Acronyms & Other Names

3TC Lamivudine

AZT Zidovudine (previously azidothymidine)

CMV Cytomegalovirus

CYP Cytochrome P450

d4T Stavudine

ddC Zalcitabine

ddI Didanosine

EBV Epstein-Barr virus

FTC Emtricitabine

HAART Highly active antiretroviral therapy

HBV Hepatitis B virus

HCV Hepatitis C virus

HHV-6 Human herpesvirus-6

HIV Human immunodeficiency virus

HPV Human papillomavirus

HSV Herpes simplex virus

IFN Interferon

NNRTI Nonnucleoside reverse transcriptase inhibitor

NRTI Nucleoside reverse transcriptase inhibitor

PI Protease inhibitor

RSV Respiratory syncytial virus

SVR Sustained antiviral response

VZV Varicella-zoster virus

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 function 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?

Antiviral Agents: Introduction

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 anticancer 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 the identification of 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, and human immunodeficiency virus (HIV). 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 very 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 of time (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.

Viral replication consists of 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) synthesis of late, structural proteins; (7) assembly (maturation) of viral particles; and (8) release from the cell. Antiviral agents can potentially target any of these steps.

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 similar 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. Neither valacyclovir nor famciclovir has been fully evaluated in pediatric patients; thus, neither is indicated for the treatment of varicella infection.

Acyclovir

Acyclovir (Figure 49–2) 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 49–3). 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.

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 genital 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). 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 infection.

Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections (Table 49–1). In immunocompromised patients with VZV infection, intravenous acyclovir reduces the incidence of cutaneous and visceral dissemination.

Topical acyclovir 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 49–3).

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible renal (ie, crystalline nephropathy or interstitial nephritis) or neurologic (eg, tremors, delirium, seizures) toxicity. 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 long-term daily suppression of genital herpes for more than 10 years.

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 zidovudine and acyclovir.

Valacyclovir

Valacyclovir is the L-valyl ester of acyclovir (Figure 49–2). 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.

Approved uses of valacyclovir include treatment of first or recurrent genital herpes, suppression of frequently recurring genital herpes, as a 1-day treatment for orolabial herpes, and as treatment for herpes zoster (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. Valacyclovir has also been shown to be effective in preventing cytomegalovirus (CMV) disease after organ transplantation when compared with placebo.

Valacyclovir is generally well tolerated, although nausea, vomiting, or rash occasionally occur. At high doses, confusion, hallucinations, and seizures have been reported. AIDS patients who received high-dosage valacyclovir chronically (ie, 8 g/d) had an increased incidence of gastrointestinal intolerance as well as thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome; this dose was associated with confusion and hallucinations in transplant patients.

Famciclovir

Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (Figure 49–2). 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, diarrhea, and nausea 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. 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%) is effective for the treatment of recurrent herpes labialis (Table 49–1). When applied within 1 hour of the onset of prodromal symptoms and continued every 2 hours during waking hours for 4 days, median time until healing was shortened by 17 hours compared with placebo. Adverse effects are uncommon, although application site reactions occur in about 1%.

Docosanol

Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion between the 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; application site reactions occur in approximately 2%. 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.

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 49–3). 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.

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 antiretroviral therapy, reactivation of CMV infection after organ transplantation is still clinically prevalent.

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

Ganciclovir

Ganciclovir is an acyclic guanosine analog (Figure 49–2) 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 49–3). 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 may be administered intravenously, orally, or via intraocular implant. The bioavailability of oral ganciclovir is poor. Cerebrospinal fluid concentrations are approximately 50% of those in serum. 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 patients with AIDS. Dual therapy with foscarnet and ganciclovir has been shown to be more effective in delaying progression of retinitis than either drug administered alone (see Foscarnet), although adverse effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis, esophagitis, and pneumonitis (the latter often treated with ganciclovir in combination with intravenous cytomegalovirus immunoglobulin) in immunocompromised patients. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipients. Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis after induction. Although less effective than intravenous ganciclovir, the risk of myelosuppression and of catheter-related complications is diminished. The risk of Kaposi's sarcoma is reduced in AIDS patients receiving long-term ganciclovir, presumably because of in vitro activity against HHV-8.

Ganciclovir may also be administered intraocularly to treat CMV retinitis, either by direct intravitreal injection or by intraocular implant. The implant has been shown to delay progression of retinitis to a greater degree than systemic ganciclovir therapy. Surgical replacement is required at intervals of 5–8 months. Concurrent therapy with a systemic anti-CMV agent is recommended to prevent other sites of end-organ CMV disease.

Resistance to ganciclovir increases with duration of usage. 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, as is the substitution of alternative therapies and concomitant reduction in immunosuppressive therapies, if possible. The addition of CMV hyperimmune globulin may also be considered.

The most common adverse effect of systemic ganciclovir treatment, particularly after intravenous administration, is myelosuppression. 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. 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 (Figure 49–2). After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases.

Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir; no other metabolites have been detected. The absolute bioavailability of oral valganciclovir is 60%; it is recommended that the drug be taken with food. The AUC_0–24h 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 indicated for the treatment of CMV retinitis in patients with AIDS and for the prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant patients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir.

Foscarnet

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog (Figure 49–2) that inhibits viral DNA polymerase, RNA polymerase, and HIVreverse 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, and HIV-1.

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 3–6.8 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 CMV retinitis, CMV colitis, CMV esophagitis, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection. 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 to 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. Penile 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 toxicities include headache, hallucinations, and seizures; seizures may be increased with concurrent use of imipenem. Foscarnet caused chromosomal damage in preclinical studies.

Cidofovir

Cidofovir (Figure 49–2) is an acyclic 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 49–3); 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 ~ 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 has been shown to reduce the serum levels of cidofovir by approximately 75%.

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus 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. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, 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 caused mammary adenocarcinomas in rats.

Investigational Agents

The benzimidazole riboside maribavir is under active clinical investigation as an anti-CMV agent. Unlike currently available agents that inhibit CMV DNA polymerase, this agent inhibits viral DNA assembly as well as egress of the viral capsid from the nucleus of infected cells.

Antiretroviral Agents

Substantial advances have been made in antiretroviral therapy since the introduction of the first agent, zidovudine, in 1987 (Table 49–3). Greater knowledge of viral dynamics through the use of viral load and resistance testing has made clear that combination therapy with maximally potent agents will reduce viral replication to the lowest possible level and decrease the likelihood of emergence of resistance. Thus, administration of highly active antiretroviral therapy (HAART), typically comprising a combination of three to four antiretroviral agents, has become the standard of care. Viral susceptibility to specific agents varies among patients and may change with time, owing to development of resistance. 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.

The retroviral genomic RNA serves as the template for synthesis of a double-stranded DNA copy, the provirus (Figure 49–4). Synthesis of the provirus is mediated by a virus-encoded RNA-dependent DNA polymerase, or "reverse transcriptase." The provirus is translocated to the nucleus and is integrated into host DNA. Transcription of this integrated DNA is regulated primarily by cellular transcriptional machinery.

Six classes of antiretroviral agents are currently available for use: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 receptor antagonists, and integrase inhibitors. As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety profile or inferior antiviral potency. It is important to recognize that the high rate of mutation of HIV-1 per replication cycle results in a great potential for genotypic variation. Genotypic resistance has been reported for each of the antiretroviral agents currently in use. Treatment that slows or stops replication is critical in reducing the number of cumulative mutations, as is the use of combinations of agents with differing susceptibility patterns.

Nucleoside & Nucleotide Reverse Transcriptase Inhibitors

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–4). Each requires intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1.

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; however, although this mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R 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 analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also, recent evidence suggests an increased risk of myocardial infarction in patients receiving abacavir or didanosine; this bears further investigation.

Abacavir

Abacavir is a guanosine analog (Figure 49–2) that is well absorbed following oral administration (83%) and is unaffected by food. The serum half-life is 1.5 hours; the intracellular half-life of 3.3 hours necessitates twice-daily dosing. The drug undergoes hepatic glucuronidation and carboxylation. Cerebrospinal fluid levels are approximately one third those of plasma.

Abacavir is often co-administered with lamivudine, and a combination formulation is available.

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 3–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, malaise, nausea, vomiting, diarrhea, and anorexia. Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels 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. Testing for the HLA-B*5701 allele before initiation of abacavir therapy is recommended to identify patients with an increased risk for an abacavir-associated hypersensitivity reaction.

Other potential adverse events are rash, fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis (rare). Abacavir should be used cautiously in patients with existing cardiac risk factors due to a possible increased risk of myocardial events.

Didanosine

Didanosine (ddI) is a synthetic analog of deoxyadenosine (Figure 49–2). 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, alcoholism, hypertriglyceridemia) are relative contraindications, and other drugs with the potential to cause pancreatitis, including zalcitabine, stavudine, and hydroxyurea, should be avoided (Table 49–3). Other reported adverse effects include peripheral distal sensory neuropathy, diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations. As with abacavir, didanosine should be used cautiously in patients with cardiac risk factors.

The buffer in didanosine tablets and powder 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).

Emtricitabine

Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (> 24 hours), allowing for once-daily dosing (Figure 49–2). 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 in vitro 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.

Like lamivudine, the M184V/I mutation is most frequently associated with emtricitabine use and may emerge rapidly in patients receiving HAART 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, diarrhea, nausea, and asthenia. In addition, hyperpigmentation of the palms and/or soles may be observed (~ 3%), particularly in blacks (up to 13%). No drug-drug interactions of note have been reported to date.

Lamivudine

Lamivudine (3TC) is a cytosine analog (Figure 49–2) 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. Activity against HBV is described below.

Oral bioavailability exceeds 80% and is not food-dependent. In children, the mean 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 lamivudine is eliminated unchanged in the urine (Table 49–3).

Lamivudine therapy rapidly selects for the M184V mutation in regimens that are not fully suppressive.

Potential adverse effects are headache, dizziness, insomnia, fatigue, and gastrointestinal discomfort, although these are typically mild. 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. Short-term safety of lamivudine has been demonstrated for both mother and infant.

Stavudine

The thymidine analog stavudine (d4T) (Figure 49–2) 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 (Table 49–3).

The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy. The incidence of neuropathy may be increased when stavudine is administered with other neuropathy-inducing drugs such as didanosine and zalcitabine, or in patients with advanced immunosuppression. Symptoms typically resolve completely 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 lipoatrophy, 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. There is no evidence of human teratogenicity in those taking stavudine.

Tenofovir

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49–2). 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 disopoxilfumarate 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.

Tenofovir is often co-administered with emtricitabine, and a combination formulation is available.

The primary mutation associated with resistance to tenofovir is K65R.

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Other potential adverse effects include headache and asthenia. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi's syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricitabine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir.

Tenofovir is associated with decreased fetal growth and reduction in fetal bone porosity in monkeys. There is significant placental passage in humans.

Zalcitabine

Zalcitabine (ddC) is a cytosine analog with high oral bioavailability (87%) and a serum half-life of 1–2 hours. Intracellular half-life of 2.6 hours necessitates thrice-daily dosing, which limits its usefulness (Figure 49–2). Plasma levels decrease by 25–39% when the drug is administered with food or antacids. The drug is excreted renally. Cerebrospinal fluid concentrations are approximately 20% of those in the plasma.

Although a variety of mutations associated with in vitro resistance to zalcitabine have been described, phenotypic resistance appears to be rare.

Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10–20% of patients but appears to be slowly reversible if treatment is stopped promptly. The potential for causing peripheral neuropathy constitutes a relative contraindication to use with other drugs that may cause neuropathy, including stavudine, didanosine, and isoniazid. Decreased creatinine clearance or concurrent use of potential nephrotoxins (eg, amphotericin B, foscarnet, and aminoglycosides) may increase the risk of zalcitabine neuropathy, as does more advanced immunosuppression. The other major reported toxicity consists of oral and esophageal ulcerations. Pancreatitis occurs less frequently than with didanosine administration, but co-administration of other drugs that cause pancreatitis may increase the frequency of this adverse effect. Headache, nausea, rash, and arthralgias may occur but tend to be mild or resolve during therapy. Zalcitabine causes thymic lymphomas in rodents, as well as hydrocephalus at high doses; clinical relevance is unclear. The AUC of zalcitabine increases when co-administered with probenecid or cimetidine, and bioavailability decreases with concurrent antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy.

Zidovudine

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–2) 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 1.1 hours, 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 often co-administered with lamivudine, and a combination formulation is available.

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. In pregnancy (Table 49–5), a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

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 exposure 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. Extremity fat loss may be more common with zidovudine than with other agents. Less common toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy. High doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date. Short-term safety has been demonstrated for both mother and infant.

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

The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–4), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase. 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. In addition, they lack in vitro activity against HIV-2.

NNRTI resistance occurs rapidly with monotherapy and can be due to a single mutation. The K103N and Y181C mutations confer resistance across the entire class of NNRTIs, with the exception of the newest agent etravirine; other mutations (eg, L100I, Y188C, G190A) may 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 HAART 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.

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 to inactive metabolites 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.

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, 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, is usually mild to moderate in severity, and typically resolves despite continuation. 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 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).

Etravirine

Etravirine has in vitro activity against a wide variety of wild-type and NNRTI-resistant HIV-1, and it was approved in the USA for use in treatment-experienced patients with HIV infection in early 2008. Etravirine may be effective against strains of HIV that have developed resistance to first-generation NNRTIs, depending on the number of mutations present. 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.

The most common symptomatic 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.

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. 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. Elevated hepatic enzyme levels may occur in up to 20% of patients and are more frequent in those with higher pre-therapy 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 may rarely occur, typically within the first 18 weeks of therapy. Other adverse effects associated with nevirapine therapy are 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 (Table 49–4). Drugs that induce the CYP3A system, such as tipranavir, 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.

Protease Inhibitors

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. 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 49–4). Protease inhibitors are active against both HIV-1 and HIV-2; unlike the NRTIs, however, they 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 PI-resistant HIV-1.

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 in patients receiving antiretroviral therapy. These abnormalities may be particularly associated with the use of PIs, although the recently licensed atazanavir appears to be an exception (see below). Concurrent increases in triglyceride and LDL levels, along with hyperglycemia and insulin resistance, have also been noted. The cause is not yet known.

Whether PI agents are associated with bone loss and osteoporosis after long-term use is controversial and under active investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B.

All 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). It is noteworthy that the potent CYP3A4 inhibitory properties of ritonavir have been 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 is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. 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.

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 (7–8%) 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. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemia, fat redistribution, or the metabolic syndrome. Atazanavir may be associated with electrocardiographic PR-interval prolongation, which is usually inconsequential but may be exacerbated by other causative agents such as calcium channel blockers. Also, a possible concentration-dependent increase in the QT_c interval may occur in patients receiving atazanavir in dosages higher than 400 mg/d or in conjunction with a CYP3A4 inhibitor such as clarithromycin.

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 76% when combined with omeprazole; thus, the combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as indinavir and irinotecan, is contraindicated because of enhanced toxicity. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.

Darunavir

Darunavir is licensed as a PI to be co-administered with ritonavir in treatment-experienced patients with resistance to other PIs.

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 should be used cautiously in patients with sulfonamide allergy.

Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Table 49–3). 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.

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 by CYP3A4 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, and rash. Up to 3% of patients may experience rashes (including Stevens-Johnson syndrome) 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 is contraindicated in patients with a history of sulfa allergy because it is itself a sulfonamide. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir and increased 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 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. In rats, high doses of indinavir are associated with development of thyroid adenomas.

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

Lopinavir should be taken with food to enhance bioavailability. The drug is highly protein bound (98–99%), and its half-life is 5–6 hours. Lopinavir is extensively metabolized by CYP3A, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.

The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Elevations in serum cholesterol and triglycerides are common. 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 increased 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 contains alcohol, concurrent disulfiram and metronidazole are contraindicated. There is no evidence of human teratogenicity of lopinavir/ritonavir; short-term safety in pregnant women has been demonstrated for mother and infant.

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 indinavir levels. Nelfinavir has a favorable safety and pharmacokinetic profile for pregnant women compared with that of other PIs (Table 49–5); there is no evidence of human teratogenicity.

Ritonavir

Ritonavir 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.

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, hypertriglyceridemia, hypercholesterolemia, 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. Liver adenomas and carcinomas have been induced in male mice receiving ritonavir; no similar effects have been observed to date in humans.

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 potency against resistant virus. Therapeutic levels of digoxin and theophylline should be monitored when co-administered with ritonavir owing to likely increase in their concentrations. There is limited experience with full-dose ritonavir during pregnancy to date; however, low-dose ritonavir as a "booster" has appeared to be well tolerated in mother and infant.

Saquinavir

In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir is poorly bioavailable (only about 4% after food). However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects.

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.

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 (Table 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 function tests should be monitored if saquinavir is co-administered with delavirdine or rifampin. There is no evidence of human teratogenicity from saquinavir; there is short-term safety data for both mother and infant.

Tipranavir

Tipranavir is a newer PI for treating patients with resistance to other PI agents. Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system. Tipranavir must be taken in combination with ritonavir to achieve effective serum levels. It 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 from tipranavir are diarrhea, nausea, vomiting, abdominal pain, and rash (urticarial or maculopapular); the latter may be accompanied by systemic symptoms or desquamation. Liver toxicity, including life-threatening hepatic decompensation, has been observed and is more common in patients with chronic HBV or HCV. Tipranavir should be discontinued in patients with increased serum transaminase levels to more than 10 times the upper limit of normal. Because of an increased risk for intracranial hemorrhage in patients receiving tipranavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression; elevations in total cholesterol, triglycerides, and 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 forms 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 coreceptors CCR5 or CXCR4. Coreceptor 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 entry into the cell (Figure 49–4). 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 has no activity against HIV-2. Enfuvirtide must be administered by subcutaneous injection. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours.

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

The most common adverse effects associated with enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions may rarely occur, are of varying severity, and may recur on rechallenge. Eosinophilia has also been noted. In one prospective clinical trial, an increased rate of bacterial pneumonia was noted in patients receiving enfuvirtide. No interactions have been identified that would require the alteration of the dosage of other antiretroviral drugs.

Maraviroc

Maraviroc binds specifically and selectively to CCR5, one of two coreceptors necessary for entrance of HIV into CD4+ cells, thus blocking entry of CCR5-tropic HIV into these cells. Maraviroc is to be used in adults with CCR5-tropic (also known as R5) HIV-1 infection that are experiencing virologic failure due to resistance to other antiretroviral agents. Studies have shown that 52–60% of patients in whom at least two antiviral regimens had failed were infected with R5 HIV. Since maraviroc is active against HIV that uses the CCR5 coreceptor exclusively, and not against HIV strains with CXCR4, dual, or mixed tropism, tropism testing should be performed before initiating treatment with maraviroc.

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. No dose adjustment is necessary for renal or hepatic impairment. Maraviroc has been shown to have 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, virologic failure of regimens containing maraviroc may potentially be caused not only by resistance but also by emergence of non–CCR5-tropic virus (eg, CXCR4-tropic virus) or by changes in viral tropism, owing to the development of multiple mutations throughout gp160.

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 other strong CYP3A inhibitors (eg, delavirdine, ketoconazole, itraconazole, or clarithromycin) and must be increased if co-administered with CYP3A inducers (eg, efavirenz, etravirine, rifampin, carbamazepine, phenytoin, or St. John's wort).

Maraviroc has been well tolerated in studies to date; potential adverse effects include cough, upper respiratory tract infections, muscle and joint pain, diarrhea, sleep disturbance, and increases in hepatic transaminase levels. Clinical trials of another CCR5 inhibitor, aplaviroc, were discontinued because of serious hepatotoxicity; therefore, caution is advised when administering maraviroc to those with preexisting liver dysfunction (eg, those with HBV or HCV co-infection). There has been some concern that blockade of CCR5—a human protein rather than a viral enzyme—may result in decreased immune surveillance, with a subsequent increased risk of development of malignancies (eg, lymphomas) or infection. To date, however, there has been no evidence of an increased risk of either malignancy or infection in patients receiving maraviroc.

Integrase Inhibitors

Raltegravir

Raltegravir is a pyrimidinone analog that 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 the provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells. It is licensed for use in treatment-experienced adult patients infected with strains of HIV-1 resistant to multiple other agents.

Absolute bioavailability of raltegravir has not been established but does not appear to be food-dependent. The drug is metabolized by glucuronidation and does not interact with the cytochrome P450 system; therefore, it is expected to have fewer drug-drug interactions than many of the other available antiretroviral agents. However, there is potential for drug-drug interactions with agents that are strong inducers (eg, rifampin, efavirenz, etravirine, tipranavir/ritonavir) or inhibitors (atazanavir, tipranavir) of UGT1A1; the clinical relevance of these interactions is under investigation. It is recommended, however, that rifampin not be co-administered with raltegravir owing to a decrease in raltegravir levels. Since polyvalent cations (eg, magnesium, calcium, and iron) may bind integrase inhibitors and interfere with their activity against integrase, antacids should be used cautiously and taken separately from raltegravir.

Although virologic failures have 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 diarrhea, nausea, dizziness, and headache. Laboratory abnormalities include increases in creatine phosphokinase, but there is minimal effect on serum lipids.

Investigational Antiretroviral Agents

New therapies are continually being sought that exploit new viral targets, have activity against resistant viral strains, have a lower incidence of adverse effects, and offer convenient dosing. New agents of existing classes that are currently in advanced stages of clinical development include the NRTI agent elvucitabine, the NNRTI agents TMC-278 and IDX899, the PI agent bracanavir, entry inhibitors such as the CCR5 receptor antagonists vicriviroc and PRO 140, and integrase inhibitors such as elvitegravir. In addition, new drug classes such as maturation inhibitors (bevirimat) and the CD4 receptor inhibitor TNX-355 are under investigation.

Antihepatitis Agents

Several agents effective against HBV and HCV are now available (Table 49–6). Current treatment is suppressive rather than curative and the high prevalence of these infections worldwide, with their concomitant morbidity and mortality, reflect a critical need for improved therapeutics.

Interferon Alfa

Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions (see Chapter 55). 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 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 subcutaneously or intramuscularly, whereas interferon alfacon-1 is administered subcutaneously. Elimination half-life is 2–5 hours for interferon alfa-2a and -2b, depending on the route of administration. The half-life of interferon alfacon-1 in patients with chronic HCV ranges from 6 to 10 hours. 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.

A recent meta-analysis of clinical trials in patients with chronic HBV infection showed that treatment with interferon alfa is associated with a higher incidence of hepatitis e antigen (HBeAg) seroconversion and undetectable HBV DNA levels than placebo. The addition of the pegylated moiety results in further increases in the proportion of patients with HBeAg seroconversion (~ 30%) and a decline by approximately 4 log copies/mL (99.99%) in HBV DNA after 1 year.

The use of pegylated interferon alfa-2a and pegylated interferon alfa-2b, as a result of slower clearance resulting in substantially longer terminal half-lives and steadier drug concentrations, allows for less frequent dosing in patients with chronic HCV infection. Renal elimination accounts for about 30% of clearance, and clearance is approximately halved in subjects with impaired renal function; dosage must therefore be adjusted.

Typical adverse effects of interferon alfa include a flu-like syndrome (ie, headache, fevers, chills, myalgias, and malaise) that occurs within 6 hours after dosing 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 levels and increased 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 to sustain suppression of HBV replication, resulting in slowing of progression of hepatic disease (with retardation of hepatic fibrosis and even reversal of cirrhosis), prevention of complications (ie, cirrhosis, hepatic failure, and hepatocellular carcinoma), and reduction of the need for liver transplantation. The goals of antiviral therapy in patients with chronic HBV infection therefore are suppression of HBV DNA to undetectable levels, seroconversion from 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 the currently licensed therapies achieve these goals. However, because current therapies suppress HBV replication rather than eradicate the virus, initial responses may not be durable. The covalently closed circular (ccc) 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 2008 seven drugs were approved for treatment of chronic HBV infection in the USA: 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, owing to once-weekly rather than daily or thrice weekly dosing. In general, nucleoside/nucleotide analog therapies have better tolerability and incur an ultimately higher response rate than the interferons (though less rapid); however, response may be less sustained after discontinuation of the nucleoside/nucleotide therapies, and emergence of resistance may be problematic. The nucleotides are effective in nucleoside resistance and vice versa. In addition, oral agents may be used in patients with decompensated liver disease, and the therapy is chronic rather than finite as with interferon therapy.

Several anti-HBV agents have anti-HIV activity as well, including lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treatment. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents.

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 (Figure 49–2). It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase to result in chain termination after incorporation into the viral DNA. Adefovir is active in vitro against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.

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. Although emergence of resistance is rare during the first year of therapy, it approaches 30% at the end of 4 years. Naturally occurring (ie, primary) adefovir-resistant rt233 HBV mutants have recently been described. There is no cross-resistance between adefovir and lamivudine.

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). 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. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d).

Adefovir is embryotoxic in rats at high doses and is genotoxic in preclinical studies.

Entecavir

Entecavir is an orally administered guanosine nucleoside analog (Figure 49–2) 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. It is excreted by the kidney, undergoing both glomerular filtration and net tubular secretion.

Comparison with lamivudine in patients with chronic HBV infection demonstrated similar rates of HBeAg seroconversion but significantly higher rates of HBV DNA viral suppression with entecavir, normalization of serum alanine aminotransferase levels, and histologic improvement in the liver. Entecavir appears to have a higher barrier to the emergence of resistance than lamivudine. Although selection of resistant isolates with the S202G mutation has been documented during therapy, clinical resistance is rare (< 1% at 4 years). Also, decreased susceptibility to entecavir may occur in association with lamivudine resistance. Entecavir is well tolerated. The most frequently reported adverse events are headache, fatigue, dizziness, and nausea. 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.

Lamivudine inhibits HBV DNA polymerase and HIVreverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA, resulting in chain termination. Lamivudine achieves 3–4 log decreases in viral replication in most patients and suppression of HBV DNA to undetectable levels in about 44% of patients. Seroconversion of HBeAg from positive to negative occurs in about 17% of patients and is durable at 3 years in about 70% of responders. Continuation of treatment for 4–8 months after seroconversion may improve the durability of response. Response in HBeAg-negative patients is initially high but less durable.

Although lamivudine results in rapid and potent virus suppression, chronic therapy may ultimately be limited by the emergence of lamivudine-resistant HBV isolates (eg, L180M or M204I/V), estimated at 15–30% 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 maintains activity against lamivudine-resistant strains of HBV.

In the doses used for HBV infection, lamivudine has an excellent safety profile. Headache, nausea, and dizziness are rare. Co-infection with HIV may increase the risk of pancreatitis. No evidence of mitochondrial toxicity has been reported.

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.

In a comparative trial against lamivudine in patients with chronic HBV infection, significantly more patients receiving telbivudine achieved the combined end point of suppression of HBV DNA to less than 5 log copies/mL plus loss of serum HBeAg. The mean reduction in HBV DNA from baseline, the proportion with ALT normalization, and HBeAg seroconversion all were greater in those receiving telbivudine. Liver biopsies performed 1 year later showed less scarring. However, emergence of resistance, typically due to the M204I mutation, may occur in up to 22% with durations of therapy exceeding 1 year, and may result in virologic rebound.

Adverse effects in clinical trials were mild, including fatigue, headache, abdominal pain, upper respiratory infection, increased creatine phosphokinase levels, and nausea and vomiting. A potential association with peripheral neuropathy is under evaluation. 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 recently gained licensure for the treatment of patients with chronic HBV infection. The characteristics of tenofovir are described earlier in this chapter. Tenofovir maintains activity against lamivudine- and entecavir-resistant isolates but has reduced activity against adefovir-resistant strains. Although similar in structure to adefovir dipivoxil, recent comparative trials showed a significantly higher rate of complete response, defined as serum HBV DNA levels less than 400 copies/mL, as well as of histologic improvement, in patients with chronic HBV infection receiving tenofovir than in those receiving adefovir dipivoxil. The emergence of resistance appears to be substantially less frequent during therapy with tenofovir than with adefovir.

Investigational Agents

Compounds in clinical development for the treatment of patients with HBV infection include the nucleoside analogs emtricitabine, clevudine, valtorcitabine, pradefovir, and alamifovir, as well as the immunologic modulator thymosin alpha-1, agents that facilitate uptake by the liver using conjugation to ligands, and RNA interference compounds.

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 for 6 months after completion of therapy. SVR is associated with improvement in liver histology and 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 (Table 49–6), 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, however, the current standard of 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. Factors associated with a favorable response to therapy include HCV genotype 2 or 3, absence of cirrhosis on liver biopsy, and low pretreatment HCV RNA levels.

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 uncorrected 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.

Investigational Agents

Investigational agents for the treatment of HCV infection are multiple and include inhibitors of the HCV RNA polymerase such as valopicitabine, PIs such as telaprevir, the ribavirin analogs merimepodib and viramidine, an anti-aminophospholipid antibody, a caspase inhibitor, and the immunomodulator thymosin alpha-1.

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 people worldwide 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 H5N1 virus, which first caused human infection (including severe disease and death) in 1997 and has become endemic in Southeast Asia poultry since 2003. It is feared that the virus will become transmissible from person to person rather than solely from poultry to human, thus initiating the potential for a global outbreak (ie, pandemic).

Although antiviral drugs available for influenza have activity against influenza A, many or most of the circulating strains of avian H5N1, as well as the H1 and H3 strains causing seasonal influenza in the United States, are resistant to the adamantane agents. Resistance to oseltamivir has also increased dramatically.

Amantadine & Rimantadine

Amantadine (1-aminoadamantane hydrochloride) and its -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. Rimantidine 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 rimantidine 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.

The primary target for both agents is the M2 protein within the viral membrane, incurring both influenza A specificity and a mutation-prone site that results in the rapid development of resistance in up to 50% of treated individuals. Resistant isolates with single-point mutations are genetically stable, retain pathogenicity, can be transmitted to close contacts, and may be shed chronically by immunocompromised patients. The marked increase in the prevalence of resistance to both agents in clinical isolates over the last decade, in influenza A H1N1 as well as H3N2, has limited the usefulness of these agents for either the treatment or the prevention of influenza. Cross-resistance to zanamivir and oseltamivir does not occur.

The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness); these are dose-related. Central nervous system toxicity may be due to alteration of dopamine neurotransmission (see Chapter 28), is less frequent with rimantadine than with amantadine, tends to diminish after the first week of use, and may increase with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Serious neurotoxic reactions, occasionally fatal, may occur in association with high amantadine plasma concentrations and are more likely in the elderly or those with renal insufficiency. Clinical manifestations of anticholinergic activity tend to be present in acute amantadine overdose. Both agents are teratogenic in rodents, and birth defects have been reported after exposure during pregnancy.

Oseltamivir & Zanamivir

The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with release of progeny influenza virus from infected to new 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 neuraminidase activity at low nanomolar concentrations and destroy the receptors recognized by viral hemagglutinin on cells, newly released virions, and respiratory tract mucins. 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. When a 5-day course of therapy is initiated within 36–48 hours after the onset of symptoms, the duration of illness is decreased by 1–2 days compared with those on placebo, severity is diminished, and the incidence of secondary complications in children and adults decreases. Once-daily prophylaxis is 70–90% effective in preventing disease after exposure. Oseltamivir is FDA-approved for patients 1 year and older, whereas zanamivir is approved in patients 7 years or older.

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; dosage must be modified in patients with renal insufficiency. 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 in the urine. 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 such patients. Potential adverse effects include nausea, vomiting, and abdominal pain, which occur in 5–10% of patients early in therapy but tend to resolve spontaneously. Taking oseltamivir with food does not interfere with absorption and may decrease nausea and vomiting. Headache, fatigue, and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare.

Zanamivir is delivered 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.

In adults, resistance to oseltamivir may be associated with point mutations in the viral hemagglutinin or neuraminidasegenes. Rates of resistance to oseltamivir among H1N1 viruses have risen abruptly and dramatically worldwide, reaching 97.4% in tested strains in the USA from 2008 to 2009. No tested H1N1 viruses were resistant to zanamivir, and all A (H3N2) and influenza B viruses were susceptible to both oseltamivir and zanmivir.

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 hepatitis C infection in combination with interferon alfa, 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 is generally well tolerated but may cause conjunctival or bronchial irritation. Health care workers should be protected against extended inhalation exposure. The aerosolized drug may precipitate on contact lenses.

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, illness severity score, and 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.

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 is also effective against actinic keratoses, and possibly, molluscum contagiosum. Local skin reactions are the most common side 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

References

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