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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Expert Opin Pharmacother. Author manuscript; available in PMC 2017 April 1.
Published in final edited form as:
PMCID: PMC4930150
NIHMSID: NIHMS797942

Sofosbuvir and Ledipasvir for HIV/HCV Co-infected Patients

Elana S. Rosenthal, M.D.,1 Shyam Kottilil, M.D., Ph.D.,2 and Michael A. Polis, M.D., M.P.H.3

Abstract

Introduction

Hepatitis C virus (HCV) is a chronic infection that disproportionately impacts people living with HIV. In the past, HCV therapy was less effective in individuals with HIV co-infection. However, the advent of direct-acting antivirals has revolutionized HCV treatment with high rates of success in patients both with and without HIV.

Areas covered

In this paper, we review the evidence supporting the use of ledipasvir and sofosbuvir (LDV/SOF) for the treatment of HCV in patients with HIV co-infection. Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of LDV/SOF in individuals with HCV and HIV co-infection.

Expert opinion

This treatment is highly effective in achieving HCV cure or sustained virologic response, however further studies need to done to address efficacy of treatment in people with uncontrolled HIV, concerns regarding drug-interactions with antiretroviral therapy, and potential for shorter duration treatment.

Keywords: Hepatitis C Virus, HIV/HCV co-infection, Ledipasvir/sofosbuvir, direct-acting antivirals

Drug Summary Box

Drug name (generic)Ledipasvir/sofosbuvir
Phase (for indication
under discussion)
IV
Indication (specific to
discussion)
Treatment of HCV genotype 1, 4, 5, 6
Pharmacology
description/mechanism
of action
Fixed dose combination pill of an HCV NS5A inhibitor (ledipasvir) and an HCV
nucleoside NS5B polymerase inhibitor (sofosbuvir)
Route of administrationOral
Chemical structureLedipasvir: Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7- {2-[(1R,3S,4S)-2-{(2S)-2-
[(methoxycarbonyl)amino]-3-methylbutanoyl}-2- azabicyclo[2.2.1]hept-3-yl]-1H-
benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5- azaspiro[2.4]hept-5-yl}-3-
methyl-1-oxobutan-2-yl]carbamate

Sofosbuvir: (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5- (2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)-
(phenoxy)phosphorylamino)propanoate
Pivotal trial(s)ION 1 [7], ION 2 [6], ION 3 [15], ION 4 [20]
ERADICATE [19]

1. Introduction

Hepatitis C virus (HCV) is a chronic infection that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Worldwide 135 million people are infected with HCV and this disease is particularly prevalent in human immunodeficiency virus (HIV) infected individuals.[1] In the United States, one in four patients with HIV are also co-infected with HCV. Globally 2.75 million people live with HIV and HCV co-infection (HIV/HCV).[2, 3] Individuals with HIV/HCV have been shown to have worse outcomes than persons with HCV infection alone, with more rapid and more frequent development of liver cirrhosis and hepatocellular carcinoma.[4] In addition, patients with HIV/HCV who undergo liver transplantation have significantly higher rates of post-transplant mortality than HCV monoinfected individuals.[5]

The goal of HCV treatment is to achieve and maintain undetectable levels of HCV RNA twelve weeks after completion of therapy. This is called sustained virologic response (SVR) and is considered to be a functional cure. Historically, treatment of HCV was incredibly challenging with modest rates of SVR. Therapeutic regimens required interferon-α with or without ribavirin with their attendant toxicities. In addition, individuals with HCV and HIV co-infection, black race, or those with IL28B non-CC haplotype had less likelihood of achieving SVR.

The advent of orally bioavailable, directly acting antivirals (DAA) has been revolutionary in the advancement of HCV treatment. These medications directly target HCV replication rather than the host immune response. DAA therapies have fewer side effects, shorter durations of treatment, and higher rates of SVR than interferon-α and ribavirin-based regimens.[6, 7] In addition, they are effective regardless of race, gender or prior treatment status. HIV co-infection was previously a factor that decreased efficacy of HCV treatment. However, with current DAAs, HIV status is no longer a barrier to achieving HCV cure. In this review, we evaluate the use of the interferon-free, fixed dose combination, directly acting antiviral regimen of ledipasvir/sofosbuvir (LDV/SOF – brand name Harvoni, Gilead) in the treatment of HCV in patients co-infected with HIV.

2. Clinical Pharmacology

2.1 Chemistry & Pharmacodynamics

2.1.1 Sofosbuvir

Sofosbuvir is a uridine nucleotide analog which specifically inhibits HCV NS5B RNA-dependent RNA polymerase activity. Sofosbuvir is a prodrug that undergoes hepatic hydrolyzation to create GS-566500. This form is then hydrolyzed and undergoes two phosphorylations resulting in the pharmacologically active nucleoside analog triphosphate GS-461203. This analog competes with naturally occurring nucleotides during viral replication. When incorporated into the primer strand by the RNA-dependent RNA polymerase, GS-461203 results in chain termination, thus halting HCV replication. Given the catalytic site of NS5B is highly conserved, sofosbuvir has activity against genotypes 1–6. Of note, dephosphorylation of GS-566500 forms the inactive nucleoside metabolite GS-331007, the main peripheral circulating form of the sofosbuvir prodrug, representing 90% of systemic exposure.[810]

2.1.2 Ledipasvir

Ledipasvir is an HCV NS5A inhibitor. It operates by binding domain 1 of the NS5A protein, thus blocking the formation of replication complex interfering with the ability to regulate viral replication and inhibiting the assembly and release of viral particles. While the NS5A inhibitor has pangenotypic, antiviral activity, this activity in vitro is more robust against genotypes 1a and 1b, with slightly less activity against genotypes 4, 5, and 6. There is only limited activity against HCV genotypes 2 and 3.[810]

2.2. Pharmacokinetics & Metabolism

2.2.1 Sofosbuvir

Sofosbuvir is bioavailable through first pass metabolism, with a time to peak concentration of 0.8–1.0 hour for sofosbuvir and 3.5–4.0 hours for GS-331007. Sofosbuvir is extensively metabolized by the liver and predominantly cleared by renal excretion. The elimination half-life is 0.5 hours for sofosbuvir and 27 hours for GS-331007. There are no significant changes in pharmacologic properties based on race, gender or age up to 75 years old, and no clinically relevant differences seen in patients with cirrhosis or advanced liver disease. However sofosbuvir is contraindicated in individuals with severe renal impairment (creatinine clearance <30 mL/min). [810]

2.2.2 Ledipasvir

Ledipasvir achieves peak concentration 4.0–4.5 hours after oral administration. Ledipasvir is slowly oxidated, and there is little appreciable metabolism by hepatic enzymes. The major route of clearance is biliary with fecal excretion. Elimination half-life is 47 hours. There are no significant changes in parameters based on race, gender, or age up to 80 years old. There are no clinically relevant differences seen in patients with cirrhosis, advanced liver disease, or in patients with severe renal impairment (creatinine clearance < 30 mL/min). [810]

2.3 Dosing

Sofosbuvir (SOF) is available in a 400mg tablet to be taken daily, as well as in a fixed dose combination tablet with ledipasvir (LDV) of LDV/SOF 90mg/400mg to be taken daily. Ledipasvir is not independently available at this time. No dose adjustment is necessary for mild, moderate, or severe hepatic impairment. Dosing is currently unknown for severe renal impairment (creatinine clearance < 30 mL/min or hemodialysis).[9]

2.4. Drug-drug interactions

Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP. P-gp inducers (such as St. John’s wort) may decrease LDV/SOF plasma concentrations and therefore concurrent use is contraindicated. Cases of severe bradycardia and heart block have been observed when LDV/SOF is used with concurrent amiodarone and therefore coadministration of amiodarone with either LDV/SOF or SOF is not recommended. [11, 12] Co-administration with rosuvastatin is contraindicated given the risk of significant increase in rosuvastatin concentrations. Several anticonvulsants (carbamazepine, phenytoin, phenobarbital, oxcarbazepine) and antimycobacterials (rifabutin, rifampin, rifapentine) are contraindicated due to concern for decreasing concentrations of LDV/SOF. Gastric acid reducing agents, such as PPI and H2 blockers, must be specifically dosed and timed, as low gastric pH is necessary for adequate absorption of LDV. In fact, in the HCV-TARGET study, PPI use was independently associated with a higher risk of virological failure. [9, 13]

Clinically significant drug interactions with LDV/SOF mediated by CYP or UGT1A1 are not expected. LDV/SOF can be safely administered with methadone, buprenorphine, tacrolimus and cyclosporine. Drug interactions with antiretrovirals (ARVs) are discussed below.[9]

2.5 Adverse events

In patients treated with LDV/SOF for a 12 week course, the most common adverse events are headache (14%), fatigue (13%), nausea (7%), insomnia (3%), and diarrhea (3%). The majority of adverse events were of grade 1 severity. Less than 1% of patients in clinical trials discontinued treatment due to adverse events when treated with LDV/SOF for 12 weeks.[9]

2.6. Resistance

2.6.1 Sofosbuvir

The primary NS5B substitution, S282T, has been associated with reduced susceptibility to sofosbuvir in vitro. Only 3 patients have been found to have the S282T mutant, all of whom relapsed with sofosbuvir-based therapy. However, a pooled analysis of phase 3 trials of sofosbuvir based regimens in the treatment of HCV genotype 3 patients who did not achieve SVR identified the selection for L159F and V321A mutants in several subjects.[14]

2.6.2 Ledipasvir

The most common NS5A amino acid substitutions identified in patients with HCV genotype 1a who failed DAA therapy were Q30E/R, L31M, Y93C/H/N. In those with genotype 1b, the most common resistance-associated variant (RAV) was Y93H. Several studies have demonstrated persistence of NS5A RAVs for over a year after treatment failure, however their clinical significance continues to be debated. When treating individuals with HCV genotype 1, without prior treatment experience or cirrhosis with LDV/SOF for 8 or 12 weeks, presence of baseline RAVs was found to be 18%. Despite this, baseline NS5A RAVs were not associated with relapse.[15] Similarly, in a study of treatment of HCV genotype 1 in individuals with advanced fibrosis, with or without treatment experience with LDV/SOF + GS-9451 (NS3/4A protease inhibitor) for 6 weeks, baseline RAV prevalence was 22%. Again, it was found that baseline RAVs had no impact on SVR.[16] Therefore, at present, there is not strong evidence that RAVs impact SVR for initial treatment with LDV/SOF, although these studies have not included patients with HIV/HCV coinfection.

In a study of 34 non-cirrhotic participants with HCV genotype 1 who previously failed 4–6 weeks of LDV/SOF with GS-9669(NS5B inhibitor) and/or GS-9451 and were subsequently retreated with LDV/SOF for 12 weeks, NS5A RAVs were detected in 85% of patients at retreatment baseline. Despite this, 97% of individuals who completed treatment achieved SVR. The one individual who relapsed had HCV with >1000-fold NS5A RAVs L31M and Y93H prior to retreatment, and NS5B RAVs S282T and V321I emerged following retreatment.[17] Therefore, RAVs were not felt to have a large impact on the success of retreatment in this study. However, RAV presence was considered to be significant in a study of 30 patients who failed 8 weeks of treatment with LDV/SOF and were subsequently retreated with LDV/SOF for 24 weeks. In patients without NS5A RAVs at retreatment, 100% achieved SVR, whereas only 60% of individuals with NS5A RAVs were successfully retreated.[18] Hence the role of baseline RAVs in retreatment of patients who fail DAA therapy, and the impact of longer duration of initial treatment, is not completely understood, particularly in HIV/HCV coinfected patients since they were not included in these trials.

3. Efficacy

3.1 Clinical Studies in HCV monoinfection

The initial ION studies of LDV/SOF were conducted in patients with HCV genotype 1 monoinfection. ION-1 evaluated cirrhotic and non-cirrhotic individuals who were treatment naïve. In patients treated for 12 weeks, 99% achieved SVR, and in patients treated for 24 weeks, 98% achieved SVR.[7] ION-2 evaluated cirrhotic and non-cirrhotic individuals with prior treatment experience with peginterferon and ribavirin, with or without a protease inhibitor. These patients achieved SVR in 94% of individuals who received 12 weeks of treatment, and 99% of those who received 24 weeks of treatment.[6] ION-3 evaluated non-cirrhotic, treatment naïve patients who achieved SVR in 94% of patients who received 8 weeks of treatment, and 96% of those who received 12 weeks.[15]

3.2 Clinical studies in HIV/HCV co-infection

3.2.1 ERADICATE

ERADICATE was the initial study evaluating LDV/SOF in patients co-infected with HIV and HCV. This study was a single center phase 2b trial and enrolled individuals who were co-infected with HIV and HCV genotype 1. Participants were treatment naïve without cirrhosis. HIV inclusion criteria included those with either 1) CD4 > 500 cells/mm3, 2) stable CD4 with HIV viral load < 500 copies/ml, or 3) CD4 > 100 cells/mm3 and HIV viral load <50 copies/ml on a stable ARV antiretroviral regimen for over 8 weeks. Accepted antiretroviral regimens were limited to a tenofovir and emtricitabine backbone with efavirenz, raltegravir, or rilpivirine In this study, 50 individuals were treated with LDV/SOF for 12 weeks. 98% of participants achieved SVR.[19]

3.2.2 ION-4

ION-4 was a multicenter phase III trial and enrolled individuals co-infected with HIV and HCV genotype 1 or 4. Participants could be treatment naïve or treatment experienced with peginterferon and ribavirin with or without a DAA, or ribavirin with a DAA. All stages of fibrosis were acceptable (20% of enrolled individuals were cirrhotic). HIV inclusion criteria included those with CD4 > 100 cells/mm3 and HIV viral load < 50 copies/ml on a stable antiretroviral regimen for over 8 weeks. Accepted antiretroviral regimens were limited to a tenofovir/emtricitabine backbone with efavirenz, raltegravir, or rilpivirine. Of 335 individuals treated with LDV/SOF for 12 weeks, 96% of all participants achieved a SVR as did 94% of cirrhotics and 97% of individuals with prior treatment experience. [20]

After multivariate analysis, the only factor associated with treatment failure was black race (34% of participants identified as black). 12 out of the 13 individuals who did not achieve SVR were black; 89.6% of black participants achieved SVR, compared to 99.5% of non-black participants. This association was not identified in trials of monoinfected individuals, nor was it identified in the ERADICATE trial, which included 84% black participants. An explanation for this disparity remains unclear, as this association was not explained by antiretroviral regimen, degree of liver fibrosis, or CYP2B6 polymorphism.[20]

3.2.3 Study Comparison

In both of these studies, high efficacy was demonstrated for the treatment of HIV/HCV co-infected individuals with LDV/SOF similar to those observed in ION—1,2 and 3 studies. There were no significant differences in overall treatment outcomes when compared to monoinfected individuals. However, there were some baseline inclusion differences worth noting. In ERADICATE, individuals with cirrhosis or treatment experience were not included. Further, the sample size was smaller (n=50 in ERADICATE, n=335 in ION-4) and a higher proportion of participants were black race (84% in ERADICATE, 34% in ION-4). In ION-4, individuals with genotype 4 were included in addition to genotype 1. Further, in ION-4 all subjects were required to be on antiretroviral therapy, compared to ERADICATE, where 26% of patients included were stable off of antiretroviral treatment. A comparison of subpopulation outcomes is described in Table 1.

Table 1
Subpopulation Outcomes in ERADICATE and ION-4

3.2.4 Resistance

In ION-4, prior to initiation of treatment, NS5A RAVs were identified in 59 of 325 patients (18%) by deep sequencing. 55 of these 59 patients (93%) achieved SVR compared to 258 out of 266 patients (97%) without baseline RAVs. Of note, this difference was not statistically significant, with p=0.24. Two patients who experienced on treatment failure had no baseline RAVs but were found to have treatment emergent variants at treatment failure. Of the 10 patients who experienced viral relapse, NS5A variants were detected in 4 patients at baseline and in 8 patients at relapse.[20]

In ERADICATE, deep sequencing was performed on the 1 participant who experienced relapse. This individual was found to have a baseline Y93H mutation that was 58% at baseline, 89% at day 3, and greater than 99% at relapse. Given the low rate of treatment failure, assessments could not be made regarding the significance of this RAV. [19]

3.2.5 Antiretroviral Drug Interactions

Though treatment of HIV/HCV co-infected patients with LDV/SOF is effective, the potential for drug interactions with antiretroviral medications can complicate treatment. Clinical trials have only evaluated a few drug regimens including combinations of the antiretroviral drugs tenofovir, emtricitabine, efavirenz, raltegravir, and rilpivirine.[19, 20] Pharmacokinetic analysis of these regimens have demonstrated LDV, SOF, and GS-331007 pharmacokinetics were similar across regimens and similar between coinfected and monoinfected patients. However, tenofovir exposure is higher with LDV/SOF. While this increase is felt to be safe, the use of LDV/SOF in combination with either ritonavir boosted atazanavir or darunavir causes further increase in tenofovir, raising concerns for nephrotoxicity. This elevation is not improved by staggered protease inhibitor administration. Therefore, use of boosted protease inhibitors in the presence of tenofovir and LDV/SOF is discouraged.[21, 22] While not tested in clinical trials, several other antiretrovirals are presumed to be safe for use in combination with LDV/SOF (see table 2).[23]

Table 2
Antiretroviral use in combination with LDV/SOF

4. Conclusion

The advent of DAAs has resulted in dramatic improvements in the ability to tolerate HCV treatment and achieve cure. LDV/SOF has been shown to be effective in patients with HCV genotype 1 and 4. In particular, studies of LDV/SOF in HIV/HCV co-infected patients have shown equivalent outcomes to those with HCV monoinfection. More needs to be understood about the risks of tenofovir associated nephrotoxicity, and the impact of uncontrolled HIV on treatment outcomes. However, at present, limited inclusion of these patients in clinical trials, due to potential drug-drug intercations between ARVs and DAAs, remains a barrier to understanding the optimal treatment of these patients. In the era of DAAs, individuals with HIV infection may no longer need to be considered a special population, and exclusion of those with HIV/HCV co-infection from general studies of HCV treatment should be reevaluated. Further, high cost of care has made wide dissemination of treatment of HCV impossible, and in particular, may limit antiretroviral options for patients with HIV co-infection. Increasing access to all DAA regimens, including LDV/SOF, will be of tremendous benefit for patients living with HIV/HCV co-infection.

5. Expert Opinion

While existing studies of HIV/HCV co-infected individuals with LDV/SOF have demonstrated equivalent efficacy, many unstudied questions remain.

5.1 Treatment duration

Both ERADICATE and ION-4 demonstrated efficacy of treatment with LDV/SOF for 12 weeks duration. While ION-3 demonstrated efficacy of LDV/SOF for 8 weeks for treatment of HCV genotype 1 in treatment naïve individuals without cirrhosis, this did not include individuals with HIV/HCV.[15] The only current data on shorter duration treatment in HIV/HCV co-infected individuals comes from the German Hepatitis C Cohort (GECCO). In this cohort, 69 of 70 people treated with LDV/SOF for 8 weeks duration achieved SVR. Of those, 7 individuals were HIV co-infected, and all 7 of these patients achieved SVR. An additional 21 HIV/HCV patients were treated, and SVR is pending.[24] No studies of treatment less than 8 weeks have been done in co-infected individuals.

5.2 Advanced HIV

In both ERADICATE and ION-4, HIV infected patients were well controlled, and most subjects were receiving antiretroviral treatment. However, the impact of uncontrolled HIV, particularly in patients with CD4 < 100 cells/mm3, remains unknown. This is an important population to study, as their impaired immune system may make effective treatment of HCV more challenging. However, given the direct antiviral activity of DAAs with minimal reliance on host immune response, optimal management of these patients will require further study.

5.3 Special populations

Though fibrosis progresses more rapidly in co-infected individuals, studies have not been done evaluating treatment of these patients with decompensated cirrhosis or liver transplant. An NIH-funded clinical trial is underway for this population (STOP-CO, NCT02533934) and may help clarify this issue. Further, the efficacy of LDV/SOF in patients with creatinine clearance less than 30 mL/min is unknown. In addition, the treatment with LDV/SOF of people living with HIV and co-infected with HCV genotype 5 and 6 has also not been evaluated.

5.4 Drug Interactions

As previously discussed, antiretroviral regimens tested in studies of HIV/HCV co-infection were limited. More information is needed to evaluate the efficacy and potential complications of LDV/SOF in combination with other commonly used antiretrovirals, such as dolutegravir, and abacavir. Real world data from co-infected patients treated with LDV/SOF may be helpful in further understanding the impact of antiretrovirals not studied in these trials.

The potential nephrotoxicity of elevated tenofovir in the setting of LDV remains a concern for co-infected patients receiving LDV/SOF, as tenofovir remains the major backbone for HIV therapy. However, this reaction seems to be idiosyncratic rather than dose related, therefore it is difficult to know how clinically significant these drug interactions may be. Of note, in the ERADICATE trial, serum creatinine, urinalysis for glucosuria and proteinuria, and urinary beta-2 microglobulin (a surrogate for renal proximal tubular dysfunction) were monitored. In these patients, no significant renal adverse events were identified.[25] The availability and use of tenofovir alafenamide, which may be associated with significantly less risk for nephrotoxicity than tenofovir disoproxil fumarate, may ultimately resolve this concern. However, this treatment is only currently FDA approved in the fixed dose combination of tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir. [26] Studies need to be done to clarify the risk of drug-drug interactions and nephrotoxicity with this new medication.

5.5 RAVs

Studies of resistance-associated variants have been inconclusive regarding the impact of RAVs on treatment efficacy. There is no evidence at present to suggest a variable effect of baseline RAVs in HIV/HCV co-infected patients as compared to HCV monoinfected patients.

5.6 DAA failures

Though treatment with LDV/SOF has been incredibly effective in all patient populations with HCV genotype 1 and 4, including those with HIV co-infection, some treatment failures occur. Advanced liver fibrosis and prior treatment experience have been identified as factors which decrease efficacy of DAA treatment. However, unlike prior IFN based treatments, HIV co-infection does not seem to impede DAA efficacy. Current phase 2 and 3 studies are being done to evaluate use of newer SOF based regimens for the retreatment of HCV after DAA failure. However, to date, HIV co-infection remains a common exclusion criteria for enrollment in these studies.

5.7 Overview of the Market

At present, there are three all oral DAA regimens, other than LDV/SOF, which have been studied for the treatment of people with HIV co-infected with HCV genotype 1 (see Table 3). These studies all demonstrate SVR greater than 90%, showing that current DAA treatments for HCV genotype 1 are effective in individuals with HIV co-infection. Of special interest is the fact that acceptable antiretroviral regimens vary depending on DAA regimen used, underscoring the need to have access to varied DAA regimens in order to increase the potential for ARV compatibility. [2729]

Table 3
DAA Studies of HCV Genotype 1 in Individuals with HIV Co-Infection

5.8 Cost

In the United States, the greatest barrier to HCV care remains the cost of treatment. high price tags set by pharmaceutical companies have resulted in rationing of care by insurance companies, which often precludes patients from receiving treatment unless they have advanced liver disease, access to specialist care, and abstain from substance use.[30, 31] HIV co-infection has also been independently associated with insurance denial for HCV treatment even though the IDSA/AASLD guidance prioritizes this group for immediate HCV therapy.[32] In addition, negotiations between pharmaceutical companies and insurers generally result in prioritization of one DAA regimen over another.[33] For patients with HIV/HCV, this may limit the options for compatible antiretroviral therapy.

In contrast, countries with single payer healthcare systems are often better able to negotiate affordable rates with pharmaceutical companies and have better mechanisms for cost control. Further, there is a degree of cost sharing and subsidizing for developing countries where the market will not bear higher price points. Gilead Sciences has allowed 101 countries access to lower-priced generic sofosbuvir, but patients in middle income countries will be left with little recourse to access affordable drugs. [34]

Acknowledgments

This manuscript was supported by the intramural program of the National Institute of Allergy and Infectious Diseases (NIAID) and has been funded in part by the National Institute of Allergy and Infectious Diseases, and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract no. HHSN2616200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.

Footnotes

Disclaimer: The manuscript was written while Dr. Polis was a federal employee. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor imply endorsement by the U.S. government.

Declaration of interest:

The authors have 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 apart from those disclosed.

Bibliography

1. Hepatitis C. 2015 8/27/2015]; Available from: http://www.who.int/mediacentre/factsheets/fs164/en/
2. CDC. HIV and Viral Hepatitis. 2014 Mar; 11/5/2015]; Available from: http://www.cdc.gov/hepatitis/populations/pdfs/hivandhep-factsheet.pdf.
3. WHO. HIV and hepatitis coinfections. 11/20/2015]; Available from: http://www.who.int/hiv/topics/hepatitis/hepatitisinfo/en/
4. Graham CS, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33(4):562–569. [PubMed]
5. Terrault NA, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 2012;18(6):716–726. [PMC free article] [PubMed]
6. Afdhal N, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483–1493. [PubMed] *Hallmark study of LDV/SOF in HCV monoinfection
7. Afdhal N, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889–1898. [PubMed] *Hallmark study of LDV/SOF in HCV monoinfection
8. Kattakuzhy S, Levy R, Kottilil S. Sofosbuvir for treatment of chronic hepatitis C. Hepatol Int. 2015;9(2):161–173. [PubMed]
9. Harvoni [package insert] Foster City, CA: Gilead Sciences; 2014. 10/1/2015]; Available from: https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf.
10. Micromedex. Ann Arbor (MI): Truven Health Analytics; Harvoni. 11/15/2015]
11. Fontaine H, et al. Bradyarrhythmias Associated with Sofosbuvir Treatment. N Engl J Med. 2015;373(19):1886–1888. [PubMed]
12. Renet S, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology. 2015;149(6):1378–1380. e1. [PubMed]
13. Terrault NA. (HCV-TARGET) - Treatment Outcomes With 8, 12 and 24 Week Regimens of Ledipasvir/Sofosbuvir for the Treatment of Hepatitis C Infection: Analysis of a Multicenter Prospective, Observational Study in AASLD 2015. San Francisco: 2015.
14. Lontok E, et al. Hepatitis C virus drug resistance-associated substitutions: State of the art summary. Hepatology. 2015;62(5):1623–1632. [PubMed]
15. Kowdley KV, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879–1888. [PubMed] *Hallmark study of LDV/SOF in HCV monoinfection
16. Kattakuzhy S, et al. Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti-Hepatitis C Virus Therapy in Patients With Advanced Liver Disease. Clin Infect Dis. 2016;62(4):440–447. [PubMed] *Study of short-course treatment of HCV monoinfection in patients with advanced fibrosis. Demonstrated no impact of baseline RAVs.
17. Wilson EM, et al. Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens. Clin Infect Dis. 2016;62(3):280–288. [PubMed] *Study of successful retreatment of HCV after prior short-course DAA failure. Demonstrated no impact of baseline RAVs.
18. Lawitz E. Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens With Ledipasvir/Sofosbuvir for 24 Weeks, in EASL - The International Liver Congress 2015. Vienna, Austria: 2015. [PMC free article] [PubMed]
19. Osinusi A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015;313(12):1232–1239. [PubMed] **Hallmark study of LDV/SOF in patients with HIV/HCV
20. Naggie S, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373(8):705–713. [PubMed] **Largest study of LDV/SOF in patients with HIV/HCV.
21. El-Sherif O, Khoo S, Solas C. Key drug-drug interactions with direct-acting antiviral in HIV-HCV coinfection. Curr Opin HIV AIDS. 2015;10(5):348–354. [PubMed]
22. German P. Pharmacokinetic Analyses of Ledipasvir/Sofosbuvir and HIV Antiretroviral Regimens in Subjects With HCV/HIV Coinfection, in AASLD 2015. San Francisco, CA: 2015.
23. AIDSinfo. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2015 11/5/2015]; Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/26/hiv-hcv.
24. Ingiliz P. Sofosbuvir Plus Ledipasvir for 8 Weeks in HCV-mono- and HIV-HCV-coinfected Patients - Results from the German Hepatitis C Cohort (GECCO). 15th European AIDS Conference; October 21–24, 2015; Barcelona. 2015.
25. Osinusi A, Townsend K, Kottilil S. Drug-Drug Interactions in Patients Co-infected With HCV and HIV--Reply. JAMA. 2015;314(2):186–187. [PubMed]
26. Genvoya [package insert] Foster City, CA: Gilead Sciences; 2015.
27. Sulkowski MS, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015;313(12):1223–1231. [PubMed] *Treatment of HCV/HIV with ombitasvir/paritaprevir/ritonavir/dasabivur and ribavirin.
28. Wyles DL, et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373(8):714–725. [PubMed] *Treatment of HCV/HIV with daclasvir/sofosbuvir.
29. Rockstroh JK, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015;2(8):e319–e327. [PubMed] *Treatment of HCV/HIV with grazoprevir/elbasvir
30. Trooskin SB, Reynolds H, Kostman JR. Access to Costly New Hepatitis C Drugs: Medicine, Money, and Advocacy. Clin Infect Dis. 2015 [PubMed] *Excellent discussion of the limitations to access to HCV treatment in the United States due to high cost of medications.
31. Barua S, et al. Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States. Ann Intern Med. 2015;163(3):215–223. [PubMed]
32. Lo Re V. Incidence and Determinants of Denial of DAA Treatment for Chronic HCV Infectionby Insurance Type During the First 6 Months of the Modern HCV Treatment Era. AASLD 2015; San Francisco, CA. 2015.
33. Silverman E. What the 'Shocking' Gilead Discounts on its Hepatitis C Drugs Will Mean. [cited 2015 10/19/15];The Wall Street Journal. 2015
34. Graham CS, Swan T. A path to eradication of hepatitis C in low- and middle-income countries. Antiviral Res. 2015;119:89–96. [PubMed]