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INTRODUCTION

On June 5, 1981, the United States (U.S.) 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 More than 30 years have passed since the 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 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 sentence high likelihood of early death to a potentially life-threatening but frequently manageable chronic disease.

An estimated, 20% to 30% of HIV-infected patients in the U.S. 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 U.S.⁴ 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 HIV infection. Treatment of both HIV and HCV infections require the use of multiple powerful antivirals that require a high level of patient adherence and have significant drug interactions and toxicities.

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

EPIDEMIOLOGY

In 2015, approximately 36.7 million people globally were living with HIV.² An estimated 2.1 million people were newly infected with HIV in 2015, representing a 6% reduction since 2010. Similarly, AIDS-related deaths have decreased by 45% since they peaked in 2005 (2 million in 2005 and 1.1 million in 2015). In 2015, approximately 46% of all adults infected with HIV had access to antiretroviral therapy (ART). 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 U.S., approximately 1.2 million people are living with HIV infection.⁵ HIV screening is important, since almost 13% 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 a relatively stable number of approximately 50,000 people newly HIV-infected each year. ⁵

Despite increased HIV awareness and education, the new infection rate in the U.S. continues to be too high. Among new HIV infections in men, the most likely route of transmission is male-to-male sexual contact, followed by heterosexual sex, followed by injection drug use (IDU).^5,6 Among new HIV infections in women, the most likely route of transmission is heterosexual sex, followed by IDU. In 2010, men who have sex with men (MSM) accounted for 63%, heterosexual sex accounted for 25%, and IDU accounted for 8% of all new HIV infections. Mother-to-infant transmission, tainted blood products, and occupational exposure of health care workers through needlesticks are other known HIV transmission mechanisms. HIV disproportionately affects blacks/African Americans and Hispanics/Latinos.^5,6 Blacks/African Americans represent approximately 12% of the U.S. population, but accounted for 44% of new HIV infections in 2010. Similarly, Hispanics/Latinos represent approximately 16% of the U.S. population, but accounted for 21% of new HIV infections in 2010. 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.^3,7 In the U.S., approximately 3.2 million people are living with HCV infection.³ 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 HIV/HCV coinfected. ³ Similarly, HIV/HCV co-infected MSM appear to have a greater risk of transmission of HCV than HIV-negative, HCV-infected MSM. This increased risk for sexual HCV transmission among HIV-infected MSMs coincides with a time period following the introduction of ART in which there was a recognized increase in high-risk sexual behavior.^3,8,9

An estimated 20% to 30% of HIV-infected patients in the U.S. are coinfected with HCV and researchers tract this statistic carefully.³ Conversely, the 2003 to 2010 National Health and Nutrition Examination Survey (NHNES) was unable to determine how many people with chronic HCV infection are coinfected with HIV because participants are allowed to opt-out of HIV testing. HCV is more prevalent than HIV and now causes more deaths. NHNES researchers identified a gap in our health care statistics—the percentage of HCV-infected patients who also have HIV—that has public health repercussions. Better estimates would help clinicians conduct more targeted screening, provide education, diagnose, and treat coinfected individuals.¹⁰

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 currently or have 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 include Pneumocystis pneumonia (PCP), Toxoplasma gondii encephalitis, Mycobacterium tuberculosis disease, and disseminated Mycobacterium avium complex (MAC) disease. There are 2 types of HIV: HIV-1 and HIV-2. In the U.S., HIV-1 is the most common type.

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 6 distinct genotypes of HCV (genotypes 1-6). HCV genotype 1 infection accounts for the majority (75%) of U.S. HCV infections.³

Fewer than 20% of patients with acute HCV have symptoms. 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 laboratory findings in acute or chronic HCV. An estimated 85% of untreated acute HCV infections progress to chronic HCV.⁴ Approximately 1 in 5 patients with chronic HCV will develop cirrhosis within 20 years of infection.³ HCV-related cirrhosis is the most common reason for liver transplants in the U.S. ⁴ HIV/HCV coinfection, particularly for those with AIDS, is associated with accelerated progression of liver disease to cirrhosis. This progression is accelerated in HIV/HCV coinfected patients, even when they are treated with ART.³ Furthermore, HIV/HCV-coinfected patients with cirrhosis progress more rapidly to end-stage liver disease and hepatocellular carcinoma than their HIV-negative counterparts.³

SCREENING/DIAGNOSIS

People can be tested voluntarily for HIV infection using a variety of FDA-approved, commercially available HIV tests. Specimens include plasma, serum, saliva, or urine. Many of these screen 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 (http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/HIVHomeTestKits/ucm126460.htm).

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

In 2006, 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 injection drug users (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 HCV antibodies' presence. 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 for hepatitis B virus and HIV infection. Furthermore, clinicians should also assess patients with current HCV for the presence of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. If a patient has a reactive HCV antibody but no detectable HCV RNA, the patient does not have current HCV infection and frequently requires no further intervention. Similar to HIV, an anonymous, confidential FDA-approved self-screening-test for HCV (the Home Access Hepatitis C Check) can be administered at home.

CDC recommends HCV 1 screening for all adults born between 1945 and 1965.^14,15 This age group, the "baby boomer" generation, has a high prevalence of HCV. 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, 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

Current treatment guidelines for the management of HIV and opportunistic infections offer HCV screening recommendations that are well-aligned with CDC recommendations.^3,16 Upon entry into HIV care, all HIV-infected patients should have routine HCV screening as outlined above. HIV-infected patients who are at high risk for HCV infection should be screened annually or as indicated by risk exposure. Patients who test positive for HCV antibodies should undergo HCV RNA testing for determination of the HCV infection's status. Patients in whom HCV RNA is detected should undergo HCV genotyping and liver disease staging as recommended by the current HCV guidelines.^16,17

MANAGEMENT OF HIV INFECTION

Currently, more than 30 different FDA-approved single or combination formulation antiretrovirals (ARVs) are available for HIV infection management. ARVs are typically used in combination to maximize their efficacy, usually combining at least 2 different pharmacologic classes in each patient regimen. Clinicians must take into account a variety of factors when considering initiating ART for any particular patient, including the patient's

• baseline clinical status
• CD4 count and viral load (HIV-RNA)
• prior experience with ARVs and genotype resistance testing
• pertinent laboratory findings (including 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 U.S., most clinicians use the Department of Health and Human Services (DHHS) guidelines, which were updated on January 28, 2016.¹⁶ These guidelines, along with other pertinent HIV-related information, are available at http://aidsinfo.nih.gov.

ART's goals 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 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 scope 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 they 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 typically 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 CDC's HIV/AIDS Prevention Research Synthesis Project (PRS) has identified interventions that can improve adherence. Theses 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 used in HIV management are classified by their method of inhibition in the viral 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 can 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

Once the provider decides to initiate ART in an antiretroviral-naive patient, he or she 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). HAART is key to suppress the virus and prevent viral mutations (which can lead to resistance). The current DHHS treatment guidelines provide guidance on recommended, alternative, and other ARV regimen options for antiretroviral-naive HIV-infected patients (see Table 1).¹⁶ The guidelines also provide further comprehensive details.¹⁶

Table 1. Recommended, Alternative, and Other Antiretroviral Treatment Regimen Options for Therapy–Naive Patients16

Recommended Initial Antiretroviral Treatment Regimens (with ratings and recommendations)a

Integrase Strand Transfer Inhibitor (INSTI)-Based Regimens Dolutegravir/abacavir/lamivudineb only for patients who are HLA-B*5701 negative (AI) Dolutegravir + tenofovir disoproxil fumarate/emtricitabineb (AI) Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine only for patients with pretreatment CrCl ≥30 mL/min (AI) Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine only for patients with pretreatment CrCl >70 mL/min (AI) Raltegravir  + tenofovir/emtricitabineb (AI)

Protease Inhibitor (PI)-Based Regimen Darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabineb (AI)

Alternative Initial Antiretroviral Treatment Regimens (with ratings and recommendations)a Regimens that are effective and tolerable, but that have potential disadvantages when compared with the recommended regimens listed above, have limitations for use in certain patient populations, or have less supporting data from randomized clinical trials. Alternative regimens may be preferred for some patients.

Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens Efavirenz/tenofovir disoproxil fumarate/emtricitabineb (BI) Rilpivirine/tenofovir disoproxil fumarate/emtricitabineb only for patients with pretreatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3 (BI)

PI-Based Regimens Atazanavir/cobicistat + tenofovir disoproxil fumarate/emtricitabineb only for patients with pre-treatment CrCl ≥70 mL/min (BI) Atazanavir/ritonavir + tenofovir disoproxil fumarate/emtricitabineb (BI) (Darunavir/cobicistat or darunavir/ritonavir) + abacavir/lamivudine b only for patients who are HLA-B*5701 negative (BIII for darunavir/cobicistat and BII for darunavir/ritonavir) Darunavir/cobicistat + tenofovir disoproxil fumarate/emtricitabineb only for patients with pretreatment CrCl ≥70 mL/min (BII)

Other Initial Antiretroviral Treatment Regimens (with ratings and recommendations)a Regimens that, in comparison with recommended and alternative regimens, may have reduced virologic activity, limited supporting data from large comparative clinical trials, or other factors such as greater toxicities, higher pill burden, drug interaction potential, or limitations for use in certain patient populations.

INSTI-Based Regimens Raltegravir + abacavir/lamivudine b only for patients who are HLA-B*5701 negative (CII)

NNRTI-Based Regimens Efavirenz + abacavir/lamivudineb only for patients who are HLA-B*5701 negative and pretreatment HIV RNA <100,000 copies/mL (CI)

PI-Based Regimens (Atazanavir/cobicistat or atazanavir/ritonavir) + abacavir/lamivudineb only for patients who are HLA-B*5701 negative and with pretreatment HIV RNA < 100,000 copies/mL (CIII for atazanavir/cobicistat and CI for atazanavir/ritonavir) Lopinavir/ritonavir (oncec or twice daily) plus abacavir/lamivudineb only for patients who are HLA-B*5701 negative (CI) Lopinavir/ritonavir (oncec or twice daily) plus tenofovir disoproxil fumarate/emtricitabineb (CI)

Other regimens when tenofovir or abacavir cannot be used Darunavir/ritonavir + raltegravir only for patients with pretreatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3 (CI) Lopinavir/ritonavir (twice daily) plus lamivudine (twice daily) (CI)

a Rating of recommendations: A = strong; B = moderate; C = optional Rating of evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion b Lamivudine may substitute for emtricitabine or vice versa. c Once-daily lopinavir/ritonavir is not recommended for pregnant patients.

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, who are treatment-experienced, or who experience treatment failure are best cared for by an experienced HIV-specialist.

Table 2. Common Characteristics of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors16,25
Generic Name (Abbreviation) Trade Name	Dosage Forms	Adult Dose	Comments
Zidovudine (ZDV) Retrovir	Capsule: 100 mg Tablet: 300 mg Syrup: 50 mg/5 mL (240 mL) Intravenous solution:10 mg/mL (20 mL)	Oral: 300 mg twice daily or 200 mg three times daily	May be taken without regard to meals.
Lamivudine (3TC) Epivir	Tablet: 150 mg, 300 mg Oral solution: 10 mg/mL (240 mL)	150 mg twice daily or 300 mg daily	May be taken without regard to meals.
Abacavir (ABC) Ziagen	Tablet: 300 mg Oral solution: 20 mg/mL (240 mL)	300 mg twice daily or 600 mg daily	May be taken without regard to meals. Alcohol may increase risk of toxicity. Use only if patient is HLA-B*5701 negative.
Tenofovir Disoproxil Fumarate (TDF) Viread	Tablet: 150 mg, 200 mg, 250 mg, 300 mg Oral powder: 40 mg/g (60 g)	300 mg daily	May be taken without regard to meals. Consider calcium and vitamin D supplementation.
Emtricitabine (FTC) Emtriva	Capsule: 200 mg Oral solution: 10 mg/mL (170 mL)	Capsule: 200 mg daily Solution: 240 mg daily	May be taken without regard to meals.

Table 3. Common NNRTIs Characteristics of Nonnucleoside Reverse Transcriptase Inhibitors16,25
Generic Name Abbreviation Trade Name	Dosage forms	Adult dose	Comments
Efavirenz (EFV) Sustiva	Capsule: 50 mg, 200 mg Tablet: 600 mg	600 mg daily at bedtime	Take on an empty stomach. Potentially teratogenic in humans.
Nevirapine (NVP) Viramune or Viramune XR	Tablet: 200 mg Oral suspension: 50 mg/5 mL (240 mL) XR Tablet: 100 mg, 400 mg	Immediate release: 200 mg once daily for 14 days then 200 mg twice daily XR: 400 mg daily	Take without regards to meals. May cause rash. Monitor during lead in period. If mild to moderate rash develops without constitutional symptoms, continue lead-in period until rash resolves but no longer than 28 days total. XR formulation must follow a lead-in period using immediate-release formulation. If therapy is interrupted for >7 days, restart with lead-in period dosing.
Etravirine (ETR) Intelence	Tablet: 25 mg 100 mg, 200 mg	200 mg twice daily	Take after meals.
Rilpivirine (RPV) Edurant	Tablet: 25 mg	25 mg daily	Take with a meal. Use with proton pump inhibitors is contraindicated. Histamine-2 blockers and antacids lower effects. Use only if viral load <100,000 copies/mL and CD4 cell count >200 cells/mm3

Table 4. Characteristics of Available Integrase Strand Transfer Inhibitors16,25
Generic Name Abbreviation Trade Name	Dosage Forms	Adult dosea	Comments
Raltegravir (RAL) Isentress	Tablet: 400 mg Chewable tablet: 25 mg, 100 mg Oral suspension: 100 mg single packet	400 mg twice daily Increase to 800 mg  twice daily if given with rifampin	Take without regard to meals. Proton pump inhibitors increase RAL levels and should be avoided if possible.
Elvitegravir (EVG) Vitekta	Tablets: 85 mg, 150 mg	With once-daily ATV/r or twice-daily LPV/r: 85 mg once daily With twice-daily DRV/r, FPV/r, or TPV/r: 150 mg once daily Unboosted EVG is not recommended.	Take with food.
Dolutegravir (DTG) Tivicay	Tablet: 50 mg	50 mg daily 50 mg twice daily when combined with EFV, FPV/r, TPV/r, rifampin or INSTI mutations/resistance present or clinically suspected	Take without regard to meals. Take 2 hours before or 6 hours after vitamins, antacids or products containing magnesium, aluminum, iron, or calcium.
aAbbreviation in which a medication name abbreviation is followed by "/r"  (e.g., ATV/r) indicates that the medication is combined with a low-dose of ritonovir. Low-dose ritonavir is being used as a pharmacokinetic enhancer for the regimen, not as a primary protease inhibitor.

Table 5. Common Protease Inhibitor Characteristics16,25
Generic Name Abbreviation Trade Name	Dosage Form	Adult Dosea	Comments
Ritonavir (RTV) Norvir	Tablet: 100 mg Capsule: 100 mg Oral solution: 80 mg/mL (240 mL)	100–400 mg per day in 1–2 divided doses as a pharmacokinetic enhancer for other protease inhibitors. It is not recommended as a primary protease inhibitor in any regimen. Refer to below regimens for appropriate dosing.	Oral solution contains 43% alcohol. Refrigerate capsules. Take with food.
Nelfinavir (NFV) Viracept	Tablets: 250 mg, 625 mg Oral Powder: 50 mg/g	1,250 mg twice daily 750 mg three times daily	Take with meals. May dissolve tablets in water if unable to swallow. Mix and take immediately.
Lopinavir + Ritonavir (LPV/r) Kaletra	Tablets: LPV 200 mg/RTV 50 mg LPV 100 mg/RTV 25 mg Oral solution: LPV 80 mg + RTV 20 mg/mL (160 mL)	LPV/r 400 mg/100 mg twice daily LPV/r 800 mg/200 mg daily Patients receiving EFV, NVP: LPV/r 500 mg/125 mg twice daily or LPV/r 533 mg/133 mg solution twice daily	Oral solution contains 42% alcohol and should be taken with meals. Tablet: Take without regard to meals.
Fosamprenavir (FPV) Lexiva	Tablet: 700 mg Oral suspension: 50 mg/mL (225 mL)	Antiretroviral-naive patients: 1. FPV 1,400 mg twice daily 2. FPV 1,400 mg + RTV 100–200 mg daily 3. FPV 700 mg +RTV 100 mg  twice daily With EFV (600 mg daily): FPV 1,400 mg + RTV 300 mg once daily (or the twice-daily regimen- see below) PI-experienced patients: FPV 700 mg + RTV 100 mg twice daily With EFV (600 mg daily): FPV 700 mg + RTV 100 mg twice daily With maraviroc (150 mg twice daily): FPV 700 mg + RTV 100 mg twice daily	Suspension: take without food Tablet: take without regard for food. If boosted with RTV, take with food.
Atazanavir (ATV) Reyataz	Capsules: 100 mg, 150 mg, 200 mg, 300 mg Oral powder: 50 mg single packet	Antiretroviral-naive patients: ATV 300 mg + RTV 100 mg daily ATV 400 mg daily (if unable to tolerate RTV, not recommended in antiretroviral-experienced) Antiretroviral-experienced or with tenofovir: ATV 300 mg + RTV 100 mg daily Antiretroviral-naive with EFV (600 mg daily): ATV 400 mg + RTV 100 mg daily	Take with food. Give ATV at least 2 hours before or 1 hour after antacids or buffered medications. Histamine-2 receptor antagonist dose should not exceed a dose equivalent to famotidine 40 mg twice daily in ART- naive patients or 20 mg twice daily in ART-experienced patients. Give ATV 300 mg + RTV 100 mg  or cobicistat 150 mg simultaneously with and/or ≥10 hours after the histamine-2 receptor antagonist. If using TDF and histamine-2 receptor antagonist in antiretroviral-experienced patients, use ATV 400 mg + RTV 100 mg daily. Proton pump inhibitors contraindicated in patients receiving unboosted ATV or protease inhibitor-experienced patients. Proton pump inhibitors should not exceed a dose equivalent to omeprazole 20 mg daily in protease inhibitor–naive patients. Proton pump inhibitors should be administered at least 12 hours before ATV/r.
Darunavir (DRV) Prezista	Tablets: 75 mg, 150 mg  600 mg, 800 mg Oral suspension: 100 mg/mL (200 mL)	Antiretroviral-naive patients or experienced with no resistance: DRV 800 mg + RTV 100 mg daily Antiretroviral-experienced: DRV 600 mg + RTV 100 mg twice daily	Take with food.

Table 6. Common Combination Products Characteristics16,25
Generic Name Trade Name	Adult Dose	Comments
Lamivudine 150 mg/zidovudine 300 mg Combivir	1 tablet twice daily	May be taken without regard to meals.
Lamivudine 300 mg/abacavir 600 mg Epzicom	1 tablet daily	May be taken without regards to meals. Use only if patient is HLA-B*5701 negative.
Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg Truvada	1 tablet daily	May be taken without regards to  meals. Consider calcium and vitamin  D supplementation.
Emtricitabine 200 mg/tenofovir alafenamide 25 mg Descovy	1 tablet daily	May be taken without regards to  meals. Consider calcium and vitamin  D supplementation.
Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg/ efavirenz 600 mg Atripla	1 tablet at or before bedtime	Take on an empty stomach. Consider calcium and vitamin D supplementation.
Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg/rilpivirine 25 mg Complera	1 tablet daily	Take with a meal. Consider calcium and vitamin  D supplementation. Do not use with proton pump inhibitors. Histamine-2 blockers and antacids lessen effects; administration should be appropriately timed.  Use only in patients with viral loads <100,000 copies/mL and CD4 cell count >200 cells/mm3.
Emtricitabine 200 mg/tenofovir alafenamide 25 mg/rilpivirine 25 mg Odefsey	1 tablet daily	Take with a meal. Consider calcium and vitamin  D supplementation. Do not use with proton pump inhibitors. Histamine-2 blockers and antacids lessen effects; administration should be appropriately timed. Use in patients with  viral loads <100,000 copies/mL.
Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg Stribild	1 tablet daily Do not initiate in patients with baseline CrCl <70 mL/min	Take with food. Not recommended with other antiretroviral agents. Consider calcium and vitamin D supplementation. Discontinue if CrCl declines to <50 mL/min. Not recommended for use in hemodialysis.
Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/ tenofovir alafenamide 10 mg Genvoya	1 tablet daily Do not initiate in patients with baseline CrCl < 30 mL/min	Take with food. Not recommended with other antiretroviral agents. Consider calcium and vitamin D supplementation.
Dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg Triumeq	1 tablet daily	Take without regard to meals. Use only if patient is HLA-B*5701 negative.
Atazanavir 300 mg/cobicistat 150 mg Evotaz	1 tablet daily With tenofovir Not recommended for patients with baseline CrCl <70 mL/min	Take with food.
Darunavir 800 mg/cobicistat 150 mg Prezcobix	1 tablet daily Not recommended for patients with 1 or more darunavir-resistance-associated mutations With tenofovir: Not recommended for patients with baseline CrCl <70 mL/min	Take with food.

MANAGEMENT OF HCV INFECTION

For many years, the treatment mainstay for chronic HCV infection was limited to combination therapy with 2 indirect-acting antivirals: injectable alpha interferon plus ribavirin. Although this treatment combination cured some patients with chronic HCV, its efficacy varied, and its administration and adverse effects made adherence and persistence challenging for patients. Since 2011, there has been a proliferation in HCV clinical and new drug research, including new oral direct-acting antiviral agents, constituting 9 single/combination FDA-approved products 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 antivirals have ushered in a new and exciting era in HCV management.⁴

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, they revise the guidance frequently. This guidance is the principal treatment guidance for chronic HCV in the U.S. The guidance was updated on February 24, 2016 (with more changes made on April 25, 2016). This guidance, along with other pertinent HCV-related information, is available at http://www.hcvguidelines.org/.

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).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.

Similar to HIV, providers must consider when and what HCV treatment to start carefully. 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 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. The current guidance identifies preferred and alternative HCV-treatment regimen options for treatment-naive HCV-infected patients based on HCV genotype (see Table 7).¹⁷ Table 8 provides an overview of the generic and brand names of available HCV treatments. 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 their evidence for both treatment-naive and treatment-experienced HCV-infected patients.¹⁷ Patients who have drug-resistant HCV strains, are treatment-experienced, or experience treatment failure are best cared for by an experienced HCV-specialist.

Table 7. Recommended and Alternative Regimen Options for HCV Treatment-Naive Patients, by Genotype (listed in alphabetical order)17, a
Genotype	Recommended Regimen (with levels of evidence)b	Alternative Regimen (with levels of evidence)b
1a	Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) x 12 weeks for patients with or without cirrhosis (I, A) Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) x 12 weeks for patients with or without cirrhosis (I, A) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-basedribavirinc x 12 weeks for patients without cirrhosis (I, A) Daily simeprevir (150 mg) plus sofosbuvir (400 mg) x 12 weeks for patients without cirrhosis (I, A)	Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) x 16 weeks plus weight-based ribavirinc for patients with or without cirrhosis (IIa, B) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-basedribavirinc x 24 weeks for patients with cirrhosis (I, A) Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-basedribavirinc x 24 weeks for patients with cirrhosis (I, A) Daily daclatasvir (60 mgd) plus sofosbuvir (400 mg) with or without weight-basedribavirinc x 24 weeks for patients with cirrhosis (IIa, B)
1b	Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) x 12 weeks for patients with or without cirrhosis (I, A) Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) x 12 weeks for patients with or without cirrhosis (I, A) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) x 12 weeks for patients with or without cirrhosis (I, A) Daily simeprevir (150 mg) plus sofosbuvir (400 mg) x 12 weeks for patients without cirrhosis (I, A) Daily daclatasvir (60 mgd) plus sofosbuvir (400 mg) x 12 weeks for patients without cirrhosis (IIa, B)	Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-basedribavirinc x 24 weeks for patients with cirrhosis (I, A) Daily daclatasvir (60 mgd) plus sofosbuvir (400 mg) with or without weight-basedribavirinc x 24 weeks for patients with cirrhosis (IIa, B)
2	Daily daclatasvir (60 mgd) plus sofosbuvir (400 mg) x 12 weeks for patients who cannot tolerate ribavirin and do not have cirrhosis (IIa, B) Extend treatment to 16–24 weeks in patients with cirrhosis (IIa, B) Daily sofosbuvir (400 mg) and weight-basedribavirinc x 12 weeks (I, A) Extend treatment to 16–24 weeks in patients with cirrhosis (IIa, C)	None
3	Daily daclatasvir (60 mgd) plus sofosbuvir (400 mg) x 12 weeks for patients without cirrhosis (I,A) Extend to 24 weeks with or without weight-basedribavirinc for patients with cirrhosis (IIa, B) Daily sofosbuvir (400 mg) and weight-basedribavirinc plus weekly pegylated interferon x 12 weeks for interferon-eligible patients with or without cirrhosis (I, A)	Daily sofosbuvir (400 mg) and weight-basedribavirinc x 24 weeks for daclatasvir and interferon-ineligible patients for patients with or without cirrhosis (1, A)
4	Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) x 12 weeks for patients with or without cirrhosis (IIa, B) Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) x 12 weeks for patients with or without cirrhosis (IIa, B) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus weight-based ribavirinc x 12 weeks for patients with (I, B) and without cirrhosis (I, A)	Daily sofosbuvir (400 mg) and weight-basedribavirinc plus weekly Pegylated Interferon x 12 weeks for interferon-eligible patients with or without cirrhosis (II, B)
5	Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) x 12 weeks for patients with or without cirrhosis (IIa, B)	Daily sofosbuvir (400 mg) and weight-basedribavirinc plus weekly pegylated interferon x 12 weeks for interferon-eligible patients with or without cirrhosis (IIa, B)
6	Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) x 12 weeks for patients with or without cirrhosis (IIa, B)	Daily sofosbuvir (400 mg) and weight-based ribavirinc plus weekly pegylated interferon x 12 weeks for interferon-eligible patients with or without cirrhosis (IIa, B)
a The appropriate choice of therapy for an individual patient is based on numerous factors, including sensitivity and resistance to antivirals. This table does not provide details regarding resistance testing; further information is available in the current treatment guideline (reference 17). Classifications and levels of evidence, provided at the end of each listed regimen, are based on the categories in footnote a. b Classifications and their descriptions Class I: Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment Class IIa: Weight of evidence and/or opinion is in favor of usefulness and efficacy Class IIb: Usefulness and efficacy are less well established by evidence and/or opinion Class III: Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful Levels of evidence and their descriptions Level A: Data derived from multiple randomized clinical trials, meta-analyses, or equivalent Level B: Data derived from a single randomized trial, nonrandomized studies, or equivalent Level C: Consensus opinion of experts, case studies, or standard of care c Weight-Based Ribavirin = (1,000 mg [<75 kg] to 1,200 mg [>75 kg]) d The dose of daclatasvir may need to be increased or decreased when used concomitantly with cytochrome P450 3A/4 inducers and inhibitors, respectively.

Table 8. FDA-Approved and Available Treatments for Hepatitis C Virus Infection26, a
Generic Name	Brand Name
Interferon alphacon-1	Infergen
Ribavirin	Rebetol
Peginterferon alfa-2b	PegIntron
Peginterferon alfa-2a	Pegasys
Simeprevir	Olysio
Sofosbuvir	Sovaldi
Ledipasvir/sofosbuvir	Harvoni
Paritaprevir/ritonavir/ombitasvir; dasabuvir	Viekira Pak
Paritaprevir/ritonavir/ombitasvir	Technivie
Daclatasvir	Daklinza
Elbasvir/grazoprevir	Zepatier
Sofosbuvir/velpatasvirb	Epclusa
aBoceprevir and telaprevir, previously FDA-approved treatment options for hepatitis C virus infections, are no longer available in the United States and are not included in this table. bThis combination product was approved by FDA in June 2016. Recommendations for its use had not been released when this article was prepared; it is the first product approved for use against all six genotypes of hepatitis C virus.

MANAGEMENT OF HIV/HCV COINFECTION

Screening for and managing either HIV or HCV infection alone can be daunting. Many factors must be considered before screening patients for these chronic infections and determining when to initiate 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 for both infections individually requires multiple powerful antivirals, 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, choice of treatment—incorporating knowledge of drug interactions and adverse reactions, medication adherence, and cost. The following section provides a brief summary of the aforementioned 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 to 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-infected patients should be screened for hepatitis B surface antigen (HBsAg). 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.^17,27

HIV/HCV coinfected patients should also receive the hepatitis A vaccine if they have not had hepatitis A in the past.¹⁶

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 guideline identifies 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. 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 should be selected with special considerations for 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 the appropriateness of medications and their dosing, particularly since many ARVs used in HIV and antivirals 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 prior ART resumes too soon after HCV treatment completion.

Clinicians should manage HCV in HIV/HCV-coinfected patients like they manage patients without HIV, after recognizing and appropriately managing drug interactions with ARVs.¹⁷ Guidance on the management of potential drug interactions is discussed further below. Daily daclatasvir and sofosbuvir (at appropriate doses), with or without ribavirin (as per treatment guideline recommendation), is recommended when ART changes cannot be made to accommodate alternative HCV direct-acting antivirals.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 antiretrovirals, the HCV antivirals, and other concomitant 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 antivirals used in HCV management are due to drug metabolism interferences. These medications are often substrates, inhibitors, or inducers of isoenzymes of the CYP 450 enzyme system and/or P-glycoprotein. They can precipitate or be affected by drug interactions when used concomitantly with medications that use and/or affect similar metabolic pathways. 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 that have similar toxicities may create synergistic risk of 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 But keeping up with changes in guidelines is a challenge. For example, the current HIV treatment guidelines (HIV/HCV coinfection section of guideline updated in April 2015), do not mention or provide guidance for the more recently approved HCV-treatment options daclatasvir and elbasvir/grazoprevir (approved July 2015 and January 2016, respectively). The current HCV treatment guidance (updated February 2016) do. 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.

Table 9. Concomitant Use of Selected Antiretrovirals and HCV Drugs for Treatment of HCV in HIV-Infected Adultsa, 16, 17
Selected Antiretrovirals	Daclatasvir	Sofosbuvir	Ledipasvir/Sofosbuvir	Paritaprevir/ritonavir/ ombitasvir plus dasabuvir	Simeprevir	Elbasvir/Grazoprevir
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Lamivudine	? 17	√	√	√	√	√17
Abacavir	? / √ 17	√	√	√	√	√17
Emtricitabine	? / √ 17	√	√	√	√	√17
Tenofovir disoproxil fumarate (TDF)	√ 17	√	√ 17 Only for patients with CrCl >60 mL/min. Monitor for TDF toxicity.	√	√	√17
Zidovudine	? 17	√	√	√	√	√17
Protease Inhibitors (PIs)
Atazanavir (unboosted)	? 17	√	√	√ Reduce atazanavir dose to 300 mg and take in AM at same time as (paritaprevir/ritonavir/ombitasvir plus dasabuvir). If ritonavir cannot be used, choose an alternative HCV regimen.	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/ elbasvir should not be used with any PI.
Atazanavir/ ritonavir or Atazanavir/ cobicistat	√  17 When combined with atazanavir/ ritonavir,  reduce daclatasvir dose to 30 mg daily. ? 17	√	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens. Ledipasvir/ sofosbuvir should not be used with cobicistat when given with TDF.	√ Take atazanavir 300 mg in morning at same time as (paritaprevir/ritonavir/ ombitasvir plus dasabuvir); discontinue ritonavir or cobicistat in HIV regimen until HCV therapy completed.	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/elbasvir should not be used with any PI.
Darunavir/ ritonavir or Darunavir/ cobicistat	√  17 ? 17	√	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens. Ledipasvir/ sofosbuvir should not be used with cobicistat when given with TDF.	X17	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/elbasvir should not be used with any PI.
Fos-amprenavir or Fos-amprenavir/ ritonavir	? 17 ? 17	√	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens.	X	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/ elbasvir should not be used with any PI.
Lopinavir/ ritonavir	√  17	√	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens.	X17	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/ elbasvir should not be used with any PI.
Saquinavir/ ritonavir	? 17	√	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens.	X	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/elbasvir should not be used with any PI.
Tipranavir/ ritonavir	? 17	X	X 17 Ledipasvir should be avoided in patients taking TDF with PI/ritonavir regimens. Ledipasvir/sofosbuvir should not be used with tipranavir.	X	X17 Simeprevir should not be used with any PI.	X17 Grazoprevir/elbasvir should not be used with any PI.
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz	√  17 When combined with efavirenz,  increase daclatasvir dose to 90 mg daily.	√	√ If efavirenz used with TDF/ emtricitabine, monitor for TDF toxicity.	X	X	X17
Etravirine	√  17 When combined with etravirine,  increase daclatasvir dose to 90 mg daily.	√	√	X	X	X17
Nevirapine	? / √ 17	√	√	X	X	?
Rilpivirine	? / √ 17	√	√	X	√	√17
Integrase Strand Transfer Inhibitors
Dolutegravir	√ 17	√	√	? √ 17	√	√17
Elvitegravir/ Cobicistat/ Tenofovir/ Emtricitabine	? / √ 17	√	X	X	X	X17
Elvitegravir (plus PI/ritonavir without cobicistat)	Refer to recommendations specific to each PI/ritonavir.
Raltegravir	? / √ 17	√	√	√	√		√17
Entry Inhibitor
Maraviroc	? / √ 17	√	√	X	√		√
aTable adapted from the current DHHS HIV Treatment Guidelines16 with certain updates cited in each instance from the current AASLD/IDSA/IAS-USA HCV Treatment Guidelines.17 √ = Antiretroviral agents that can be used concomitantly. X = Antiretroviral agents not recommended. ? = Data on pharmacokinetic interactions with the antiretroviral drug are unavailable or insufficient to make a recommendation. ? / √ = Data on pharmacokinetic interactions with the antiretroviral drug are unavailable or insufficient to make a recommendation but substantial interactions are not expected based on the pharmacology of these agents at this time.

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

• 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.org)
• 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). Assessment of adherence should be done 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 patient who cannot afford medications would benefit more from patient prescription assistance programs that may significantly decrease out-of-pocket medication costs.¹⁶

Cost

The cost of medications can be a significant barrier to patients' access to HIV/HCV medicine. 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 U.S. Both the HIV and HCV treatment guidelines specifically include information on the cost of medications used to treat the respective infections.^16,17 The HCV treatment guideline reviews 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 for HIV and HCV infections have each shifted dramatically. 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 have shifted these prognoses. Approximately 20% to 30% of HIV-infected patients are coinfected with HCV infection. 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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