Basic and Clinical Pharmacology, 13th Ed.

Antiviral Agents

Sharon Safrin, MD

CASE STUDY

A 35-year-old white woman who recently tested seropositive for both HIV and hepatitis B virus surface antigen is referred for evaluation. She is feeling well overall but reports a 25-pack-year smoking history. She drinks 3-4 beers per week and has no known medication allergies. She has a history of heroin use and is currently receiving methadone. Physical examination reveals normal vital signs and no abnormalities. White blood cell count is 5800 cells/mm3 with a normal differential, hemoglobin is 11.8 g/dL, all liver tests are within normal limits, CD4 cell count is 278 cells/mm3, and viral load (HIV RNA) is 110,000 copies/mL. What other laboratory tests should be ordered? Which antiretroviral medications would you begin?

Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Therefore, to be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. As a corollary, nonselective inhibitors of virus replication may interfere with host cell function and result in toxicity.

Progress in antiviral chemotherapy began in the early 1950s, when the search for anti-cancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two first-generation antiviral agents, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cell DNA as well as viral DNA) that rendered them too toxic for systemic use. However, both agents are effective when used topically for the treatment of herpes keratitis.

Knowledge of the mechanisms of viral replication has provided insights into critical steps in the viral life cycle that can serve as potential targets for antiviral therapy. Recent research has focused on identifying agents with greater selectivity, higher potency, in vivo stability, and reduced toxicity. Antiviral therapy is now available for herpesviruses, hepatitis C virus (HCV), hepatitis B virus (HBV), papillomavirus, influenza, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV). Antiviral drugs share the common property of being virustatic; they are active only against replicating viruses and do not affect latent virus. Whereas some infections require monotherapy for brief periods of time (eg, acyclovir for herpes simplex virus), others require dual therapy for prolonged periods of time (interferon alfa/ribavirin for HCV), whereas still others require multiple drug therapy for indefinite periods (HIV). In chronic illnesses such as viral hepatitis and HIV infection, potent inhibition of viral replication is crucial in limiting the extent of systemic damage.

ACRONYMS & OTHER NAMES

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Viral replication requires several steps (Figure 49–1): (1) attachment of the virus to receptors on the host cell surface; (2) entry of the virus through the host cell membrane; (3) uncoating of viral nucleic acid; (4) synthesis of early regulatory proteins, eg, nucleic acid polymerases; (5) synthesis of new viral RNA or DNA; (6) integration into the nuclear genome; (7) synthesis of late, structural proteins; (8) assembly (maturation) of viral particles; and (9) release from the cell. Antiviral agents can potentially target any of these steps.

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FIGURE 49–1 The major sites of antiviral drug action. Note: Interferon alfas are speculated to have multiple sites of action. (Modified and reproduced, with permission, from Trevor AJ, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 9th ed. McGraw-Hill, 2010. Copyright © The McGraw-Hill Companies, Inc.)

image AGENTS TO TREAT HERPES SIMPLEX VIRUS (HSV) & VARICELLA-ZOSTER VIRUS (VZV) INFECTIONS

Three oral nucleoside analogs are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and comparable indications for clinical use; all are well tolerated. Acyclovir has been the most extensively studied; it was licensed first and is the only one of the three that is available for intravenous use in the United States. Comparative trials have demonstrated similar efficacies of these three agents for the treatment of HSV but modest superiority of famciclovir and valacyclovir for the treatment of herpes zoster infections.

ACYCLOVIR

Acyclovir (eFigure 49–1.1) is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than against VZV. In vitro activity against Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) is present but weaker.

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by host cell enzymes (Figure 49–2). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates—only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.

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FIGURE 49–2 Mechanism of action of antiherpes agents.

The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food. An intravenous formulation is available. Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route.

Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is 2.5–3 hours in patients with normal renal function and 20 hours in patients with anuria. Acyclovir diffuses readily into most tissues and body fluids. Cerebrospinal fluid concentrations are 20–50% of serum values.

Oral acyclovir has multiple uses. In first episodes of genital herpes, oral acyclovir shortens the duration of symptoms by approximately 2 days, the time to lesion healing by 4 days, and the duration of viral shedding by 7 days. In recurrent anogenital herpes, the time course is shortened by 1–2 days. Treatment of first-episode genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term suppression with oral acyclovir in patients with frequent recurrences of genital herpes decreases the frequency of symptomatic recurrences and of asymptomatic viral shedding, thus decreasing the rate of sexual transmission. However, outbreaks may resume upon discontinuation of suppressive acyclovir. Oral acyclovir is only modestly beneficial in recurrent herpes labialis. In contrast, acyclovir therapy significantly decreases the total number of lesions, duration of symptoms, and viral shedding in patients with varicella (if begun within 24 hours after the onset of rash) or cutaneous zoster (if begun within 72 hours); the risk of post-herpetic neuralgia is also reduced if treatment is initiated early. However, because VZV is less susceptible to acyclovir than HSV, higher doses are required (Table 49–1). When given prophylactically to patients undergoing organ transplantation, oral or intravenous acyclovir prevents reactivation of HSV and VZV infection. Evidence from clinical trials suggests that the use of daily acyclovir (400 mg twice daily) may reduce the plasma viral load of HIV-1 and the risk of HIV-associated disease progression in individuals dually infected with HSV-2 and HIV-1.

TABLE 49–1 Agents to treat or prevent herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections.

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Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections (Table 49–1). In neonates with central nervous system HSV, oral acyclovir suppression for 6 months following acute treatment improves neurodevelopmental outcomes. In immunocompromised patients with VZV infection, intravenous acyclovir reduces the incidence of cutaneous and visceral dissemination.

Topical acyclovir cream is substantially less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrent genital herpes.

Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase, and clinically resistant infections have been reported in immunocompromised hosts. Most clinical isolates are resistant on the basis of deficient thymidine kinase activity and thus are cross-resistant to valacyclovir, famciclovir, and ganciclovir. Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir-resistant strains (Figure 49–2).

Acyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. Intravenous infusion may be associated with reversible renal toxicity (ie, crystalline nephropathy or interstitial nephritis) or neurologic effects (eg, tremors, delirium, seizures). However, these are uncommon with adequate hydration and avoidance of rapid infusion rates. High doses of acyclovir cause chromosomal damage and testicular atrophy in rats, but there has been no evidence of teratogenicity, reduction in sperm production, or cytogenetic alterations in peripheral blood lymphocytes in patients receiving daily suppression of genital herpes for more than 10 years. A recent study found no evidence of increased birth defects in 1150 infants who were exposed to acyclovir during the first trimester. In fact, the American College of Obstetricians and Gynecologists recommends suppressive acyclovir therapy beginning at week 36 in pregnant women with active recurrent genital herpes to reduce the risk of recurrence at delivery and possibly the need for cesarean section. The impact of this intervention on neonatal infection has not been established.

Concurrent use of nephrotoxic agents may enhance the potential for nephrotoxicity. Probenecid and cimetidine decrease acyclovir clearance and increase exposure. Somnolence and lethargy may occur in patients receiving concomitant zidovudine and acyclovir.

VALACYCLOVIR

Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are three to five times greater than those achieved with oral acyclovir and approximate those achieved with intravenous acyclovir. Oral bioavailability is 54–70%, and cerebrospinal fluid levels are about 50% of those in serum. Elimination half-life is 2.5–3.3 hours.

Twice-daily valacyclovir is effective for treatment of first or recurrent genital herpes and varicella and zoster infections; it is approved for use as a 1-day treatment for orolabial herpes and as suppression of frequently recurring genital herpes (Table 49–1). Once-daily dosing of valacyclovir for chronic suppression in persons with recurrent genital herpes has been shown to markedly decrease the risk of sexual transmission. In comparative trials with acyclovir for the treatment of patients with zoster, rates of cutaneous healing were similar, but valacyclovir was associated with a shorter duration of zoster-associated pain. Higher doses of valacyclovir (2 g four times daily) are effective in preventing CMV disease after organ transplantation and suppressive valacyclovir prevents VZV reactivation after hematopoietic stem cell transplantation.

Valacyclovir is generally well tolerated, although nausea, headache, vomiting, or rash may occur. At high doses, confusion, hallucinations, and seizures have been reported. AIDS patients who received high-dosage valacyclovir chronically (ie, 8 g/d) had increased gastrointestinal intolerance as well as thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome; this dose has also been associated with confusion and hallucinations in transplant patients. In a recent study, there was no evidence of increased birth defects in 181 infants who were exposed to valacyclovir during the first trimester.

FAMCICLOVIR

Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (eFigure 49–2.1). After oral administration, famciclovir is rapidly deacetylated and oxidized by first-pass metabolism to penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV, and HBV. As with acyclovir, activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, however, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient; these are cross-resistant to acyclovir and famciclovir.

The bioavailability of penciclovir from orally administered famciclovir is 70%. The intracellular half-life of penciclovir triphosphate is prolonged, at 7–20 hours. Penciclovir is excreted primarily in the urine.

Oral famciclovir is effective for the treatment of first and recurrent genital herpes, for chronic daily suppression of genital herpes, for treatment of herpes labialis, and for the treatment of acute zoster (Table 49–1). One-day usage of famciclovir significantly accelerates time to healing of recurrent genital herpes and of herpes labialis. Comparison of famciclovir to valacyclovir for treatment of herpes zoster in immunocompetent patients showed similar rates of cutaneous healing and pain resolution; both agents shortened the duration of zoster-associated pain compared with acyclovir.

Oral famciclovir is generally well tolerated, although headache, nausea, or diarrhea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) for 18 weeks had no changes in sperm morphology or motility. In a recent study, there was no evidence of increased birth defects in 32 infants who were exposed to famciclovir during the first trimester. The incidence of mammary adenocarcinoma was increased in female rats receiving famciclovir for 2 years.

PENCICLOVIR

The guanosine analog penciclovir, the active metabolite of famciclovir, is available for topical use. Penciclovir cream (1%) shortened the median duration of recurrent herpes labialis by ~ 17 hours compared to placebo when applied within 1 hour of the onset of prodromal symptoms and continued every 2 hours during waking hours for 4 days. Adverse effects are uncommon, other than application site reactions in ~1%.

DOCOSANOL

Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion between the host cell plasma membrane and the HSV envelope, thereby preventing viral entry into cells and subsequent viral replication. Topical docosanol 10% cream is available without a prescription. When applied within 12 hours of the onset of prodromal symptoms, five times daily, median healing time was shortened by 18 hours compared with placebo in recurrent orolabial herpes. Application site reactions occur in ~2%.

TRIFLURIDINE

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49–2). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.

INVESTIGATIONAL AGENTS

Valomaciclovir is an inhibitor of the viral DNA polymerase; it is currently under clinical evaluation for the treatment of patients with acute zoster and acute EBV infection (infectious mononucleosis).

image AGENTS TO TREAT CYTOMEGALOVIRUS (CMV) INFECTIONS

CMV infections occur primarily in the setting of advanced immunosuppression and are typically due to reactivation of latent infection. Dissemination of infection results in end-organ disease, including retinitis, colitis, esophagitis, central nervous system disease, and pneumonitis. Although the incidence in HIV-infected patients has markedly decreased with the advent of potent anti-retroviral therapy, clinical reactivation of CMV infection after organ transplantation is still prevalent.

The availability of oral valganciclovir has decreased the use of intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir for the prophylaxis and treatment of end-organ CMV disease (Table 49–2). Oral valganciclovir has replaced oral ganciclovir because of its lower pill burden.

TABLE 49–2 Agents to treat cytomegalovirus (CMV) infection.

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GANCICLOVIR

Ganciclovir is an acyclic guanosine analog (eFigure 49–2.1) that requires activation by triphosphorylation before inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation (Figure 49–2). Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.

Ganciclovir is administered intravenously; the bioavailability of oral ganciclovir is poor, and it is no longer available in the US. Ganciclovir gel is available for the treatment of acute herpetic keratitis. Cerebrospinal fluid concentrations are approximately 50% of serum concentrations. The elimination half-life is 4 hours, and the intracellular half-life is prolonged at 16–24 hours. Clearance of the drug is linearly related to creatinine clearance. Ganciclovir is readily cleared by hemodialysis.

Intravenous ganciclovir has been shown to delay progression of CMV retinitis in immunocompromised patients. Dual therapy with foscarnet and ganciclovir is more effective in delaying progression of retinitis than either drug alone in patients with AIDS (see Foscarnet), although adverse effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis, esophagitis, and pneumonitis (the latter often in combination with intravenous cytomegalovirus immunoglobulin) in immunocompromised patients. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduced the risk of CMV infection in transplant recipients. Limited data in infants with symptomatic congenital neurologic CMV disease suggest that treatment with IV ganciclovir may reduce hearing loss. The risk of Kaposi’s sarcoma is reduced in AIDS patients receiving long-term ganciclovir, presumably because of activity against HHV-8.

Intravitreal injections of ganciclovir may be used to treat CMV retinitis. Concurrent therapy with a systemic anti-CMV agent is necessary to prevent other sites of end-organ CMV disease. The intraocular ganciclovir implant is no longer available in the USA.

Resistance to ganciclovir increases with duration of use. The more common mutation, in UL97, results in decreased levels of the triphosphorylated (ie, active) form of ganciclovir. The less common UL54 mutation in DNA polymerase results in higher levels of resistance and potential cross-resistance with cidofovir and foscarnet. Antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically.

The most common adverse effect of intravenous ganciclovir treatment is myelosuppression, which although reversible may be dose-limiting. Myelosuppression may be additive in patients receiving concurrent zidovudine, azathioprine, or mycophenolate mofetil. Other potential adverse effects are nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy. Central nervous system toxicity (confusion, seizures, psychiatric disturbance) and hepatotoxicity have been rarely reported. Intravitreal ganciclovir has been associated with vitreous hemorrhage and retinal detachment. Ganciclovir is mutagenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical significance of these preclinical data is unclear.

Levels of ganciclovir may rise in patients concurrently taking probenecid or trimethoprim. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.

VALGANCICLOVIR

Valganciclovir is an L-valyl ester prodrug of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by esterases in the intestinal wall and liver.

Valganciclovir is well absorbed; the bioavailability of oral valganciclovir is 60% and it is recommended that the drug be taken with food. The AUC0–24h resulting from valganciclovir (900 mg once daily) is similar to that after 5 mg/kg once daily of intravenous ganciclovir and approximately 1.65 times that of oral ganciclovir. The major route of elimination is renal, through glomerular filtration and active tubular secretion. Plasma concentrations of valganciclovir are reduced approximately 50% by hemodialysis.

Valganciclovir is as effective as intravenous ganciclovir for the treatment of CMV retinitis and is also indicated for the prevention of CMV disease in high-risk solid organ and bone marrow transplant recipients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir.

FOSCARNET

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2.

Foscarnet is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43–67% of steady-state serum concentrations. Although the mean plasma half-life is 3–7 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced approximately 50% by hemodialysis.

Foscarnet is effective in the treatment of end-organ CMV disease (ie, retinitis, colitis, and esophagitis), including ganciclovir-resistant disease; it is also effective against acyclovir-resistant HSV and VZV infections. The dosage of foscarnet must be titrated according to the patient’s calculated creatinine clearance before each infusion. Use of an infusion pump to control the rate of infusion is important to prevent toxicity, and large volumes of fluid are required because of the drug’s poor solubility. The combination of ganciclovir and foscarnet is synergistic in vitro against CMV and has been shown to be superior to either agent alone in delaying progression of retinitis; however, toxicity is also increased when these agents are administered concurrently. As with ganciclovir, a decrease in the incidence of Kaposi’s sarcoma has been observed in patients who have received long-term foscarnet.

Foscarnet has been administered intravitreally for the treatment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are incomplete.

Resistance to foscarnet in HSV and CMV isolates is due to point mutations in the DNA polymerase gene and is typically associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been described. Although foscarnet-resistant CMV isolates are typically cross-resistant to ganciclovir, foscarnet activity is usually maintained against ganciclovir- and cidofovir-resistant isolates of CMV.

Potential adverse effects of foscarnet include renal impairment, hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia. Saline preloading helps prevent nephrotoxicity, as does avoidance of concomitant administration of drugs with nephrotoxic potential (eg, amphotericin B, pentamidine, aminoglycosides). The risk of severe hypocalcemia, caused by chelation of divalent cations, is increased with concomitant use of pentamidine. Genital ulcerations associated with foscarnet therapy may be due to high levels of ionized drug in the urine. Nausea, vomiting, anemia, elevation of liver enzymes, and fatigue have been reported; the risk of anemia may be additive in patients receiving concurrent zidovudine. Central nervous system toxicity includes headache, hallucinations, and seizures; the risk of seizures may be increased with concurrent use of imipenem. Foscarnet caused chromosomal damage in preclinical studies.

CIDOFOVIR

Cidofovir (eFigure 49–2.1) is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes (Figure 49–2); thus activity is maintained against thymidine kinase-deficient or -altered strains of CMV or HSV. Cidofovir diphosphate acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Cidofovir-resistant isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscarnet.

Although the terminal half-life of cidofovir is approximately 2.6 hours, the active metabolite cidofovir diphosphate has a prolonged intracellular half-life of 17–65 hours, thus allowing infrequent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemodialysis reduces serum levels of cidofovir by approximately 75%.

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus, human papillomavirus, BK polyomavirus, vaccinia, and poxvirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Before each infusion, cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity.

The primary adverse effect of intravenous cidofovir is a dose-dependent proximal tubular nephrotoxicity, which may be reduced with prehydration using normal saline. Proteinuria, azotemia, metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential adverse effects include uveitis, ocular hypotony, and neutropenia (15–24%). Concurrent probenecid use may result in other toxicities or drug-drug interactions (see Chapter 36). Cidofovir is mutagenic, gonadotoxic, and embryotoxic, and causes hypospermia and mammary adenocarcinomas in animals.

image ANTIRETROVIRAL AGENTS

Substantial advances have been made in antiretroviral therapy since the introduction of the first agent, zidovudine, in 1987. Six classes of antiretroviral agents are currently available for use: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists (also called entry inhibitors), and HIV integrase strand transfer inhibitors (INSTIs) (Table 49–3). These agents inhibit HIV replication at different parts of the cycle (Figure 49–3). Structures of some of these drugs are shown in eFigure 49–3.1.

TABLE 49–3 Currently available antiretroviral agents.

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FIGURE 49–3 Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors.

Greater knowledge of viral dynamics through the use of viral load and resistance testing has made it clear that combination therapy with maximally potent agents will reduce viral replication to the lowest possible level, thereby reducing the number of cumulative mutations and decreasing the likelihood of emergence of resistance. Thus, administration of combination antiretroviral therapy, typically including at least three antiretroviral agents with differing susceptibility patterns, has become the standard of care. Viral susceptibility to specific agents varies among patients and may change with time. Therefore, such combinations must be chosen with care and tailored to the individual, as must changes to a given regimen. In addition to potency and susceptibility, important factors in the selection of agents for any given patient are tolerability, convenience, and optimization of adherence. As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety or inferior antiviral efficacy. Zalcitabine (ddC; dideoxycytidine), for example, is no longer marketed.

Decrease of the circulating viral load by antiretroviral therapy is correlated with enhanced survival as well as decreased morbidity. Also, recent evidence suggests that in addition to providing clinical benefits for the patient, the use of antiretroviral therapy strongly reduces the risk for heterosexual HIV transmission.

Discussion of antiretroviral agents in this chapter is specific to HIV-1. Patterns of susceptibility of HIV-2 to these agents may vary; however, there is generally innate resistance to the NNRTIs and lower barriers of resistance to NRTIs and PIs; data regarding maraviroc are inconclusive.

NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

NRTIs are considered the “backbone” of antiretroviral therapy and are generally used in combination with other classes of agents, such as an NNRTI, PI, or integrase inhibitor. NRTIs are usually given in pairs, and many are available as coformulations in order to decrease pill burden and improve adherence. However, certain NRTI combinations should be avoided, due to either drug-drug interactions (eg, didanosine plus tenofovir; see Table 49–4), similar resistance patterns (eg, lamivudine plus emtricitabine) or overlapping toxicities (eg, stavudine plus didanosine).

TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1

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The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–3). Each agent requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.

Typical resistance mutations include M184V, L74V, D67N, and M41L. Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive. While the M184V mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R/N mutation is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogs zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also, some evidence suggests an increased risk of myocardial infarction in patients receiving abacavir; this remains unproven.

ABACAVIR

Abacavir is a guanosine analog that is well absorbed following oral administration (83%) and is unaffected by food. The serum half-life is 1.5 hours. The drug undergoes hepatic glucuronidation and carboxylation. Since the drug is metabolized by alcohol dehydrogenase, serum levels of abacavir may be increased with concurrent alcohol (ie, ethanol) ingestion. Cerebrospinal fluid levels are approximately one-third those of plasma. Abacavir is available in a fixed dose formulation with lamivudine and also with zidovudine plus lamivudine.

High-level resistance to abacavir appears to require at least two or three concomitant mutations and thus tends to develop slowly.

Hypersensitivity reactions, occasionally fatal, have been reported in up to 8% of patients receiving abacavir and may be more severe in association with once-daily dosing. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients. The laboratory abnormalities of a mildly elevated serum aminotransferase or creatine kinase level may be present but are nonspecific. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir results in return of symptoms within hours and may be fatal. Screening for HLA-B*5701 before initiation of abacavir therapy is recommended to identify patients with a markedly increased risk for abacavir-associated hypersensitivity reaction. Although the positive predictive value of this test is only about 50%, it has a negative predictive value approaching 100%.

Other potential adverse events are rash, fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis (rare). In some studies but not in others, abacavir has been associated with a higher risk of myocardial infarction. Since abacavir may lower methadone levels, patients receiving these two agents concurrently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.

DIDANOSINE

Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral bioavailability is approximately 40%. Dosing on an empty stomach is optimal, but buffered formulations are necessary to prevent inactivation by gastric acid (Table 49–3). Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. Serum half-life is 1.5 hours, but the intracellular half-life of the activated compound is as long as 20–24 hours. The drug is eliminated by both cellular metabolism and renal excretion.

The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcohol abuse, hypertriglyceridemia) are relative contraindications, and concurrent use of drugs with the potential to cause pancreatitis, including zalcitabine, stavudine, ribavirin, and hydroxyurea, should be avoided (Table 49–3). The risk of peripheral distal sensory neuropathy, another potential toxicity, may be increased with concurrent use of stavudine, isoniazid, vincristine, or ribavirin. Other reported adverse effects include diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Due to an increased risk of lactic acidosis and hepatic steatosis when combined with stavudine, this combination should be avoided, especially during pregnancy. Previously asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals; concurrent use of allopurinol may increase levels of didanosine. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations. Lipoatrophy appears to be more common in patients receiving didanosine or other thymidine analogs.

The buffer in didanosine tablets interferes with absorption of indinavir, delavirdine, atazanavir, dapsone, itraconazole, and fluoroquinolone agents; therefore, administration should be separated in time. Serum levels of didanosine are increased when co-administered with tenofovir or ganciclovir, and are decreased by atazanavir, delavirdine, ritonavir, tipranavir, and methadone (Table 49–4). Didanosine should not be used in combination with ribavirin.

EMTRICITABINE

Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (> 24 hours), allowing for once-daily dosing. Oral bioavailability of the capsules is 93% and is unaffected by food, but penetration into the cerebrospinal fluid is low. Elimination is by both glomerular filtration and active tubular secretion. The serum half-life is about 10 hours.

The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, because of its activity against HBV, patients co-infected with HIV and HBV should be closely monitored if treatment with emtricitabine is interrupted or discontinued, owing to the likelihood of hepatitis flare.

Emtricitabine is available in a fixed-dose formulation with tenofovir, either alone or in combination with efavirenz, rilpivirine, or elvitegravir plus cobicistat (a boosting agent). Based on results of clinical trials, the combination of tenofovir and emtricitabine is now recommended as pre-exposure prophylaxis to reduce HIV acquisition in men who have sex with men, in heterosexually active men and women, and in injection drug users.

Like lamivudine, the M184V/I mutation is most frequently associated with emtricitabine use and may emerge rapidly in patients receiving regimens that are not fully suppressive. Because of their similar mechanisms of action and resistance profiles, the combination of lamivudine and emtricitabine is not recommended.

The most common adverse effects observed in patients receiving emtricitabine are headache, insomnia, nausea, and rash. In addition, hyperpigmentation of the palms or soles may be observed (~ 3%), particularly in African-Americans (up to 13%).

LAMIVUDINE

Lamivudine (3TC) is a cytosine analog (eFigure 49–3.1) with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs—including zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. As with emtricitabine, lamivudine has activity against HBV; therefore, discontinuation in patients that are co-infected with HIV and HBV may be associated with a flare of hepatitis. Lamivudine therapy rapidly selects for the M184V mutation in regimens that are not fully suppressive.

Oral bioavailability exceeds 80% and is not food-dependent. In children, the average cerebrospinal fluid:plasma ratio of lamivudine was 0.2. Serum half-life is 2.5 hours, whereas the intracellular half-life of the triphosphorylated compound is 11–14 hours. Most of the drug is eliminated unchanged in the urine. Lamivudine remains one of the recommended antiretroviral agents in pregnant women (Table 49–5). Lamivudine is available in a fixed-dose formulation with zidovudine and also with abacavir.

TABLE 49–5 The use of antiretroviral agents in pregnancy.1

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Potential adverse effects are headache, dizziness, insomnia, fatigue, dry mouth, and gastrointestinal discomfort, although these are typically mild and infrequent. Lamivudine’s bioavailability increases when it is co-administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible.

STAVUDINE

The thymidine analog stavudine (d4T) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active tubular secretion and glomerular filtration.

The major toxicity is a dose-related peripheral sensory neuropathy. The incidence of neuropathy may be increased when stavudine is administered with other potentially neurotoxic drugs such as didanosine, vincristine, isoniazid, or ribavirin, or in patients with advanced immunosuppression. Symptoms typically resolve upon discontinuation of stavudine; in such cases, a reduced dosage may be cautiously restarted. Other potential adverse effects are pancreatitis, arthralgias, and elevation in serum aminotransferases. Lactic acidosis with hepatic steatosis, as well as lipodystrophy, appear to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents. Moreover, because the co-administration of stavudine and didanosine may increase the incidence of lactic acidosis and pancreatitis, concurrent use should be avoided. This combination has been implicated in several deaths in HIV-infected pregnant women. A rare adverse effect is a rapidly progressive ascending neuromuscular weakness. Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should not be used together.

TENOFOVIR

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine. Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. Tenofovir is also approved for the treatment of patients with HBV infection.

Tenofovir disoproxil fumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability in fasted patients is approximately 25% and increases to 39% after a high-fat meal. The prolonged serum (12–17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion, and dosage adjustment in patients with renal insufficiency is recommended.

Tenofovir is available in several fixed-dose formulations with emtricitabine, either alone or in combination with efavirenz, rilpivirine, and elvitegravir plus cobicistat. Based on results of several clinical trials, the combination of tenofovir and emtricitabine is now recommended as pre-exposure prophylaxis to reduce HIV acquisition in men who have sex with men, in heterosexually active men and women, and in injection drug users. The primary mutations associated with resistance to tenofovir are K65R/N and K70E.

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Since tenofovir is formulated with lactose, these may occur more frequently in patients with lactose intolerance. Other potential adverse effects include headache, rash, dizziness, and asthenia. Cumulative loss of renal function has been observed, possibly increased with concurrent use of boosted PI regimens. Acute renal failure and Fanconi’s syndrome have also been reported. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Serum creatinine levels should be monitored during therapy and tenofovir discontinued for new proteinuria, glycosuria, or calculated glomerular filtration rate < 30 mL/min. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D. Osteomalacia has been demonstrated in several animal species, and tenofovir use has been an independent risk factor for bone fracture in some studies. Therefore, monitoring of bone mineral density should be considered with long-term use in those with risk factors for (or known) osteoporosis, as well as in children; additionally, alternative agents could be considered in post-menopausal women. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Concurrent use of atazanavir or lopinavir/ritonavir may increase serum levels of tenofovir (Table 49–4).

ZIDOVUDINE

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.

Zidovudine is available in a fixed-dose formulation with lamivudine, either alone or in combination with abacavir.

Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. Studies evaluating the use of zidovudine during pregnancy, labor, and postpartum showed significant reductions in the rate of vertical transmission, and zidovudine remains one of the first-line agents for use in pregnant women (Table 49–5).

High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V for didanosine and M184V for lamivudine) may enhance zidovudine susceptibility in previously zidovudine-resistant strains. Withdrawal of zidovudine may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.

The most common adverse effect of zidovudine is myelosuppression, resulting in macrocytic anemia (1–4%) or neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Lipoatrophy appears to be more common in patients receiving zidovudine or other thymidine analogs. Less common toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy. High doses can cause anxiety, confusion, and tremulousness.

Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. Zidovudine may decrease phenytoin levels. Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided due to in vitro antagonism.

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–3), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.

Baseline genotypic testing is recommended prior to initiating NNRTI treatment because primary resistance rates range from approximately 2% to 8%. NNRTI resistance occurs rapidly with monotherapy and can result from a single mutation. The K103N and Y181C mutations confer resistance to the first-generation NNRTIs, but not to the newer agents (ie, etravirine, rilpivirine). Other mutations (eg, L100I, Y188C, G190A) may also confer cross-resistance among the NNRTI class. However, there is no cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs.

As a class, NNRTI agents tend to be associated with varying levels of gastrointestinal intolerance and skin rash, the latter of which may infrequently be serious (eg, Stevens-Johnson syndrome). A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions (Tables 49–3 and 49–4). All NNRTI agents are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine). Given the large number of non-HIV medications that are also metabolized by this pathway (see Chapter 4), drug-drug interactions must be expected and looked for; dosage adjustments are frequently required and some combinations are contraindicated.

DELAVIRDINE

Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids or H2-blockers. It is extensively bound (~ 98%) to plasma proteins and has correspondingly low cerebrospinal fluid levels. Serum half-life is approximately 6 hours.

Skin rash occurs in up to 38% of patients receiving delavirdine; it typically occurs during the first 1–3 weeks of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other possible adverse effects are headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels. Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at dosages not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.

Delavirdine is extensively metabolized by the CYP3A and CYP2D6 enzymes and also inhibits CYP3A4 and 2C9. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49–3 and 49–4). The concurrent use of delavirdine with fosamprenavir and rifabutin is not recommended because of decreased delavirdine levels. Other medications likely to alter delavirdine levels include didanosine, lopinavir, nelfinavir, and ritonavir. Co-administration of delavirdine with indinavir or saquinavir prolongs the elimination half-life of these protease inhibitors, thus allowing them to be dosed twice rather than thrice daily.

EFAVIRENZ

Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%). Since toxicity may increase owing to increased bioavailability after a high-fat meal, efavirenz should be taken on an empty stomach. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (~ 99%), and cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels.

The principal adverse effects of efavirenz involve the central nervous system. Dizziness, drowsiness, insomnia, nightmares, and headache tend to diminish with continued therapy; dosing at bedtime may also be helpful. Psychiatric symptoms such as depression, mania, and psychosis have been observed and may necessitate discontinuation. Skin rash has also been reported early in therapy in up to 28% of patients; the rash is usually mild to moderate in severity and typically resolves despite continuation. Rarely, rash has been severe or life-threatening. Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities, such as neural tube defects, occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Therefore, efavirenz should be avoided in pregnant women, particularly in the first trimester.

As both an inducer and an inhibitor of CYP3A4, efavirenz induces its own metabolism and interacts with the metabolism of many other drugs (Tables 49–3 and 49–4). Since efavirenz may lower methadone levels, patients receiving these two agents concurrently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.

ETRAVIRINE

Etravirine was designed to be effective against strains of HIV that had developed resistance to first-generation NNRTIs, due to mutations such as K103N and Y181C, and is recommended for treatment-experienced patients that have resistance to other NNRTIs. Although etravirine has a higher genetic barrier to resistance than the other NNRTIs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine.

Etravirine should be taken with a meal to increase systemic exposure. It is highly protein-bound and is primarily metabolized by the liver. Mean terminal half-life is approximately 41 hours.

The most common adverse effects of etravirine are rash, nausea, and diarrhea. The rash is typically mild and usually resolves after 1–2 weeks without discontinuation of therapy. Rarely, rash has been severe or life-threatening. Laboratory abnormalities include elevations in serum cholesterol, triglyceride, glucose, and hepatic transaminase levels. Transaminase elevations are more common in patients with HBV or HCV co-infection.

Etravirine is a substrate as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19; it has many therapeutically significant drug-drug interactions (Tables 49–3 and 49–4). Some of the interactions are difficult to predict. For example, etravirine may decrease itraconazole and ketoconazole concentrations but increase voriconazole concentrations. Etravirine should not be given with other NNRTIs, unboosted protease inhibitors, atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir.

NEVIRAPINE

The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels that are 45% of those in plasma. Serum half-life is 25–30 hours. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.

A single dose of nevirapine (200 mg) is effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2 mg/kg oral dose to the neonate within 3 days after delivery, and nevirapine remains one of the recommended agents in pregnant women (Table 49–5). There is no evidence of human teratogenicity. However, resistance has been documented after this single dose.

Rash, usually a maculopapular eruption that spares the palms and soles, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose-limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash. Severe and life-threatening skin rashes have been rarely reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with accompanying constitutional symptoms; since rash may accompany hepatotoxicity, liver tests should be assessed. Symptomatic liver toxicity may occur in up to 4% of patients, may be severe, and is more frequent in those with higher pretherapy CD4 cell counts (ie, > 250 cells/mm3 in women and > 400 cells/mm3 in men), in women, and in those with HBV or HCV co-infection. Fulminant, life-threatening hepatitis has been reported, typically within the first 18 weeks of therapy. Other adverse effects include fever, nausea, headache, and somnolence.

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir, saquinavir, efavirenz, and methadone. Drugs that induce the CYP3A system, such as rifampin, rifabutin, and St. John’s wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithromycin, can increase nevirapine levels. Since nevirapine may lower methadone levels, patients receiving these two agents concurrently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.

RILPIVIRINE

Rilpivirine is recommended only in treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL, and only in combination with at least 2 other antiretroviral agents. It is available in a fixed dose formulation with emtricitabine and tenofovir.

Rilpivirine must be administered with a meal (preferably high fat or > 400 kcal). Its oral bioavailability can be significantly reduced in the presence of acid lowering agents. It should be used with caution with antacids and H2-receptor antagonists. Rilpivirine use with proton-pump inhibitors (PPIs) is contraindicated. The drug is highly protein bound and the terminal elimination half-life is 50 hours.

The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. There is cross-resistance with other NNRTIs, and the combination of rilpivirine with other NNRTIs is not recommended.

Rilpivirine is primarily metabolized by CYP3A4, and drugs that induce or inhibit CYP3A4 may thus affect the clearance of rilpivirine. However, clinically significant drug-drug interactions with other antiretroviral agents have not been identified to date. Concurrent use of carbamazepine, dexamethasone, phenobarbital, phenytoin, proton pump inhibitors, rifabutin, rifampin, rifapentine, and St John’s wort is contraindicated. Methadone withdrawal may be precipitated with concurrent usage.

The most common adverse effects associated with rilpivirine therapy are rash, depression, headache, insomnia, and increased serum aminotransferases. Increased serum cholesterol, and fat redistribution syndrome have been reported. Higher doses have been associated with QTc prolongation.

PROTEASE INHIBITORS (PIs)

During the later stages of the HIV growth cycle, the gag and gag-pol gene products are translated into polyproteins, and these become immature budding particles. The HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core. By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles (Figure 49–3). Unlike the NRTIs, PIs do not need intracellular activation.

Specific genotypic alterations that confer phenotypic resistance are fairly common with these agents, thus contraindicating monotherapy. Some of the most common mutations conferring broad resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90 codons; the number of mutations may predict the level of phenotypic resistance. The I50L substitution emerging during atazanavir therapy has been associated with increased susceptibility to other PIs. Darunavir and tipranavir appear to have improved virologic activity in patients harboring HIV-1 resistant to other PIs.

As a class, PIs are associated with mild-to-moderate nausea, diarrhea, and dyslipidemia. A syndrome of redistribution and accumulation of body fat that results in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed, perhaps less commonly with atazanavir (see below). Concurrent increases in triglyceride and low-density lipoprotein levels, along with hyperglycemia and insulin resistance, have also been noted. Abacavir, lopinavir/ritonavir, and fosamprenavir/ritonavir have been associated with an increased risk of cardiovascular disease in some, but not all, studies. All PIs may be associated with cardiac conduction abnormalities, including PR or QT interval prolongation or both. A baseline electrocardiogram and avoidance of other agents causing prolonged PR or QT intervals should be considered. Drug-induced hepatitis and rare severe hepatotoxicity have been reported to varying degrees with all PIs; the frequency of hepatic events is higher with tipranavir/ritonavir than with other PIs. Whether PI agents are associated with bone loss and osteoporosis after long-term use is under investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B; an increased risk of intracranial hemorrhage has been reported in patients receiving tipranavir with ritonavir.

All of the antiretroviral PIs are extensively metabolized by CYP3A4, with ritonavir having the most pronounced inhibitory effect and saquinavir the least. Some PI agents, such as amprenavir and ritonavir, are also inducers of specific CYP isoforms. As a result, there is enormous potential for drug-drug interactions with other antiretroviral agents and other commonly used medications (Tables 49–3 and 49–4). Expert resources about drug-drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated. It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir are used to clinical advantage by having it “boost” the levels of other PI agents when given in combination, thus acting as a pharmacokinetic enhancer rather than an antiretroviral agent. Ritonavir boosting increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is raised.

ATAZANAVIR

Atazanavir (eFigure 49–3.1) is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, it should be taken with meals and separation of ingestion from acid-reducing agents by at least 12 hours is recommended; concurrent proton pump inhibitors are contraindicated. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6–7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency. Atazanavir is one of the recommended antiretroviral agents for pregnant women (Table 49–5).

Resistance to atazanavir has been associated with various known PI mutations as well as with the novel I50L substitution. Whereas some atazanavir resistance mutations have been associated in vitro with decreased susceptibility to other PIs, the I50L mutation has been associated with increased susceptibility to other PIs.

The most common adverse effects in patients receiving atazanavir are diarrhea and nausea; vomiting, abdominal pain, headache, peripheral neuropathy, and skin rash may also occur. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur in approximately 10% of patients, owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of hepatic enzymes has also been observed, usually in patients with underlying HBV or HCV co-infection. Nephrolithiasis has been described in association with atazanavir use, and prolonged use of boosted atazanavir is associated with cumulative loss of renal function. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia, fat redistribution, or the metabolic syndrome.

As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Atazanavir AUC is reduced by up to 76% when combined with a proton pump inhibitor; thus, this combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as irinotecan, may increase its levels. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.

DARUNAVIR

Darunavir is licensed as a PI that must be co-administered with ritonavir. Darunavir should be taken with meals to improve bioavailability. It is highly protein-bound and primarily metabolized by the liver.

Symptomatic adverse effects of darunavir include diarrhea, nausea, headache, and rash. Laboratory abnormalities include dyslipidemia (though possibly less frequent than with other boosted PI regimens) and increases in amylase and hepatic transaminase levels. Liver toxicity, including severe hepatitis, has been reported in some patients taking darunavir; the risk of hepatotoxicity may be higher for persons with HBV, HCV, or other chronic liver disease. Darunavir contains a sulfonamide moiety and may cause a hypersensitivity reaction, particularly in patients with sulfa allergy.

Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Tables 49–3 and 49–4). In addition, the co-administered ritonavir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems.

FOSAMPRENAVIR

Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir.

After hydrolysis of fosamprenavir, amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–11 hours). Amprenavir is metabolized in the liver and should be used with caution in the setting of hepatic insufficiency.

The most common adverse effects of fosamprenavir are headache, nausea, diarrhea, perioral paresthesias, depression. Fosamprenavir contains a sulfa moiety and may cause a rash in up to 3% of patients, sometimes severe enough to warrant drug discontinuation.

Amprenavir is both an inducer and an inhibitor of CYP3A4 and is contraindicated with numerous drugs (Tables 49–3 and 49–4). The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solution also contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided. Amprenavir, a sulfonamide, is contraindicated in patients with a history of sulfa allergy. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir and altered lopinavir exposures. An increased dosage of amprenavir is recommended when co-administered with efavirenz (with or without the addition of ritonavir to boost levels).

INDINAVIR

Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60–65%). The serum half-life is 1.5–2 hours, protein binding is approximately 60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to urinary crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. There have also been rare cases of acute hemolytic anemia.

Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Combination with ritonavir (boosting) allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised.

LOPINAVIR

Lopinavir is currently available only in combination with ritonavir, which inhibits the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. In addition to improved patient compliance due to reduced pill burden, lopinavir/ritonavir is generally well tolerated.

Lopinavir is highly protein bound (98–99%), and its half-life is 5–6 hours. It is extensively metabolized by CYP3A, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment. Lopinavir/ritonavir is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5).

The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Ritonavir-boosted lopinavir may be more commonly associated with gastrointestinal adverse events than other PIs. Elevations in serum cholesterol and triglycerides are common. Prolonged use of boosted lopinavir is associated with cumulative loss of renal function, and lopinavir use has been an independent risk factor for bone fracture in some (but not all) studies.

Potential drug-drug interactions are extensive (Tables 49–3 and 49–4). Increased dosage of lopinavir/ritonavir is recommended when co-administered with efavirenz or nevirapine, which induce lopinavir metabolism. Concurrent use of fosamprenavir should be avoided owing to altered exposure to lopinavir with decreased levels of amprenavir. Also, concomitant use of lopinavir/ritonavir and rifampin is contraindicated due to an increased risk for hepatotoxicity. Since the oral solution of lopinavir/ritonavir contains alcohol, concurrent disulfiram and metronidazole are contraindicated.

NELFINAVIR

Nelfinavir has high absorption in the fed state (70–80%), undergoes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours, and the drug is more than 98% protein-bound.

The most common adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea often responds to antidiarrheal medications but can be dose-limiting. Nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur (Tables 49–3 and 49–4). An increased dosage of nelfinavir is recommended when co-administered with rifabutin (with a decreased dose of rifabutin), whereas a decrease in saquinavir dose is suggested with concurrent nelfinavir. Co-administration with efavirenz should be avoided due to decreased nelfinavir levels.

RITONAVIR

Ritonavir (eFigure 49–3.1) has a high bioavailability (about 75%) that increases with food. It is 98% protein-bound and has a serum half-life of 3–5 hours. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Caution is advised when administering the drug to persons with impaired hepatic function. Ritonavir is one of the recommended antiretroviral agents for use in pregnant women (Table 49–5).

Potential adverse effects of ritonavir, particularly when administered at full dosage, are gastrointestinal disturbances, paresthesias (circumoral or peripheral), elevated serum aminotransferase levels, altered taste, headache, and elevations in serum creatine kinase. Nausea, vomiting, diarrhea, or abdominal pain typically occur during the first few weeks of therapy but may diminish over time or if the drug is taken with meals. Dose escalation over 1–2 weeks is recommended to decrease the dose-limiting side effects.

Ritonavir is a potent inhibitor of CYP3A4, resulting in many potential drug interactions (Tables 49–3 and 49–4). However, this characteristic has been used to great advantage when ritonavir is administered in low doses (100–200 mg twice daily) in combination with any of the other PI agents, in that increased blood levels of the latter agents permit lower or less frequent dosing (or both) with greater tolerability as well as the potential for greater efficacy against resistant virus. Therapeutic levels of digoxin and theophylline should be monitored when co-administered with ritonavir owing to a likely increase in their concentrations. The concurrent use of saquinavir and ritonavir is contraindicated due to an increased risk of QT prolongation (with torsades de pointes arrhythmia) and PR interval prolongation.

SAQUINAVIR

In its original formulation as a hard gel capsule, oral saquinavir was poorly bioavailable (only about 4% after food). However, reformulation of saquinavir for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects. A previous formulation of saquinavir in soft gel capsules is no longer available.

Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) and rhinitis. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. However, the concurrent use of saquinavir and ritonavir may confer an increased risk of QT prolongation (with torsades de pointes arrhythmia) and PR interval prolongation.

Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate; thus, there are many potential drug-drug interactions (Tables 49–3 and 49–4). A decreased dose of saquinavir is recommended when co-administered with nelfinavir. Increased saquinavir levels when co-administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels may increase if co-administered with saquinavir and should therefore be monitored. Liver tests should be monitored if saquinavir is co-administered with delavirdine or rifampin.

TIPRANAVIR

Tipranavir is a newer PI indicated for use in treatment-experienced patients who harbor strains resistant to other PI agents. It is used in combination with ritonavir to achieve effective serum levels.

Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system and is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy.

The most common adverse effects of tipranavir are diarrhea, nausea, vomiting, and abdominal pain. An urticarial or maculopapular rash is more common in women and may be accompanied by systemic symptoms or desquamation. Liver toxicity, including life-threatening hepatic decompensation, has been observed and may be more common than with other PIs, particularly in patients with chronic HBV or HCV infection. Tipranavir should be discontinued in patients who have increased serum transaminase levels that are more than 10 times the upper limit of normal or more than 5 times normal in combination with increased serum bilirubin. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir/ritonavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression, elevation in amylase, and decreased white blood cell count.

Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces P-glycoprotein transporter and thus may alter the disposition of many other drugs (Table 49–4). Concurrent administration of tipranavir with fosamprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs. Tipranavir/ritonavir may also decrease serum levels of valproic acid and omeprazole. Levels of lovastatin, simvastatin, atorvastatin, and rosuvastatin may be increased, increasing the risk for rhabdomyolysis and myopathy.

ENTRY INHIBITORS

The process of HIV-1 entry into host cells is complex; each step presents a potential target for inhibition. Viral attachment to the host cell entails binding of the viral envelope glycoprotein complex gp160 (consisting of gp120 and gp41) to its cellular receptor CD4. This binding induces conformational changes in gp120 that enable access to the chemokine receptors CCR5 or CXCR4. Chemokine receptor binding induces further conformational changes in gp120, allowing exposure to gp41 and leading to fusion of the viral envelope with the host cell membrane and subsequent entry of the viral core into the cellular cytoplasm.

ENFUVIRTIDE

Enfuvirtide is a synthetic 36-amino-acid peptide fusion inhibitor that blocks HIV entry into the cell (Figure 49–3). Enfuvirtide binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. It is administered in combination with other antiretroviral agents in treatment-experienced patients with evidence of viral replication despite ongoing antiretroviral therapy.

Enfuvirtide, which must be administered by subcutaneous injection, is the only parenterally administered antiretroviral agent. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours.

Resistance to enfuvirtide can result from mutations in gp41; the frequency and significance of this phenomenon are being investigated. However, enfuvirtide lacks cross-resistance with the other currently approved antiretroviral drug classes.

The most common adverse effects associated with enfuvirtide therapy are local injection site reactions, consisting of painful erythematous nodules. Although frequent, these are typically mild-to-moderate and rarely lead to discontinuation. Other side effects may include insomnia, headache, dizziness, and nausea. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge. Eosinophilia is the primary laboratory abnormality seen with enfuvirtide administration. No drug-drug interactions have been identified that would require the alteration of the dosage of concomitant antiretroviral or other drugs.

MARAVIROC

Maraviroc (eFigure 49–3.1) is approved for use in combination with other antiretroviral agents in treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable who are resistant to other antiretroviral agents. Maraviroc binds specifically and selectively to the host protein CCR5, one of two chemokine receptors necessary for entrance of HIV into CD4+ cells. Since maraviroc is active against HIV that uses the CCR5 co-receptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, co-receptor tropism should be determined by specific testing before maraviroc is started, using the enhanced sensitivity tropism assay. Substantial proportions of patients, particularly those with advanced HIV infection, are likely to have virus that is not exclusively CCR5-tropic.

The absorption of maraviroc is rapid but variable, with the time to maximum absorption generally being 1–4 hours after ingestion of the drug. Most of the drug (≥ 75%) is excreted in the feces, whereas approximately 20% is excreted in urine. The recommended dose of maraviroc varies according to renal function and the concomitant use of CYP3A inducers or inhibitors. Maraviroc is contraindicated in patients with severe or end-stage renal impairment who are taking concurrent CYP3A inhibitors or inducers, and caution is advised when used in patients with preexisting hepatic impairment and in those co-infected with HBV or HCV. Maraviroc has excellent penetration into the cervicovaginal fluid, with levels almost four times higher than the corresponding concentrations in blood plasma.

Resistance to maraviroc is associated with one or more mutations in the V3 loop of gp120. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfuvirtide. However, emergence of CXCR4 virus (either previously undetected or newly developed) appears to be a more common cause of virologic failure than the development of resistance mutations.

Maraviroc is a substrate for CYP3A4 and therefore requires adjustment in the presence of drugs that interact with these enzymes (Tables 49–3 and 49–4). It is also a substrate for P-glycoprotein, which limits intracellular concentrations of the drug. The dosage of maraviroc must be decreased if it is co-administered with strong CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole, clarithromycin, or any protease inhibitor other than tipranavir) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, rifampin, carbamazepine, phenytoin, or St. John’s wort).

Potential adverse effects of maraviroc include cough, upper respiratory tract infections, muscle and joint pain, diarrhea, sleep disturbance, and elevations in serum aminotransferases. Hepatotoxicity has been reported, which may be preceded by a systemic allergic reaction (ie, pruritic rash, eosinophilia, or elevated IgE); discontinuation of maraviroc should be prompt if this constellation occurs. Also, caution should be used in patients with pre-existing liver dysfunction or who are co-infected with HBV or HCV. Myocardial ischemia and infarction have been observed in patients receiving maraviroc; therefore caution is advised in patients at increased cardiovascular risk.

There has been concern that blockade of the chemokine CCR5 receptor—a human protein—may result in decreased immune surveillance, with a subsequent increased risk of malignancy (eg, lymphoma) or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.

INTEGRASE STRAND TRANSFER INHIBITORS (INSTIs)

This class of agents binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells (Figure 49–3). As a class, these agents tend to be well tolerated, with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism are favorable compared with efavirenz and PIs, with more variable findings for elvitegravir than raltegravir and dolutegravir due to co-administration with the boosting agent cobicistat. Rare and severe events include systemic hypersensitivity reactions and rhabdomyolysis.

DOLUTEGRAVIR

Dolutegravir may be taken with or without food. The absolute oral bioavailability has not been established. Dolutegravir should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications. The terminal half-life is approximately 14 hours.

Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Therefore, drug-drug interactions may occur (Table 49–4). Co-administration with the metabolic inducers phenytoin, phenobarbital, carbamazepine, and St. John’s wort should be avoided. Dolutegravir inhibits the renal organic cation transporter OCT2, thereby increasing plasma concentrations of drugs eliminated via OCT2 such as dofetilide and metformin. For this reason, co-administration with dofetilide is contraindicated and close monitoring, with potential for dose adjustment, is recommended for co-administration with metformin.

Current evidence suggests that dolutegravir retains activity against some viruses resistant to both raltegravir and elvitegravir.

The most common adverse reactions associated with dolutegravir are insomnia and headache. Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported and may be life-threatening. The drug should be discontinued immediately if this occurs and not restarted. Other reported side effects include elevations in serum aminotransferases and the fat redistribution syndrome.

ELVITEGRAVIR

Elvitegravir requires boosting with an additional drug, such as cobicistat (a pharmacokinetic enhancer that inhibits CYP3A4 as well as certain intestinal transport proteins) or ritonavir. Elvitegravir is therefore available only as a component of a fixed-dose combination, with cobicistat, emtricitabine, and tenofovir. The combined formulation should be taken with food.

Cobicistat can inhibit renal tubular secretion of creatinine, causing increases in serum creatinine that may not be clinically significant; in the fixed-dose formulation it may be difficult to distinguish between cobicistat effect and tenofovir-induced nephrotoxicity. The recommendation is that the fixed-dose combination elvitegravir/cobicistat/tenofovir/emtricitabine should not be initiated in patients with calculated creatinine clearance < 70 mL/min and should be discontinued in those with creatinine clearance < 50 mL/min; discontinuation should be considered if the serum creatinine increases by 0.4 mg/dL or more.

RALTEGRAVIR

Absolute bioavailability of the pyrimidinone analog raltegravir has not been established but does not appear to be food-dependent. The drug does not interact with the cytochrome P450 system but is metabolized by glucuronidation, particularly UGT1A1. Inducers or inhibitors of UGT1A1 may affect serum levels of raltegravir. For example, since concurrent use of rifampin substantially decreases raltegravir concentrations, the dose of raltegravir should be increased. Since polyvalent cations (eg, magnesium, calcium, and iron) may bind integrase inhibitors and interfere with their activity, antacids should be used cautiously and ingestion separated by at least 4 hours from raltegravir. The chewable tablets may contain phenylalanine, which can be harmful to patients with phenylketonuria.

Although virologic failure has been uncommon in clinical trials of raltegravir to date, in vitro resistance requires only a single point mutation (eg, at codons 148 or 155). The low genetic barrier to resistance emphasizes the importance of combination therapies and of adherence. Integrase mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

Potential adverse effects of raltegravir include insomnia, headache, dizziness, diarrhea, nausea, fatigue, and muscle aches. Increases in pancreatic amylase, serum aminotransferases, and creatine kinase (with rhabdomyolysis) may occur. Severe, potentially life-threatening and fatal skin reactions have been reported, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis.

image ANTIHEPATITIS AGENTS

INTERFERON ALFA

Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions (see Chapter 55) and some have proven useful in both HBV and HCV. Interferon alfa appears to function by induction of intracellular signals following binding to specific cell membrane receptors, resulting in inhibition of viral penetration, translation, transcription, protein processing, maturation, and release, as well as increased host expression of major histocompatibility complex antigens, enhanced phagocytic activity of macrophages, and augmentation of the proliferation and survival of cytotoxic T cells.

Injectable preparations of interferon alfa are available for treatment of both HBV and HCV infections (Table 49–6). Interferon alfa-2a and interferon alfa-2b may be administered either subcutaneously or intramuscularly; half-life is 2–5 hours, depending on the route of administration. Alfa interferons are filtered at the glomerulus and undergo rapid proteolytic degradation during tubular reabsorption, such that detection in the systemic circulation is negligible. Liver metabolism and subsequent biliary excretion are considered minor pathways.

TABLE 49–6 Drugs used to treat viral hepatitis.

image

The use of pegylated (polyethylene glycol-complexed) interferon alfa-2a and pegylated interferon alfa-2b results in slower clearance, longer terminal half-lives, and steadier concentrations, thus allowing for less frequent dosing. Renal elimination accounts for about 30% of clearance, and clearance is approximately halved in subjects with impaired renal function; dosage must therefore be adjusted.

The adverse effects of interferon alfa include a flu-like syndrome (ie, headache, fevers, chills, myalgias, and malaise) that typically occurs within 6 hours after dosing; this syndrome occurs in more than 30% of patients during the first week of therapy and tends to resolve upon continued administration. Transient hepatic enzyme elevations may occur in the first 8–12 weeks of therapy and appear to be more common in responders. Potential adverse effects during chronic therapy include neurotoxicities (mood disorders, depression, somnolence, confusion, seizures), myelosuppression, profound fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy, pneumonitis, and possibly cardiotoxicity. Induction of autoantibodies may occur, causing exacerbation or unmasking of autoimmune disease (particularly thyroiditis). The polyethylene glycol molecule is a nontoxic polymer that is readily excreted in the urine.

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline and methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias.

TREATMENT OF HEPATITIS B VIRUS INFECTION

The goals of chronic HBV therapy are the suppression of HBV DNA to undetectable levels, seroconversion of HBeAg (or more rarely, HBsAg) from positive to negative, and reduction in elevated hepatic transaminase levels. These end points are correlated with improvement in necroinflammatory disease, a decreased risk of hepatocellular carcinoma and cirrhosis, and a decreased need for liver transplantation. All of the currently licensed therapies achieve these goals. However, because current therapies suppress HBV replication without eradicating the virus, initial responses may not be durable. The covalently closed circular (ccc) viral DNA exists in stable form indefinitely within the cell, serving as a reservoir for HBV throughout the life of the cell and resulting in the capacity to reactivate. Relapse is more common in patients co-infected with HBV and hepatitis D virus.

As of 2013 seven drugs were approved for treatment of chronic HBV infection in the United States: five oral nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, tenofovir, entecavir, telbivudine) and two injectable interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a) (Table 49–6). The use of interferon has been supplanted by long-acting pegylated interferon, allowing once-weekly rather than daily or thrice-weekly dosing. In general, nucleoside/nucleotide analog therapies have better tolerability and produce a higher response rate than the interferons and are now considered the first line of therapy. Combination therapies may reduce the development of resistance. The optimal duration of therapy remains unknown.

Several anti-HBV agents have anti-HIV activity as well, including tenofovir, lamivudine, and adefovir dipivoxil. Emtricitabine, an NRTI used in HIV infection, has resulted in excellent biochemical, virologic, and histologic improvement in patients with chronic HBV infection, although it is not approved for this indication. Agents with dual HBV and HIV activity are particularly useful as part of a first-line regimen in co-infected patients. However, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents; this may be severe or even fatal.

ADEFOVIR DIPIVOXIL

Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog (eFigure 49–4.1). It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase and causes chain termination after incorporation into viral DNA. Adefovir is active in vitro against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.

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FIGURE 49–4 Life cycle of HCV and mechanisms of drug action. (Adapted, with permission, from Asselah T, Marcellin P: Direct-acting antivirals for the treatment of chronic hepatitis C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.)

Oral bioavailability of adefovir dipivoxil is about 59% and is unaffected by meals; it is rapidly and completely hydrolyzed to the parent compound by intestinal and blood esterases. Protein binding is low (< 5%). The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours in various cells; this makes once-daily dosing feasible. Adefovir is excreted by a combination of glomerular filtration and active tubular secretion and requires dose adjustment for renal dysfunction; however, it may be administered to patients with decompensated liver disease.

Of the oral agents, adefovir may be slower to suppress HBV DNA levels and the least likely to induce HBeAg seroconversion. Emergence of resistance is 20% to 30% after 5 years of use. Naturally occurring (ie, primary) adefovir-resistant rt233 HBV mutants have been described. There is no cross-resistance between adefovir and lamivudine or entecavir.

Adefovir is well tolerated. A dose-dependent nephrotoxicity, manifested by increased serum creatinine and decreased serum phosphorous, may occur and is more common with use of higher doses (30-60 mg/d) or pre-existing azotemia. Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. Pivalic acid, a by-product of adefovir metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). Severe acute exacerbations of hepatitis have been reported in up to 25% of patients who discontinued adefovir. Adefovir is embryotoxic in rats at high doses and is genotoxic in preclinical studies.

ENTECAVIR

Entecavir is an orally administered guanosine nucleoside analog. that competitively inhibits all three functions of HBV DNA polymerase, including base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA. Oral bioavailability approaches 100% but is decreased by food; therefore, entecavir should be taken on an empty stomach. The intracellular half-life of the active phosphorylated compound is 15 hours and plasma half-life is prolonged at 128-149 hours, allowing once-daily dosing. It is excreted by the kidney, undergoing both glomerular filtration and net tubular secretion.

Suppression of HBV DNA levels was greater with entecavir than with lamivudine or adefovir in comparative trials. Entecavir appears to have a higher barrier to the emergence of resistance than lamivudine but resistance may be more likely in the setting of lamivudine resistance. Although selection of resistant isolates with the S202G mutation has been documented during therapy, clinical resistance is rare (< 1% at 4 years). Entecavir has weak anti-HIV activity and can induce development of the M184V variant in HBV/HIV co-infected patients, resulting in resistance to emtricitabine and lamivudine.

Entecavir is well tolerated. Potential adverse events are headache, fatigue, dizziness, nausea, rash, and fever. Lung adenomas and carcinomas in mice, hepatic adenomas and carcinomas in rats and mice, vascular tumors in mice, and brain gliomas and skin fibromas in rats have been observed at varying exposures. Co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug.

LAMIVUDINE

The pharmacokinetics of lamivudine are described earlier in this chapter (see section, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV cell lines (17–19 hours) than in HIV-infected cell lines (10.5–15.5 hours) allows for lower doses and less frequent administration. Lamivudine can be safely administered to patients with decompensated liver disease. Prolonged treatment has been shown to decrease clinical progression of HBV, as well as development of hepatocellular cancer by approximately 50%. Also, lamivudine has been effective in preventing vertical transmission of HBV from mother to newborn when given in the last 4 weeks of gestation.

Lamivudine inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA, resulting in chain termination. Although lamivudine initially results in rapid and potent virus suppression, chronic therapy is limited by the emergence of lamivudine-resistant HBV isolates (eg, L180M or M204I/V), estimated to occur in 15–30% of patients at 1 year and 70% at 5 years of therapy. Resistance has been associated with flares of hepatitis and progressive liver disease. Cross-resistance between lamivudine and emtricitabine or entecavir may occur; however, adefovir and tenofovir maintain activity against lamivudine-resistant strains of HBV.

In the doses used for HBV infection, lamivudine has an excellent safety profile. Headache, nausea, diarrhea, dizziness, myalgia, and malaise are rare. Co-infection with HIV may increase the risk of pancreatitis.

TELBIVUDINE

Telbivudine is a thymidine nucleoside analog with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. The phosphorylated compound competitively inhibits HBV DNA polymerase, resulting in incorporation into viral DNA and chain termination. It is not active in vitro against HIV-1.

Oral bioavailability is unaffected by food. Plasma protein-binding is low (3%) and distribution wide. The serum half-life is approximately 15 hours and excretion is renal. There are no known metabolites and no known interactions with the CYP450 system or other drugs.

Telbivudine induced greater rates of virologic response than either lamivudine or adefovir in comparative trials. However, emergence of resistance, typically due to the M204I mutation, may occur in up to 22% of patients with durations of therapy exceeding 1 year, and may result in virologic rebound. Telbivudine is not effective in patients with lamivudine-resistant HBV.

Adverse effects are mild; they include fatigue, headache, cough, nausea, diarrhea, rash, and fever. Both uncomplicated myalgia and myopathy have been reported, concurrent with increased creatine kinase levels, as has peripheral neuropathy. As with other nucleoside analogs, lactic acidosis and severe hepatomegaly with steatosis may occur during therapy as well as flares of hepatitis after discontinuation.

TENOFOVIR

Tenofovir, a nucleotide analog of adenosine in use as an antiretroviral agent, has potent activity against HBV. The characteristics of tenofovir are described earlier in this chapter. Tenofovir maintains activity against lamivudine- and entecavir-resistant hepatitis virus isolates but has reduced activity against adefovir-resistant strains. Although similar in structure to adefovir dipivoxil, comparative trials show a higher rate of virologic response and histologic improvement, and a lower rate of emergence of resistance to tenofovir in patients with chronic HBV infection. The most common adverse effects of tenofovir in patients with HBV infection are nausea, abdominal pain, diarrhea, dizziness, fatigue, and rash; other potential adverse effects are those listed earlier.

TREATMENT OF HEPATITIS C INFECTION

In contrast to the treatment of patients with chronic HBV infection, the primary goal of treatment in patients with HCV infection is viral eradication. In clinical trials, the primary efficacy end point is typically achievement of sustained viral response (SVR), defined as the absence of detectable viremia 24 weeks after completion of therapy. SVR is associated with improvement in liver histology, reduction in risk of hepatocellular carcinoma, and, occasionally, with regression of cirrhosis as well. Late relapse occurs in less than 5% of patients who achieve SVR.

In acute hepatitis C, the rate of clearance of the virus without therapy is estimated at 15–30%. In one (uncontrolled) study, treatment of acute infection with interferon alfa-2b, in doses higher than those used for chronic hepatitis C, resulted in a sustained rate of clearance of 95% at 6 months. Therefore, if HCV RNA testing documents persistent viremia 12 weeks after initial seroconversion, antiviral therapy is recommended.

Treatment of patients with chronic HCV infection is recommended for those with an increased risk for progression to cirrhosis. The parameters for selection are complex. In those who are to be treated, the traditional standard treatment is once-weekly pegylated interferon alfa in combination with daily oral ribavirin. Pegylated interferon alfa-2a and -2b have replaced their unmodified interferon alfa counterparts because of superior efficacy in combination with ribavirin, regardless of genotype. It is also clear that combination therapy with oral ribavirin is more effective than monotherapy with either interferon or ribavirin alone. Therefore, monotherapy with pegylated interferon alfa is recommended only in patients who cannot tolerate ribavirin. Interferon plus ribavirin therapy is active against all genotypes of HCV infection, with SVR rates of 70 to 80% among patients with HCV genotype 2 or 3 infection and rates of 45 to 70% among patients with any of the other genotypes. A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860) is a strong predictor of response to peginterferon alfa and ribavirin.

However, the recent advent of NS3/4A protease inhibitors and the NS5B polymerase inhibitors is changing the face of chronic HCV therapy. Administration of boceprevir, simeprevir, or telaprevir, in combination with peginterferon and ribavirin, dramatically increased the rate of viral clearance in patients with HCV genotype 1; sofosbuvir is effective against HCV genotypes 1, 2, 3, and 4. Although all four of these new agents are licensed to be administered in combination with peginterferon and ribavirin, recent results of clinical trials have provided evidence that one or more of them may be effective in interferon- and ribavirin-free regimens.

POLYMERASE INHIBITORS

Sofosbuvir

Sofosbuvir is a nucleotide analog that inhibits the HCV NS5B RNA-dependent RNA polymerase in patients infected with HCV genotype 1, 2, 3, or 4. It is administered once daily, with or without food, in combination with peginterferon alfa and ribavirin, for a total of 12–24 weeks (the longer duration is recommended in patients infected with HCV genotype 3). Very high cure rates are reported but the drug is extraordinarily expensive.

Sofosbuvir is 61–65% bound to plasma proteins and is metabolized in the liver to form the active nucleoside analog triphosphate GS-461203. Elimination is by renal clearance, and safety has not been established in patients with severe renal insufficiency.

Sofosbuvir is a substrate of drug transporter P-gp; therefore, potent P-gp inducers in the intestine should not be co-administered. Commonly reported adverse effects are fatigue and headache.

PROTEASE INHIBITORS

Three oral protease NS3/4A inhibitors have recently become available for the treatment of HCV genotype 1 infection, in combination with peginterferon and ribavirin: boceprevir, simeprevir, and telaprevir. These agents inhibit HCV replication directly by binding to the NS3/4A protease that cleaves HCV-encoded polyproteins (Figure 49–4). Of concern is the enhanced toxicity when used in combination with peginterferon and ribavirin, the high potential for drug-drug interactions, and the low genetic barrier to resistance, which may develop as early as 4 days after initiation of therapy when administered as monotherapy. Use of these agents in the treatment of other HCV genotypes is not recommended. Cross-resistance is expected among NS3/4A protease inhibitors.

All three agents are inhibitors and substrates of CYP3A inhibitors. Drug-drug interactions are to be expected with many concurrent agents, particularly the NNRTIs and PIs in patients with HIV/HCV co-infection. Co-administration with strong CYP3A4 inducers (including rifampin) is contraindicated due to potential decrease in serum levels of the anti-HCV agent, and co-administration with statin agents is contraindicated due to increased serum levels of the statin agent. The effectiveness of hormonal contraceptives may be reduced by co-administration with boceprevir or telaprevir.

Since boceprevir, simeprevir, and telaprevir are always co-administered with ribavirin, their use in pregnant women and in men with pregnant partners is contraindicated.

Boceprevir

Boceprevir therapy is initiated after the administration of peginterferon and ribavirin therapy for 4 weeks. The duration of therapy is dependent on the achievement of undetectable virus.

Boceprevir should be taken with food to maximize absorption. It is ~75% protein-bound and has a mean plasma half-life of approximately 3.4 hours. Boceprevir is metabolized by the aldo-keto-reductase and CYP3A4/5 pathways and is an inhibitor of CYP3A4/5 and P-glycoprotein transporter. Co-administration of boceprevir with numerous drugs is contraindicated, including carbamazepine, phenobarbital, phenytoin, rifampin, ergot derivatives, cisapride, lovastatin, simvastatin, St. John’s wort, drospirenone, alfuzosin, sildenafil or tadalafil when used for pulmonary hypertension, pimozide, triazolam, midazolam, and efavirenz.

The most commonly reported adverse effects associated with boceprevir therapy are fatigue, anemia, neutropenia, nausea, headache, and dysgeusia. Rates of anemia are higher in patients taking boceprevir with peginterferon and ribavirin than in those taking peginterferon and ribavirin alone (~ 50% vs 25%, respectively); rates of neutropenia are also higher.

Simeprevir

Simeprevir is administered once daily in combination with peginterferon and ribavirin for a total of 12 weeks in patients with compensated liver disease (including cirrhosis) that are infected with HCV genotype 1.

Simeprevir must be taken with food to maximize absorption. It is extensively bound to plasma proteins (> 99%), metabolized in the liver by CYP3A pathways, and undergoes biliary excretion. Its safety in patients with moderate to severe liver insufficiency has not been established. Mean simeprevir exposures are more than threefold higher in Asian patients compared with Caucasians, leading to potentially higher frequencies of adverse events. Simeprevir is a substrate and mild inhibitor of CYP3A and a substrate and inhibitor of P-gp and OATP1B1/3. Co-administration with moderate or strong inhibitors or inducers of CYP3A may significantly increase or decrease the plasma concentration of simeprevir.

The presence of the NS3 Q80K polymorphism at baseline is associated with reduced efficacy of therapy, and screening is recommended prior to the initiation of therapy. Emergence of amino acid substitutions resulting in decreased drug susceptibility has been documented during therapy and may be associated with reduced responsiveness.

Reported adverse events include photosensitivity reaction and rash (most common within the first 4 weeks of therapy). Since simeprevir contains a sulfa moiety, caution should be used in patients with a history of sulfa allergy.

Telaprevir

Therapy with telaprevir plus peginterferon and ribavirin is administered for at least 12 weeks in treatment-naïve patients with HCV infection. As with boceprevir, the duration of therapy is dependent on the achievement of undetectable virus.

Telaprevir must be taken with food to maximize absorption. It is 59–76% bound to plasma proteins and the effective half-life at steady state is 9–11 hours. Telaprevir is metabolized by the CYP pathways in the liver and is an inhibitor of CYP3A4 and P-glycoprotein. Co-administration of telaprevir with numerous drugs is contraindicated, including rifampin, ergot derivatives, cisapride, lovastatin, simvastatin, alfuzosin, sildenafil or tadalafil when used for pulmonary hypertension, pimozide, St. John’s wort, triazolam, and midazolam. The dosage of telaprevir must be increased when co-administered with efavirenz, due to lowered levels of telaprevir.

The most commonly reported adverse effects associated with telaprevir therapy are rash (30–55%), anemia, fatigue, pruritus, nausea, and anorectal discomfort. Severe rash or Stevens-Johnson syndrome has been reported; in these patients, the drug should be stopped and not restarted. Rates of anemia are higher in patients taking telaprevir with peginterferon and ribavirin than in those taking peginterferon and ribavirin alone (~ 36% vs 17%, respectively). Leukopenia, thrombocytopenia, increased serum bilirubin levels, hyperuricemia, and anorectal burning may also occur.

RIBAVIRIN

Ribavirin is a guanosine analog that is phosphorylated intracellularly by host cell enzymes. Although its mechanism of action has not been fully elucidated, it appears to interfere with the synthesis of guanosine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA-dependent polymerase of certain viruses. Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1.

The absolute oral bioavailability of ribavirin is 45–64%, increases with high-fat meals, and decreases with co-administration of antacids. Plasma protein binding is negligible, volume of distribution is large, and cerebrospinal fluid levels are about 70% of those in plasma. Ribavirin elimination is primarily through the urine; therefore, clearance is decreased in patients with creatinine clearances less than 30 mL/min.

Higher doses of ribavirin (ie, 1000–1200 mg/d, according to weight, rather than 800 mg/d) or a longer duration of therapy or both may be more efficacious in those with a lower likelihood of response to therapy (eg, those with genotype 1 or 4) or in those who have relapsed. This must be balanced with an increased likelihood of toxicity. A dose-dependent hemolytic anemia occurs in 10–20% of patients. Other potential adverse effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Contraindications to ribavirin therapy include anemia, end-stage renal failure, ischemic vascular disease, and pregnancy. Ribavirin is teratogenic and embryotoxic in animals as well as mutagenic in mammalian cells. Patients exposed to the drug should not conceive children for at least 6 months thereafter.

NEW & INVESTIGATIONAL AGENTS

Second-generation NS3/NS4A protease inhibitors (eg, faldaprevir, simeprevir, asunaprevir), nucleoside/nucleotide NS5B polymerase inhibitors (eg, sofosbuvir, see above), and non-nucleoside NS5B polymerase inhibitors (eg, deleobuvir) are currently under clinical investigation. The goal is to identify potent and well tolerated regimens that do not require concurrent administration of interferon or ribavirin; in addition agents are needed with activity against HCV genotypes other than 1 (such as sofosbuvir). Other classes of agents in development include NS5A inhibitors (eg, daclatasvir), p7 and NS4B inhibitors, cyclophilin inhibitors, and antisense oligonucleotides inhibiting miR122 (eg, miravirsen).

image ANTI-INFLUENZA AGENTS

Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation. Influenza A, the only strain that causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) known subtypes based on surface proteins. Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts. Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2. Fifteen subtypes are known to infect birds, providing an extensive reservoir. Although avian influenza subtypes are typically highly species-specific, they have on rare occasions crossed the species barrier to infect humans and cats. Viruses of the H5 and H7 subtypes (eg, H5N1, H7N7, and H7N3) may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. Of particular concern is the avian H5N1 virus, which first caused human infection (including severe disease and death) in 1997 and has become endemic in Southeast Asian poultry since 2003. To date, the spread of H5N1 virus from person to person has been rare, limited, and unsustained. However, the emergence of the 2009 H1N1 influenza virus (previously called “swine flu”) in 2009–2010 caused the first influenza pandemic (ie, global outbreak of disease caused by a new flu virus) in more than 40 years.

OSELTAMIVIR & ZANAMIVIR

The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with release of progeny influenza virus from infected host cells, thus halting the spread of infection within the respiratory tract. These agents competitively and reversibly interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations. Inhibition of viral neuraminidase results in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Unlike amantadine and rimantadine, oseltamivir and zanamivir have activity against both influenza A and influenza B viruses. Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness. Initiation of a 5-day course of therapy within 48 hours after the onset of illness decreases the duration of symptoms, viral shedding and transmission, and the rate of complications such as pneumonia, asthma, hospitalization, and mortality. Once-daily prophylaxis is 70–90% effective in preventing disease after exposure.

Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. The dosage is 75 mg twice daily for 5 days for treatment and 75 mg once daily for prevention. Oral bioavailability is approximately 80%, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma. The half-life of oseltamivir is 6–10 hours, and excretion is by glomerular filtration and tubular secretion. Probenecid reduces renal clearance of oseltamivir by 50%. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function; therefore, dosage should be adjusted in patients with renal insufficiency. Potential adverse effects include nausea, vomiting, and headache. Taking oseltamivir with food does not interfere with absorption and may decrease nausea and vomiting. Fatigue and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare. Neuropsychiatric events (self-injury or delirium) have been reported, particularly in adolescents and adults living in Japan.

Zanamivir is administered directly to the respiratory tract via inhalation. Ten to twenty percent of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours. Five to fifteen percent of the total dose (10 mg twice daily for 5 days for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism. Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. Zanamivir administration is not recommended for patients with underlying airway disease. Both oseltamivir and zanamivir are available in intravenous formulations on a compassionate use basis from the manufacturer.

Although resistance to oseltamivir and zanamivir may emerge during therapy and be transmissible, nearly 100% of strains of H1N1, H3N2, and influenza B virus tested by the Centers for Diseases Control for the 2012-2013 season retained susceptibility to both agents. Oseltamivir resistance, however, has been documented in strains of the novel avian H7N9 virus, in one instance appearing to emerge during treatment.

AMANTADINE & RIMANTADINE

Amantadine (1-aminoadamantane hydrochloride) and its α-methyl derivative, rimantadine, are tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication. They are active against influenza A only. Rimantadine is four to ten times more active than amantadine in vitro. Amantadine is well absorbed and 67% protein-bound. Its plasma half-life is 12–18 hours and varies by creatinine clearance. Rimantadine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal secretion and salivary levels approximate those in the serum, and cerebrospinal fluid levels are 52–96% of those in the serum; nasal mucus concentrations of rimantadine average 50% higher than those in plasma. Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in patients with renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency.

In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70–90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1–2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1–2 days. However, due to high rates of resistance in both H1N1 and H3N2 viruses, these agents are no longer recommended for the prevention or treatment of influenza.

The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness). More serious side effects (eg, marked behavioral changes, delirium, hallucinations, agitation, and seizures) may be due to alteration of dopamine neurotransmission (see Chapter 28); are less frequent with rimantadine than with amantadine; are associated with high plasma concentrations; may occur more frequently in patients with renal insufficiency, seizure disorders, or advanced age; and may increase with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Clinical manifestations of anticholinergic activity tend to be present in acute amantadine overdose. Both agents are teratogenic and embryotoxic in rodents, and birth defects have been reported after exposure during pregnancy.

INVESTIGATIONAL AGENTS

The neuraminidase inhibitor peramivir, a cyclopentane analog, has activity against both influenza A and B viruses. Peramivir received temporary emergency use authorization by FDA for intravenous administration in November 2009 due to the H1N1 pandemic, but is not now approved for use in the USA. Reported side effects include diarrhea, nausea, vomiting, and neutropenia. A long-acting neuraminidase inhibitor, laninamivir octanoate, may retain activity against oseltamivir-resistant virus. DAS181 is a host-directed antiviral agent that acts by removing the virus receptor, sialic acid, from adjacent glycan structures.

image OTHER ANTIVIRAL AGENTS

INTERFERONS

Interferons have been studied for numerous clinical indications. In addition to HBV and HCV infections (see Antihepatitis Agents), intralesional injection of interferon alfa-2b or alfa-n3 may be used for treatment of condylomata acuminata (see Chapter 61).

RIBAVIRIN

In addition to oral administration for HCV infection in combination with interferon alfa (see Antihepatitis Agents), aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness. Aerosolized ribavirin has also been used to treat influenza A and B infections but has not gained widespread use. Systemic absorption is low (< 1%). Aerosolized ribavirin may cause conjunctival or bronchial irritation and the aerosolized drug may precipitate on contact lenses. Ribavirin is teratogenic and embryotoxic. Health care workers and pregnant women should be protected against extended inhalation exposure.

Intravenous ribavirin decreases mortality in patients with Lassa fever and other viral hemorrhagic fevers if started early. High concentrations inhibit West Nile virus in vitro, but clinical data are lacking. Clinical benefit has been reported in cases of severe measles pneumonitis and certain encephalitides, and continuous infusion of ribavirin has decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. At steady state, cerebrospinal fluid levels are about 70% of those in plasma.

PALIVIZUMAB

Palivizumab is a humanized monoclonal antibody directed against an epitope in the A antigen site on the F surface protein of RSV. It is licensed for the prevention of RSV infection in high-risk infants and children, such as premature infants and those with bronchopulmonary dysplasia or congenital heart disease. A placebo-controlled trial using once-monthly intramuscular injections (15 mg/kg) for 5 months beginning at the start of the RSV season demonstrated a 55% reduction in the risk of hospitalization for RSV in treated patients, as well as decreases in the need for supplemental oxygen, the illness severity score, and the need for intensive care. Although resistant strains have been isolated in the laboratory, no resistant clinical isolates have yet been identified. Potential adverse effects include upper respiratory tract infection, fever, rhinitis, rash, diarrhea, vomiting, cough, otitis media, and elevation in serum aminotransferase levels.

Agents under investigation for the treatment or prophylaxis of patients with RSV infection include the RNA interference (RNAi) therapeutic ALN-RSV01and the benzodiazepine RSV604.

IMIQUIMOD

Imiquimod is an immune response modifier shown to be effective in the topical treatment of external genital and perianal warts (ie, condyloma acuminatum; see Chapter 61). The 5% cream is applied three times weekly and washed off 6–10 hours after each application. Recurrences appear to be less common than after ablative therapies. Imiquimod may also be effective against molluscum contagiosum but is not licensed in the United States for this indication. Local skin reactions are the most common adverse effect; these tend to resolve within weeks after therapy. However, pigmentary skin changes may persist. Systemic adverse effects such as fatigue and influenza-like syndrome have occasionally been reported.

PREPARATIONS AVAILABLE

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REFERENCES

Antiviral drugs. Med Lett Drugs Ther 2013;11:19.

Hsu J et al: Antivirals for treatment of influenza. A systematic review and meta-analysis of observational studies. Ann Intern Med 2012;156:512.

Liang TJ, Ghany MG: Current and future therapies for hepatitis C virus infection. N Engl J Med 2013;368:1907.

Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles.AdultandAdolescentGL.pdf.

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission: Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. July 31, 2012. http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf.

Thompson MA et al: Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society - USA panel. JAMA 2012;308(4):387.

RELEVANT WEBSITES

http://www.aidsinfo.nih.gov

http://www.hiv-druginteractions.org

http://www.hivinsite.com

http://www.iasusa.org

CASE STUDY ANSWER

Combination antiviral therapy against both HIV and hepatitis B virus (HBV) is indicated in this patient, given the high viral load and low CD4 cell count. However, the use of methadone and possibly excessive alcohol consumption necessitate caution. Tenofovir and emtricitabine (two nucleoside/nucleotide reverse transcriptase inhibitors) would be excellent choices as components of an initial regimen, since both are active against HIV-1 and HBV, do not interact with methadone, and are available in a once-daily, fixed-dose combination. Efavirenz, a nonnucleoside reverse transcriptase inhibitor, could be added and still maintain a once-daily regimen. There are several other alternatives as well. Prior to initiation of this regimen, renal function should be checked, HBV DNA level should be assessed, and a bone mineral density test should be considered. Pregnancy should be ruled out, and the patient should be counseled that efavirenz should not be taken during pregnancy. Avoidance of alcohol should be recommended. The potential for lowered methadone levels with efavirenz necessitates close monitoring and possibly an increased dose of methadone. Finally, the patient should be made aware that abrupt cessation of these medications may precipitate an acute flare of hepatitis.