The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 101).
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chronic hepatitis C; direct-acting antiviral; drug-to-drug interactions; HIV/hepatitis C virus coinfection
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