JENNIFER ANDRES, PHARMD, BCPS

Amid the ongoing opioid epidemic, hepatitis C virus (HCV) infection should be at the forefront of health care providers’ minds. Although HCV has been widely viewed as predominantly affecting baby boomers—those born between 1945 and 1965&mdash;a younger generation is experiencing increased incidence of infection.

From 2010 to 2015, the number of newly reported HCV diagnoses almost tripled, with the highest rate among people in their 20s.

 These new cases are likely a result of injection drug use in younger patients.

 These patients may be referred to as persons who inject drugs (PWIDs) or intravenous drug users. Because HCV is a blood-borne pathogen, intravenous (IV) drug use is a major risk factor for acquisition. In fact, a recent analysis suggested that in the United States, approximately 50% of PWIDs are infected with HCV.

The use of new syringes is a viable way to avoid HCV infection; however, the virus also can be found and transmitted via preparation equipment including containers, filters, and rinse water. Practicing “back-loading”—injecting drugs from 1 syringe to the back of another open syringe&mdash;also can lead to HCV transmission. Furthermore, the development of antibodies against HCV is not protective, leading to a risk of reinfection in treated patients who later have another exposure.

 Although genotype 1 infection is most common in the United States, genotype 3 infection has been increasingly linked with PWIDs.

 Genotype 3 is linked to faster cirrhosis development than other genotypes, and so it is urgent to treat patients infected with this genotype.

Results of studies have shown that, compared with the other types, genotype 3 is more easily treated with interferon regimens, with response rates of approximately 60% compared with 30% for genotype 1 infection. However, with the advent and use of direct acting antivirals (DAAs), genotype 3 became harder to treat relative to other types, with lower sustained viral response (SVR) rates at 12 weeks (SVR12) than genotype 1.

 SVR12 rates are >97% for all preferred regimens in treatment-naïve individuals with genotype 1 infection without cirrhosis. There are fewer available DAA regimens for genotype 3 infection compared with genotype 1; however, all preferred available regimens are equally effective. Current treatment recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America are listed in the 

 Since the approval of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, ribavirin is not needed for most treatment-naïve individuals. SVR12 rates have improved, from 90% with sofosbuvir/ribavirin in those without cirrhosis to 95% and 98% with glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, respectively.

Glecaprevir/pibrentasvir can be used for an 8-week duration in most treatment-naïve patients. Notably, the presence of compensated cirrhosis in an individual lowers the likelihood of SVR12 attainment. Baseline resistance testing for the 

mutations should be considered for patients with cirrhosis, either compensated or decompensated, and patients who have failed previous treatment, also referred to as treatment-experienced patients.

 Presence of these mutations could signify a lower chance of treatment success. 

Patients being treated for opioid use disorders are frequently on maintenance medications, or opiate substitution therapy, to prevent withdrawal and aid recovery. Commonly used medications include buprenorphine/naloxone, buprenorphine alone, and methadone. No drug—drug interactions exist with opioid substitution therapy that would reduce efficacy or cause toxicity of DAAs; however, additional characteristics relevant to the PWID population, including the age of the infected patient, could have an impact on choice of treatment. Because these cases may involve younger patients, childbearing potential should be evaluated. Female patients of childbearing age will need contraception. No DAA regimens have been studied in pregnancy; all regimens should be avoided in patients who are pregnant or breastfeeding. HCV can be transmitted from mother to fetus, so children born to infected women should be screened for HCV. If ribavirin will be a part of an HCV regimen, female patients must avoid pregnancy during treatment and for 6 months following its completion.

From both public health and ethical perspectives, concerns exist regarding the treatment of HCV in PWIDs. Many current PWIDs are excluded from clinical trials, leading to fear that DAAs may be ineffective in this population; however, a recent real-world study in the United States found similar SVR12 rates in groups that continued to use IV drugs and in those who did not use IV drugs.

Fear that current or past PWIDs will not adhere to their medication regimen may be a barrier to treatment. Strategies for adherence include the use of patient navigators, group therapy, and directly observed treatment. With patient support, including access to substance abuse treatment, HCV treatment in these populations is possible. A recent study in New York evaluated 3 models of HCV treatment, comparing 150 patients on opiate agonist treatment with directly observed treatment, group treatment, and treatment as usual, in which patients took their own medication. Overall, 94% of patients achieved SVR12. More patients did so in the directly observed and group treatment arms than in the treatment as usual arm, but this was not statistically significant.

Of note is that private or public health insurance plans may deny patients treatment based on current IV drug use. Furthermore, some insurance plans may require 6 or more months of abstinence prior to approval. Current AASLD/IDSA guidelines do not list being a current or former PWID as a contraindication to treatment and should not be used to limit treatment access.

Reacquisition of HCV infection following successful treatment is a valid concern. All current and past PWIDs should receive risk-reduction education, including information about injection techniques that minimize risk.

 Additionally, although HCV can be reacquired, some small studies show that the reacquisition rate, estimated at 2.9 per 100 person-years, is lower than the new acquisition rate, estimated at 6.1 to 27.2 per 100 person-years. Even in those who continue to use IV drugs, the reinfection rate is 6.44 per 100 person-years.

 This rate is similar to the late relapse rate, according to a recent meta-analysis, indicating that most patients—even those at high risk&mdash;will not become reinfected.

 This will need to be followed in the future because most of these analyses included patients on pegylated interferon and ribavirin rather than DAAs. Treating the large cohort of infected HCV individuals could also reduce incidence and prevalence in the PWID population, which may help mitigate the reinfection rate.

Because of these concerns, the AASLD/IDSA guidelines have been updated to include patients with current or past injection drug use as a unique population. Routine HCV screening should be performed annually, if not more frequently, based on risk. The need for harm reduction services, such as patient counseling, needle syringe exchange, and substance use disorder treatment, to minimize the risk of infection and transmission are also highlighted in the new guidelines.

IV drug use is the largest risk factor for hepatitis C transmission, and IV opioid use has increased in the United States, augmenting the likelihood of acquiring HCV infection, especially of genotype 3. Treatment of HCV in current or past PWIDs should be considered to prevent transmission of HCV, as no drug—drug interactions exist between opioid substitution therapy and DAAs. In addition, risk-reduction education should focus on this population to prevent HCV infection from occurring in the first place.    

Dr. Andres is a clinical assistant professor at Temple University School of Pharmacy in Philadelphia, Pennsylvania who practices in a hepatology clinic. She received a PharmD from Temple and completed PGY-1 pharmacy practice residency at the Martinsburg Veterans Affairs Medical Center in West Virginia. She is an active member of SIDP.

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An increase in injection drug use in the United States has augmented the likelihood of acquiring HCV, particularly genotype 3. 

Another Adverse Effect of the Opioid Epidemic: Hepatitis C Infections

Chronic hepatitis C virus (HCV) infection affects an estimated 2.7 million to 3.9 million people in the United States.

 HCV can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease if left untreated. In patients with HIV, the progression to cirrhosis is more rapid than in mono-infected patients.

 In the United States, about one-quarter of HIV infected patients are also coinfected with HCV.

Across the world, patients with HIV are 6 times more likely to be infected with HCV than the general population. People who inject drugs are most likely to have coinfection, and in the United States, 50% to 90% of HIV-infected injection drug users are also coinfected with HCV.

 All patients with HIV infection should be screened at least once for HCV. In patients with continued risk factors, such as intravenous (IV) drug use or men who have sex with men, HCV screening should be repeated.

 Consequently, there are several treatment sensitivities that need to be taken into account when treating coinfected individuals.

The overall treatment response to interferon and ribavirin has been found to be low in HCV-mono-infected patients, and HIV coinfected patients have been shown to have an even lower response.

 Well-tolerated and efficacious oral drug regimens now exist for the treatment of the general patient population with HCV, which now includes patients coinfected with HIV. With one exception, there is no difference in the efficacy of direct-acting antivirals (DAAs) in an HIV-coinfected or mono-infected patient, and the current guidelines recommend that HIV-infected patients be treated the same as noninfected patients.

When the decision is made to treat HCV, consideration must be given to drug interactions with HIV therapy. None of the currently available DAAs are free from drug interactions with HIV antiviral agents. Although some clinicians may choose to defer antiretroviral therapy (ART) until HCV therapy is completed, the US Department of Health and Human Services HIV guidelines recommend ART should be initiated in all HIV/HCV coinfected patients regardless of their CD4 cell count.

 HIV therapy should not be withheld to facilitate easier treatment with DAAs; rather, the patient should be referred to an HIV specialist who can select an HIV regimen to accommodate HCV therapy by avoiding drug—drug interactions and toxicities. In general, most pharmacy benefit managers require patients to be on a stable HIV regimen prior to beginning HCV therapy.

Prior to August 2017, shortened regimens were not recommended for HCV treatment in coinfected patients. Ledipasvir/ sofosbuvir was not recommended to be shortened to 8 weeks, even if the patient was treatment-naïve and noncirrhotic and had a low-baseline HCV viral load.

 Now, the recommendations include glecaprevir/pibrentasvir (GLE/PIB), a newly approved pangenotypic combination of an NS3/4A protease inhibitor and an NS5A inhibitor. It is administered as 3 tablets of GLE 100 mg/ PIB 40 mg once daily with food, and can be used for 8 weeks in select populations. In addition to having pangenotypic properties, GLE/PIB does not undergo renal excretion, allowing it to be used without dose adjustment in patients with chronic kidney disease and on dialysis.

In the EXPEDITION-2 trial to study GLE/ PIB, a total of 137 coinfected patients without cirrhosis received 8 weeks of GLE/PIB, while 16 patients with cirrhosis received 12 weeks of GLE/PIB. All the patients were treatment- naïve or previously treated with pegylated interferon/ribavirin with or without sofosbuvir. The treatment duration in the study is identical to current US Food and Drug Administration (FDA)—approved treatment durations and is the same for mono-infected patients.

The study results showed 99.3% sustained viral response for 12 or more weeks (SVR12) in patients receiving GLE/PIB for 8 weeks. This includes 1 patient who withdrew from the study due to an unrelated adverse effect. In patients with cirrhosis, all but 1 patient attained SVR12, although this was a small group of patients. None of the patients had HIV breakthrough. The combination of GLE/PIB was well tolerated, with none of the patients reporting an adverse effect related to the study drug. Efficacy was similar to other clinical trials that did not include the HIV-infected population. All ART agents used in the trial were free of drug interactions with GLE/ PIB. None of the patients were on protease inhibitor—boosted antivirals, in whom coadministration with GLE/PIB is not recommended.

 Efavirenz should also be avoided with GLE/PIB due to the risk of decreased GLE/PIB levels. Of note, when using GLE/PIB with elvitegravir/cobicistat-based regimens, a dose adjustment is not required.

 The current guidelines do not yet address the use of GLE/PIB; however, it is likely that this agent will be recommended for use in the HIV population.

Additional research has shown that currently available nonstructural protein 5A (NS5A) inhibitors for HCV infection— ledipasvir and velpatasvir&mdash;interacted with the HIV therapy drug tenofovir disoproxil fumarate (TDF).

 Because 4 out of 5 of the first-line—recommended HIV regimens contain tenofovir, this interaction could affect a number of coinfected patients.

Through P-glycoprotein inhibition, levels of TDF could increase, potentially causing increased (stronger or more) adverse effects. This is more concerning in patients with preexisting renal impairment, even with a glomerular filtration rate of 60 mL/min.

 No dose adjustment is required; however, it is necessary to monitor for TDF toxicity. In April 2016, the FDA approved the new formulation of tenofovir, tenofovir alafenamide (TAF), as part of the combination drug Descovy (emtricitabine/tenofovir alafenamide). TAF is a new oral prodrug of TDF, a nucleotide analogue that inhibits HIV-1 transcription. Unlike TDF, TAF is a more stable prodrug of tenofovir (TFV) in the plasma, which allows for high concentrations of TFV inside target cells. This reduces the plasma TFV exposures at approximately one-tenth the clinically approved dose of TDF.

Intracellular activation of TAF allows for higher concentrations inside target cells and a lower concentration of TFV in the plasma, reducing off-target toxicities such as renal and bone complications. TAF is much safer to use in patients with renal impairment as part of their nucelos(t)ide reverse transcriptase inhibitor (NRTI) backbone. This makes tenofovir one of the safest NRTIs, with minimal hepatic toxicity and few to no drug interactions with HCV drug regimens.

Highly active agents against HCV are available for HIV-infected individuals coinfected with HCV, including a new option allowing for an 8-week treatment duration in treatment-naïve patients without cirrhosis. Although there is no difference in efficacy in coinfected patients, the HIV-infected patient will still need special considerations regarding drug interactions when considering treatment for HCV infection. Consultation with HIV and HCV specialists is crucial when drug interactions exist. Fortunately, most of the commonly used HIV therapies do not have many drug interactions with HCV therapy. Five out of the 6 recommended first-line antiretroviral therapies are integrase strand transfer inhibitor-based regimens, which do not have any drug interactions with HCV therapy, with the exception of elvitegravir boosted cobicistat (See 

). Because HIV-infected patients remain a less-studied population in the treatment of HCV, despite the high risk for coinfection, more research should be done on medications with less potential for cross-reactivity.

Dr. Andres is a clinical assistant professor at Temple University School of Pharmacy who practices in a hepatology clinic. She received a PharmD from Temple University School of Pharmacy and completed PGY-1 pharmacy practice residency at the Martinsburg Veterans 

Affairs Medical Center in Martinsburg, West Virginia.

Dr. Cheng is a clinical assistant professor with a specialty in HIV pharmacotherapy at Temple University School of Pharmacy. She received her PharmD at the University of Maryland School 

of Pharmacy and completed a PGY-1 pharmacy practice residency at Penn Presbyterian Medical Center and a PGY-2 HIV ambulatory care/clinical pharmacogenetics residency at the University of Houston College of Pharmacy. She is an active member of AAHIVM.

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Despite the availability of highly active agents against HCV, HIV-infected patients require special considerations for drug interactions when considering treatment options.  

JENNIFER ANDRES, PHARMD, BCPS

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