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INTRODUCTION

On June 5, 1981, the United States Centers for Disease Control and Prevention (CDC) published the first official case reports of what would ultimately be known as acquired immunodeficiency syndrome (AIDS).¹ Nearly 40 years have passed since human immunodeficiency virus (HIV) was identified as the cause of AIDS. HIV/AIDS continues to be a significant cause of morbidity and mortality for people across the world. Worldwide, an estimated 35.4 million people have died from AIDS-related illnesses.² Despite the lack of a cure for HIV infection, research continues to contribute to the development and enhanced effectiveness of medications used to help control HIV replication and prevent complications. For those with access to critical medications and high-quality medical care, HIV infection has largely shifted from an acute disease with a high likelihood of early death to a manageable chronic disease.

An estimated 20% to 30% of patients living with HIV in the United States are coinfected with hepatitis C virus (HCV).³ HIV and HCV infections share similar transmission methods, which explains the relatively high incidence of coinfection. HCV is the most prevalent blood-borne chronic infection in the United States and when percutaneous blood exposures occur, it is approximately 10 times more infectious than HIV.^3,4

HCV was first identified in 1989 and until recently was extremely difficult to cure. In recent years, several new medications have been approved for the treatment of chronic HCV, drastically increasing cure rates. Complications of chronic HCV infection include: cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As with HIV, no preventive HCV vaccine exists.

HIV/HCV coinfection has the potential to complicate the management of both infections. Treatment of HIV and HCV infections involves the use of multiple antiviral agents, and these require a high level of patient adherence and may have significant drug interactions and toxicities.

With their unique education and skills, pharmacists play an integral role in the management of HIV- and HCV-infected patients. This continuing education article provides readers with an overview of current management of HIV and HCV, emphasizing considerations for antiviral therapy in coinfected patients. This review focuses on HIV type 1, the predominant type of HIV found in the United States, and on the management of HIV and HCV infection in antiviral-naive adult patients.

EPIDEMIOLOGY

In 2017, approximately 36.9 million people globally were living with HIV.² An estimated 1.8 million people were newly infected with HIV in 2017, representing a 16% reduction since 2010. Similarly, AIDS-related deaths have decreased by 51% since they peaked in 2004 (1.9 million in 2004 versus 940,000 in 2017). In 2017, approximately 59% of all adults infected with HIV had access to antiretroviral therapy (ART).² HIV clearly remains a major global public health issue despite a significant degree of success. Improved access to medications, research, care, and funding are still needed. Global organizations such as the World Health Organization, the Joint United Nations Programme on HIV/AIDS, and the International AIDS Society, have long advocated for the appropriate prevention, management, research, and resource allocation for global HIV/AIDS relief.

In the United States, approximately 1.2 million people are living with HIV infection.⁵ HIV screening is important, since almost 15% of those who are HIV infected are unaware of their infection. During the past decade, the number of Americans living with HIV has increased. The increased prevalence is not unexpected and is considered largely a result of the large-scale access to effective ART that prolongs life, along with an unfortunately consistent number of about 50,000 people newly infected with HIV each year. ⁵

This rate of new infections in the United States continues despite increased HIV awareness and education. New HIV infections in men are most often the result of male-to-male sexual contact, followed by heterosexual sex and then injection drug use (IDU). The most likely route of transmission for newly infected women is heterosexual sex, followed by IDU. Of all new HIV infections in 2017, men who have sex with men (MSM) accounted for 66%, heterosexual sex for 24%, and IDU for 6%.^5,6 Mother-to-infant transmission, contaminated blood products, and occupational exposure of health care workers through needlesticks are other known HIV transmission mechanisms.

HIV disproportionately affects African Americans and Hispanics/Latinos. African Americans represent approximately 13% of the U.S. population, but accounted for 43% of new HIV infections in 2017. Similarly, Hispanics/Latinos represent approximately 18% of the U.S. population, but accounted for 26% of new HIV infections in 2017.^5,6 The disparities in incidence of HIV infection by race/ethnicity remain an important area of research and outreach focus.

The estimated global prevalence of HCV infection is 3%, resulting in an estimated 170 million HCV-infected people.³ In the United States, approximately 3.7 million people are HCV seropositive (indicating previous exposure), with 2.4 million of these people being HCV-RNA positive (indicating current infection). Between 2013 and 2016, the number of people with current HCV infection decreased, while the number of HCV-seropositive people increased. This increase is likely due to newly available direct-acting antiviral therapies (DAAs).⁷

HCV infection can be transmitted via mechanisms similar to those that transmit HIV: percutaneous exposure to blood or blood products, sexual intercourse, and mother-to-infant transmission. IDU remains the most common HCV transmission method. Other factors associated with HCV transmission include occupational exposure through needlesticks, tattoo placement, intranasal cocaine use, and long-term hemodialysis. Heterosexual HCV transmission is uncommon, but the risk is greater when partners are coinfected with HIV/HCV. ³ Similarly, HIV/HCV-coinfected MSM appear to have a greater risk of transmission of HCV than do individuals who are HIV negative.^3,8,9

PATHOLOGY/PATHOPHYSIOLOGY

HIV is a single-stranded, enveloped, RNA retrovirus of the Retroviridae family. After infecting a person, HIV attacks various cells of the immune system, most notably T-cell lymphocytes. T-cell lymphocytes are frequently referred to as CD4 cells because they have CD4 receptors on their surface. CD4 cells occupy a vital role: regulating cell-mediated immunity to fight infection and maintain immunocompetent individuals’ health. HIV infection destroys CD4 cells and inhibits new CD4 cell production.

Over time, this cyclical process leads to immune system destruction and leaves the HIV-infected person vulnerable to opportunistic infections (OIs) and further morbidity and mortality. On average, HIV-infected patients who do not receive ART following infection survive 10 to 15 years.¹¹ Following infection, patients may be asymptomatic or may not recognize the signs and symptoms of acute HIV infection until years later when they develop OIs and/or AIDS.

Adult HIV-infected patients are classified as having AIDS if they have or have had a history of a CD4 count less than 200 cells/mm³ (less than 14% of total lymphocytes) and/or an AIDS-defining clinical condition as defined by the CDC. Examples of AIDS-defining clinical conditions are Pneumocystis jirovecii pneumonia, Toxoplasma gondii encephalitis, Mycobacterium tuberculosis disease, and disseminated Mycobacterium avium complex (MAC) disease. Of the two types of HIV (HIV-1 and HIV-2), HIV-1 is the most common type in the United States.

HCV is a single-stranded, enveloped, RNA virus in the Flaviviridae family. Viral replication primarily occurs in the cytoplasm of the hepatocytes and may also occur in peripheral blood cells.⁴ There are 7 distinct genotypes of HCV (genotypes 1–7) with several subtypes (a,b,c). HCV genotype 1 infection accounts for the majority (75%) of HCV infections in Americans.⁷

HCV can cause acute or chronic infection, with 85% of acute infections persisting and resulting in chronic infection. Fewer than 20% of patients with acute HCV have symptoms.⁴ Acute HCV symptoms include low-grade fever, right upper-quadrant pain, nausea, vomiting, anorexia, dark urine, and jaundice. Elevations of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations may be the only abnormal laboratory findings in acute or chronic HCV. Untreated chronic infection can progress over years and cause asymptomatic damage to the liver. Approximately 1 in 5 patients with chronic HCV will develop cirrhosis within 20 years of infection, though the rate of progression to cirrhosis can be significantly increased in patients who consume alcohol.³ HCV-related cirrhosis is the most common reason for liver transplants in the United States. ⁴ Additionally, HIV/HCV coinfection, particularly for those with AIDS, is associated with accelerated progression of liver disease to cirrhosis, even when patients are treated with ART.³ Furthermore, HIV/HCV-coinfected patients with cirrhosis progress more rapidly to hepatocellular carcinoma than their HIV-negative counterparts.³

SCREENING/DIAGNOSIS

People can be tested voluntarily for HIV infection using a variety of HIV tests that are approved by the Food and Drug Administration (FDA). Specimens include plasma, serum, saliva, or urine. Many of these products test for antibodies to HIV-1 and/or HIV-2. The presence of these antibodies indicates that HIV has infected the person’s blood. Other products test directly for the presence of HIV RNA.

Of particular interest to pharmacists are over-the-counter (OTC) anonymous and confidential FDA-approved self-tests: the Home Access HIV-1 Test and the OraQuick In-Home HIV Test. The Home Access HIV-1 Test requires the patient to mail a dried blood specimen to a laboratory for analysis. The laboratory provides results in 3–7 business days. The OraQuick In-Home HIV Test tests a fluid sample from the patient’s mouth and typically provides results in 20–40 minutes. The OraQuick test is a screening test only and requires confirmation with a diagnostic test if the patient’s results are positive. More information on testing and a complete list of FDA-approved screening and diagnostic HIV assays is available on the FDA website.

The HIV screening and diagnostic tests described above are highly accurate; however, in rare cases, inaccurate results can occur. Upon being infected with HIV it can take up to 6 months for a person to develop antibodies.¹¹ Because of this, the most common cause of a false-negative result is when an individual is tested during this 6-month “window” between exposure to HIV and HIV antibody development. Patients with risk factors for HIV transmission should receive repeat antibody testing at an appropriate interval based on this 6-month window. 

In 2006, the CDC released revised HIV-testing recommendations.¹² The guidance advocated for voluntary HIV screening as a routine part of medical practice, and recommended a simplified consent process to encourage increased HIV screening. The CDC recommended routine HIV screening for the following populations: all patients aged 13–64 years, all pregnant women, and all patients initiating treatment for tuberculosis or sexually transmitted infections. The guidance also stated that patients at “high risk” for HIV should be screened at least annually. People at high risk include those who are IDUs (and their sex partners), people who exchange sex for money or drugs, sex partners of HIV-infected persons, and MSM or heterosexual persons who themselves or whose partners have had more than 1 sex partner since their most recent HIV test.

Similar to HIV, screening for HCV typically uses serology to determine the presence of HCV antibodies. Patients with a recent exposure to HCV (i.e., less than 6 months) and/or who are in an immunocompromised state may falsely test negative for HCV antibodies and thus should receive repeat antibody testing or HCV RNA testing.^4,13 A “reactive” HCV antibody test should be interpreted as presumptive HCV infection, though it could indicate a current infection, past resolved infection, or an incorrect test result. Reactive HCV antibody test results should prompt testing for HCV RNA for clarification of the infection’s status. Patients with a reactive HCV antibody who subsequently have HCV RNA detected should be considered as having current HCV infection, and they should be educated and linked to appropriate care and treatment. Clinicians should evaluate patients with current HCV infection for hepatitis B virus and HIV infection. Furthermore, clinicians should also assess patients with current HCV infection for the presence of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. A patient with a reactive HCV antibody but no detectable HCV RNA does not have current HCV infection and frequently requires no further intervention. As with HIV, an anonymous, confidential FDA-approved self-screening-test for HCV (the Home Access Hepatitis C Check) is available over the counter and can be administered at home.

The CDC recommends one-time HCV screening for all adults born between 1945 and 1965 without regard to HCV risk factors.^14,15 This age group, the “baby boomer” generation, has a high prevalence of HCV. Routine HCV screening is also recommended for those at “high risk.”¹⁴ People at high risk include those currently injecting drugs, those who injected drugs in the past, those with certain medical conditions (e.g., those receiving clotting factor concentrates produced before 1987, those who were ever on long-term hemodialysis, those with persistently abnormal ALT, and those who are HIV-infected) and those who were prior recipients of transfusions or organ transplants. Additionally, health care workers with occupational exposure through needlesticks or other exposure to HCV-positive blood and children born to HCV-infected women should also be screened.¹⁴

MANAGEMENT OF HIV INFECTION

Currently, more than 40 different FDA-approved single-ingredient or combination formulations of antiretrovirals (ARVs) are available for HIV infection management. ARVs are used in combination to maximize their efficacy, usually combining at least 2 different pharmacologic classes in each patient’s ART. Clinicians must take into account a variety of factors when considering initiating ART for any particular patient, including the following:

• Baseline clinical status
• CD4 count and viral load (HIV-RNA)
• Prior experience with ARVs and genotype resistance testing
• Pertinent laboratory findings (e.g., renal and hepatic function)
• Concomitant prescription/OTC medications and herbal use
• Willingness to accept and adhere to ART

The difficulty in balancing the ARVs’ efficacy with their risks led to the development of domestic and international guidelines.^16,18-20 To keep current with the constantly evolving field of HIV-related research, these guidelines are revised frequently, incorporating the most recent advancements in HIV practice and research. In the United States, most clinicians use the Department of Health and Human Services (DHHS) guidelines, which were last updated on October 25, 2018.¹⁶ These guidelines, along with other pertinent HIV-related information, are available at http://aidsinfo.nih.gov.

The goals of ART are to reduce HIV-associated morbidity and prolong the duration and quality of survival, restore and preserve immunologic function, suppress plasma HIV viral load maximally and durably, and prevent HIV transmission.¹⁶ Use of pretreatment drug resistance testing, appropriate ART selection, patient adherence to recommended ART, and appropriate prophylaxis and treatment of OIs can achieve these goals. Clinicians often monitor patients with HIV by measuring their CD4 counts at entry into care, 3 months after start of ART, and then every 3 to 6 months thereafter. They also measure their viral load (VL) at baseline, within 2 to 4 weeks after ART initiation, every 4 to 8 weeks until VL suppression, and then every 3 to 4 months. In addition, clinicians monitor patients routinely for clinical outcomes such as the development of OIs and other AIDS-defining clinical conditions.

Based on the extent of clinical research demonstrating that early therapy initiation produces positive patient and population outcomes, the guidelines recommend initiating ART for all HIV-infected people, regardless of CD4 cell count or VL. Early therapy reduces the risk of HIV disease progression and can prevent HIV transmission. The guidelines indicate patients must be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. This is a critical point. The guidelines emphasize that all HIV-infected patients should start ART as soon as possible, but recommend deferring ART if patients are not yet ready to commit or demonstrate clinical and/or psychosocial factors that would significantly hinder their ability to adhere to therapy. This approach minimizes development of ART resistance and poor patient outcomes.¹⁶

Clinicians should closely monitor patients for whom ART is deferred and educate them. The health care team should engage them and initiate ART as soon as patients are ready to commit to recommended treatment. For those who choose to start HIV treatment, adherence can be challenging since ART is a lifelong commitment. Poor adherence has been associated with mental illness, neurocognitive impairment, substance-abuse issues, low health literacy, poverty, homelessness, denial, younger age, and nondisclosure of HIV-positive status.¹⁶ HIV-related stigma has been found to compromise adherence by undermining social support and adaptive coping. Concealment of HIV status to avoid stigma may contribute to treatment interruptions leading to poor adherence.

Interventions to reduce HIV-related stigma may improve ART adherence.²¹ Clinical settings that provide nonjudgmental multidisciplinary supportive care may improve adherence.¹⁶ Further research on adherence and its measurement and improvement is necessary.²² The CDC’s HIV/AIDS Prevention Research Synthesis Project (PRS) has identified interventions that can improve adherence. These interventions can include home visits from health care providers, directly administered ART, peer support, needs assessments, medication education, tailored medication regimens, and assessment to identify adherence barriers.²³

ARVs are classified by their method of inhibition in the HIV lifecycle, namely their mechanism of action. There are currently 5 broad pharmacologic ARV classes: (1) entry inhibitors; (2) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs); (3) nonnucleoside reverse transcriptase inhibitors (NNRTIs); (4) integrase strand transfer inhibitors (INSTIs); and (5) protease inhibitors (PIs). In addition to these ARVs, clinicians may prescribe pharmacokinetic enhancing agents, which “boost” the levels of the concomitantly prescribed ARVs. These agents themselves do not function as ARVs but instead enhance prescribed ARV efficacy and simplify dosing/administration. Common pharmacokinetic enhancing agents used in HIV include low-dose ritonavir and cobicistat, which must be prescribed carefully since they can cause significant drug interactions. A detailed review of the specific pharmacology, adverse effects, and drug interactions for each of these ARV agents is available in the treatment guidelines, antiviral product labeling, and other review articles.^16,24

To initiate ART in an antiretroviral-naive patient, the provider must select an appropriate, evidence-based, individualized combination ART regimen based on the factors previously discussed. Such regimens typically include 2 NRTIs plus an INSTI, or 2 NRTIs plus a NNRTI, or 2 NRTIs plus a PI; these may be combined with a pharmacokinetic-enhancing agent. These regimens combine potent ARVs and are frequently referred to as highly active antiretroviral therapy (HAART) or more recently ART. ART is key to suppress the virus and prevent viral mutations (which can lead to resistance). The current DHHS treatment guidelines provide guidance on recommended initial regimens for most people with HIV (see Table 1).¹⁶ The guidelines also provide further comprehensive details.¹⁶

Although the guidelines recommend various ARTs, individual patient factors will often determine the best choice for that patient. It is critical that medical providers and the health care team (including pharmacists) work collaboratively to engage the patient and identify the best treatment choices with appropriate monitoring and follow-up. Tables 2 through 6 provide an overview of the names, doses, and important pharmacist notes on the commonly prescribed ARVs in the antiretroviral-naive patient.^16,25 Patients with multidrug-resistant HIV strains, those who are treatment-experienced or have treatment failure are best cared for by an experienced HIV specialist.

MANAGEMENT OF HCV INFECTION

For many years, the mainstay of treatment for chronic HCV infection was limited to combination therapy with 2 indirect-acting antiviral agents: injectable alpha interferon plus ribavirin. Although this treatment combination cured some patients with chronic HCV, its efficacy varied, and its administration and significant adverse effect profile made adherence and persistence challenging for patients. Since 2011, a proliferation in HCV clinical and new drug research has resulted in development of new oral direct-acting antiviral agents (DAAs), and 11 single/combination FDA-approved products are available for management of chronic HCV.²⁶ The availability of these new antivirals—which generally have greater efficacy, improved tolerability, and better adverse effect profiles than older drugs—simplified administration and shortened therapy duration. These new antiviral agents have ushered in a new and exciting era in HCV management.⁴ Currently, 3 classes of DAAs are available: NS5A inhibitors, NS5B inhibitors, and NS3/4A protease inhibitors. When used in combination, cure rates as high as 95% to 99% have been observed, depending on HCV genotype.²⁷

The American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the International Antiviral Society–USA have jointly issued treatment guidance for HCV management.¹⁷ To keep current with the constantly evolving field of HCV-related research, these groups revise the guidance frequently. This guidance is the principal treatment guidance for chronic HCV in the United States. The guidance was last updated on May 24, 2018, and is available online with other pertinent HCV-related information.

The goal of HCV treatment is to reduce all-cause morbidity and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma. Clinicians aim for virologic cure as evidenced by a “sustained virologic response” (SVR; the continued absence of detectable HCV RNA at least 12 weeks following completion of HCV therapy [SVR12]).¹⁷ Large studies have shown that more than 99% of patients with HCV followed for 5 or more years experience lasting SVR.¹⁷ Among HCV-infected people, SVR is associated with more than a 70% reduction in the risk of hepatocellular carcinoma and a 90% reduction in the risk of liver-related mortality and liver transplantation.³⁰

Similar to HIV, providers must carefully consider when to start HCV treatment and which regimen to use. Determination of priority for HCV treatment has historically been based on noninvasive testing or liver biopsy results (to assess the extent of fibrosis), need for organ transplantation, comorbidities (e.g., HIV), and identification of those at high risk for HCV transmission.¹⁷ In older guidelines, immediate HCV treatment was assigned the highest priority for those patients at the highest risk for liver-related complications. The current treatment guidance no longer emphasizes such prioritization and now recommends treatment for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, transplantation, or other directed therapy. This shift from prioritization to treatment for all patients with chronic HCV is based on real-world experience and improved tolerability and efficacy with the newer HCV medications.

On an annual basis, all HCV-infected patients, regardless of treatment, should discuss modifiable risk factors for HCV progression (e.g., alcohol consumption, obesity, insulin resistance, nonalcoholic fatty liver disease) with their providers and have updated testing for liver function and markers of disease progression.¹⁷ Patients with advanced fibrosis should be monitored every 6 months for liver cancer screening.

Once the provider decides to initiate HCV treatment in a treatment-naive patient, it is necessary to select an appropriate evidence-based treatment regimen and confirm it is appropriate for the individual patient. Appropriate HCV treatment choices and therapy duration is typically determined based on the patient’s HCV genotype/subtype, liver status, and prior treatment history. Other considerations in selecting an appropriate treatment agent include presence of comorbid conditions, drug-drug interactions, social history, medication cost, and baseline resistance-associated substitutions (RASs). Baseline RASs can occur in a subset of patients with chronic HCV infection and can result in resistance to HCV DAAs, especially NS5A inhibitors. This resistance may ultimately lead to treatment failure. Because of this, baseline testing for RASs may be recommended prior to treatment initiation with certain DAAs.¹⁷

The current guidance identifies preferred HCV-treatment regimen options for treatment-naive HCV-infected patients (see Table 7).¹⁷ Detailed information on alternative treatment regimens and regimens for treatment-experienced patients can be found in the guidelines.¹⁷ Table 8 provides an overview of the generic and brand names, and important pharmacist notes on the commonly prescribed HCV DAAs. Of note, as of January 2019, Viekira Pak (ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg, dasabuvir 250 mg), Viekira XR (ombitasvir 8.33 mg/paritaprevir 50 mg/ritonavir 33.33 mg/dasabuvir 200 mg), and Technivie (ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) are no longer being manufactured and therefore are not discussed in this review.

Although the guidance recommends HCV treatments, individual patient factors (including comorbidities that may influence treatment response and the risk for drug interactions) will often determine the best choice for a particular patient. Clinicians should monitor all patients carefully during HCV treatment, particularly for anemia if ribavirin is included in the regimen. The guidance provides comprehensive details regarding appropriate timing, choices for HCV therapy, and evidence supporting use in treatment-naive and treatment-experienced HCV-infected patients.¹⁷ Patients who have drug-resistant HCV strains, are treatment-experienced, or experience DAA-treatment failure are best cared for by an experienced HCV specialist.

MANAGEMENT OF HIV/HCV COINFECTION

Screening for and managing infection with either HIV or HCV can be daunting, and the decisions become much difficult when both viruses are present. Many factors must be considered before screening patients for these chronic infections and determining when to initiate therapy and what treatment options to use. Both treatment guidelines provide evidence-based screening and treatment recommendations based on epidemiological evidence, clinical research, and expert opinion. They also emphasize the importance of considering patient-specific factors in all clinical decisions. Treatment requires multiple powerful antiviral agents, almost perfect treatment adherence, and vigilance for drug interactions and adverse effects. Coinfection with HCV in HIV-infected patients further complicates screening and managing HIV infection.

HIV/HCV coinfection issues of particular interest to pharmacists include screening recommendations, timing of treatment, and choice of treatment, including knowledge of drug interactions and adverse reactions, medication adherence, and cost. The following section provides a brief summary of these HIV/HCV coinfection issues; the treatment guidelines contain detailed explanations.^16,17

Screening

Because of the prevalence of HIV/HCV coinfection and recognition of HIV as a poor prognostic predictor for HCV outcomes, current treatment guidelines recommend screening for coinfection. All HIV-infected patients should be screened for HCV infection.¹⁶ Clinicians should screen HIV-infected patients at high risk for HCV infection annually and whenever HCV infection is suspected.¹⁶ Annual HCV screening is recommended for all HIV-infected men who have unprotected sex with men.¹⁷ Similarly, all HCV-infected patients with unknown HIV status should be screened for HIV infection.

Furthermore, because of the overlapping risk factors for hepatitis B virus (HBV) infection and recognition of HBV as a poor prognostic predictor for HCV outcomes, all HCV/HIV-coinfected patients should be screened for hepatitis B surface antigen. HIV-infected patients and those with chronic liver disease who are HBV-negative and eligible for vaccination should receive the HBV vaccination and appropriate prevention counseling.^17,28

HBV reactivation has been observed in individuals with HBV undergoing HCV treatment with DAAs. Therefore, in patients with HIV/HCV coinfection and active HBV infection, ART therapy should include two agents with anti-HBV activity prior to initiation of HCV treatment.^16,29

HIV/HCV-coinfected patients should also receive the hepatitis A vaccine if they have not had hepatitis A in the past.²⁸

Timing of Therapy in HIV/HCV-Coinfected Patients

HIV coinfection independently accelerates liver fibrosis and HCV disease progression, particularly in individuals with low CD4 cell counts (350 cells/mm³ or fewer).^16,17 Appropriate ART may slow this progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.¹⁶ Consequently, ART initiation is recommended in most HIV/HCV-coinfected patients as soon as possible, regardless of CD4 count or VL, to optimize treatment success and patient outcomes.¹⁶ Similarly, HCV treatment is also important in HIV-infected patients (particularly those who are immunocompromised), regardless of the current fibrosis stage.¹⁷ Patients may therefore be treated for both HIV and HCV simultaneously, with drug therapy adjustments and monitoring when necessary.

The DHHS HIV treatment guidelines identify 2 situations in which clinicians may choose to temporarily defer HIV or HCV therapy while treating the other infection.¹⁶ To avoid drug interactions, some clinicians may choose to defer the initiation of ART in antiretroviral-naive, HIV-infected patients with CD4 cell counts exceeding 500 cells/mm³ until HCV treatment is completed. In patients who are already receiving antiretroviral therapy, treatment interruption to allow HCV treatment is not currently recommended.¹⁷ Additionally, some clinicians may choose to defer HCV treatment initiation in HIV-infected patients with CD4 cell counts lower than 200 cells/mm³ until the patient is stable on the more urgently needed ART.

Choice of Therapy in HIV/HCV-Coinfected Patients

The ART regimens recommended for most HIV-infected antiretroviral-naive patients with HCV remain the same as those recommended for patients without HCV infection.¹⁶ When initiating concomitant treatment for both HIV and HCV, the ART regimen should be selected with special considerations for comorbid conditions, potential drug interactions, and overlapping toxicities with the HCV treatment. Experts in advanced liver disease should closely monitor HIV/HCV-coinfected patients with cirrhosis. They should look for signs of liver decompensation and for appropriateness of medications and their dosing, particularly since many ARVs used in HIV and antiviral agents used in HCV are metabolized hepatically. Because of the concern for potential drug-induced liver injury, clinicians should monitor ALT and AST levels at 2–8 weeks following ART initiation and every 3–6 months thereafter.¹⁶ They should carefully evaluate patients who develop significantly elevated AST/ALT, or other signs and symptoms of liver disease. Short-term interruption of the ART or the specific drug suspected of causing hepatotoxicity may be warranted.

HIV-infected patients on ART who have undetectable VLs may need modifications to their HIV-related ART regimens when HCV treatment commences. When patients’ HIV regimens are changed, clinicians must assess their HIV RNA within 4–8 weeks to confirm ART effectiveness.¹⁶ After completing HCV treatment, the modified ART should be continued for at least 2 weeks before reinitiating the original ART (if so desired). The rationale for this recommendation is the prolonged half-life of some HCV drugs and the potential risk for drug interactions if the prior ART regimen is resumed too soon after HCV treatment completion.

Clinicians should manage HCV in HIV/HCV-coinfected patients just as they do in patients without HIV but with additional recognition and appropriate management of drug interactions with ARVs.¹⁷ Recommendations on medication dose adjustments, monitoring for increased risk of adverse effects, and avoidance of certain combinations is highly dependent on which DAAs are being used. Advanced expertise and detailed screening of medications is needed to ensure appropriateness of regimens in these cases.¹⁷ When different providers manage HIV and HCV infection, provider/health care team communication is critical to ensure optimal treatment choices and patient outcomes.

Drug Interactions/Adverse Effects

Drug interaction awareness, screening, management, and monitoring are important for HIV/HCV-coinfected patients. Numerous and potentially dangerous drug interactions between the HIV antiretroviral agents, the HCV antiviral agents, and concomitantly used drugs have been identified in pharmacokinetic research or theoretically predicted based on the known metabolic pathways of the associated drugs. Consequences of such interactions may include decreased efficacy of HIV and/or HCV treatment or increased risk for medication-related toxicity, which can lead to poor patient outcomes and treatment failure. Depending on the type of anticipated drug interactions, clinicians’ strategies may vary. Clinically significant interactions may require:

• No change in therapy but close monitoring
• A change in dosing of 1 or more medications with monitoring
• A change in administration of 1 or more medications with monitoring
• Deferring therapy with monitoring (as previously discussed)
• Avoidance of certain concomitant treatments necessitating the need to identify and use alternative treatment choices with monitoring

Many of the recognized pharmacokinetic interactions between ART and the antiviral agents used in HCV management affect drug metabolism. These medications are often substrates, inhibitors, or inducers of isoenzymes of the CYP 450 enzyme system and/or P-glycoprotein. They can cause or be affected by drug interactions when used concomitantly with medications that are metabolized by those pathways or that inhibit or induce the metabolic isoenzymes. For example, the standard dose of daclatasvir should be reduced from 60 mg daily to 30 mg daily when used concomitantly with the potent CYP3A4 inhibitor atazanavir/ritonavir; this maintains daclatasvir’s therapeutic levels and avoids toxicity.¹⁷

Pharmacodynamic drug interactions can also be a concern in HCV/HIV-coinfected patients. Concomitant use of drugs with similar toxicities may create a risk of synergistic toxicity. For example, ribavirin should not be concomitantly used with zidovudine because of the increased risk for worsening anemia.¹⁶

The rapidly evolving nature of HIV and HCV infections, continuous research, and new drug development and approvals make up-to-date drug interaction awareness and management recommendations particularly challenging for clinicians caring for HIV/HCV-coinfected patients. The current HIV and HCV treatment guidelines have dedicated and detailed sections focused on HIV/HCV drug interactions. They are frequently updated to reflect evidence-based and expert opinion-based drug interaction management recommendations.^16,17 Although not fully comprehensive, Table 9 provides a summary of drug interactions between commonly prescribed antiretrovirals and drugs used for HCV for HIV/HCV-coinfected patients.^16,17 Whenever HIV and HCV medications are used concomitantly, clinicians should monitor patients closely for HIV and HCV virologic efficacy and potential toxicities. Again, the current guidelines and the latest manufacturer product labeling provide comprehensive information for individual drugs.

Additional resources that may be of assistance to pharmacists regarding HIV/HCV drug interactions include the following:

• The University of Liverpool drug interactions website (http://hep-druginteractions.org/ and http://www.hiv-druginteractions.org/)
• The New York State (NYS) Department of Health (DOH) AIDS Institute Guidelines (www.hivguidelines.gov)
• NYS DOH AIDS Institute HIV/HCV/STD Clinical Education Initiative (http://www.ceitraining.org/), and AIDS Education and Training Centers (http://aidsetc.org/, including www.nynjaetc.org).

Additionally, pharmacists may use PubMed (http://www.ncbi.nlm.nih.gov/pubmed) to search the published literature for specific drug interactions.

Medication Adherence

Full adherence to prescribed HIV and HCV treatments is crucial. Patients who do not adhere to prescribed therapy risk selection for viral mutations and drug-resistant virus, treatment failure and related morbidity/mortality, decreased future treatment options because of the development of cross-resistance, and infection transmission. Pharmacists may play an important role in assisting patients and the medical team to optimize patient adherence. Before patients start therapy for HIV or HCV, the health care team should engage them, educate them about their treatment choice(s), and ensure they are ready to commit to full treatment adherence. Pharmacists should counsel/educate the patient on proper medication dose, administration, and adverse effects (including how to manage adverse effects, should they occur). Patients should be screened for medication adherence at each clinical encounter (including visits to the pharmacy for new prescriptions or refills). Adherence should be assessed in a nonjudgmental format (e.g., “In the last 7 days, how many doses of Drug X have you missed taking?”). Pharmacy prescription records (prescription/refill dates versus days supply) and pill counts are other indirect adherence measures.

The pharmacist and health care team should identify patients with adherence-related challenges and implement appropriate strategies to enhance adherence. Such strategies include employing treatment adherence interventions that are tailored to the specific cause of nonadherence. For example, patients who are nonadherent because they have trouble remembering to take their medications may benefit from the use of pill boxes or reminder devices, whereas patients who cannot afford medications would benefit more from patient prescription assistance programs that may significantly decrease out-of-pocket medication costs.¹⁶

When patients receiving HCV or HIV medications are admitted to hospitals or other health care facilities, pharmacists should assist with continued medication adherence by facilitating availability of the antiviral medications. Often times, coordination between outpatient pharmacies, patient families, and inpatient pharmacies may be necessary to ensure the patient has an adequate supply of medication while in the hospital.

Cost

The cost of medications can be a significant barrier to patients’ access to HIV/HCV regimens. Lack of access to medicine prevents individual patients from obtaining maximal benefits from medications and thereby undermines public health.

The new HCV medications’ cost has recently assumed a prominent role in the national discussion on medicine’s high cost in the United States. However, as more antiviral agents become available, HCV treatment is increasingly affordable. Recently, Gilead Sciences Inc. announced its plan to release generic versions of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir to help expand access to these medications.

Both the HIV and HCV treatment guidelines specifically include information on the cost of medications used to treat infections of these viruses.^16,17 The HCV treatment guidelines review cost, reimbursement, and cost-effectiveness considerations for HCV treatment.¹⁷ Medication pricing and cost-effectiveness are complex, and pharmacists may be directly confronted with these issues by patients, payers, or other stakeholders. Pharmacists can play an important role in providing access to medicine to HIV/HCV-coinfected patients by assisting patients through prior authorization approval processes (when needed) and by recommending appropriate resources to patients who are unable to afford their prescribed medications (e.g., medication discount cards, patient assistance programs).

CONCLUSION

During the past 30 years, the prognosis has shifted dramatically for patients living with HIV and/or HCV. HIV infection has largely transitioned from an infectious disease with imminent morbidity and mortality to a generally manageable chronic infectious disease. Chronic HCV infection has transitioned from a disease that causes significant liver disease, cirrhosis, and hepatocellular carcinoma to a frequently curable infectious disease.

Development of highly potent medications with improved tolerability and ease of administration has shifted these prognoses. Approximately 20% to 30% of patients with HIV are coinfected with HCV. Clinicians need to understand the nuances and significant changes to screening and management that arise in coinfection. Pharmacists — with their unique medication knowledge, patient care skills, and wide accessibility within the community and institutional settings — are well prepared and positioned to be integral members of the health care team caring for HIV/HCV-coinfected patients. 

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