ANTIVIRAL ANTIFUNGAL AGENTS, ANTITUBERCULAR AGENTS, ANTIMALARIAL, ANTIPROTOZOAL, ANTIHELMINTIC AGENTS
Antiviral agents
3TC: Lamivudine
ara-A: Vidarabine
AZT: Zidovudine (previously azidothymidine)
CMV: Cytomegalovirus
CYP: Cytochrome P450
d4T: Stavudine
ddC: Zalcitabine
ddl: Didanosine
EBV: Epstein-Barr virus
HAART: Highly active antiretroviral therapy
HBV: Hepatitis B virus
HCV: Hepatitis C virus
HHV-6, -8: Human herpesvirus-6, -8
HIV: Human immunodeficiency virus
HSV-1, -2: Herpes simplex virus-1, -2
IDU, IDUR: Idoxuridine
IFN: Interferon
NNRTI: Nonnucleoside reverse transcriptase inhibitor
NRTI: Nucleoside reverse transcriptase inhibitor
PI: Protease inhibitor
RSV: Respiratory syncytial virus
VZV: Varicella-zoster virus
Antiviral Agents: Introduction
Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell.
Consequently, 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 produce toxicity. The search for chemicals that inhibit virus-specific functions is currently one of the most active areas of pharmacologic investigation. Research 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 firstgeneration antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. Recent research has focused on the identification of agents with greater selectivity, in vivo stability, and lack of toxicity. Selective antiretroviral agents that inhibit a critical HIV-1 enzyme such as 3TC: Lamivudine
ara-A: Vidarabine
AZT: Zidovudine (previously azidothymidine)
CMV: Cytomegalovirus
CYP: Cytochrome P450
d4T: Stavudine
ddC: Zalcitabine
ddl: Didanosine
EBV: Epstein-Barr virus
HAART: Highly active antiretroviral therapy
HBV: Hepatitis B virus
HCV: Hepatitis C virus
HHV-6, -8: Human herpesvirus-6, -8
HIV: Human immunodeficiency virus
HSV-1, -2: Herpes simplex virus-1, -2
IDU, IDUR: Idoxuridine
IFN: Interferon
NNRTI: Nonnucleoside reverse transcriptase inhibitor
NRTI: Nucleoside reverse transcriptase inhibitor
PI: Protease inhibitor
RSV: Respiratory syncytial virus
VZV: Varicella-zoster virus
Agents to Treat Herpes Simplex Virus (HSV) & Varicella Zoster Virus (VZV) Infections Three oral agents 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, licensed first, has been the most extensively studied; in addition, it is the only anti-HSV agent available for intravenous use in the
Acyclovir
Acyclovir (Figure 49–2) is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV. In vitro activity against Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6 is present but comparatively 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 the host’s cellular enzymes
(Figure 49–3). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competitive inhibition 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.
Pharmacokinetics
The bioavailability of oral acyclovir is 15–20% and is unaffected by food. Peak serum concentrations of approximately 1 g/mL after a 200 mg oral dose and 1.5–2 g/mL after an 800 mg dose are reached 1.5–2 hours after dosing. Peak serum concentrations are 10 g/mL and 20 g/mL after intravenous infusions (over 1 hour) of 5 mg/kg and 10 mg/kg, respectively. Topical formulations produce local concentrations that may exceed 10 g/mL in herpetic lesions, but systemic concentrations are undetectable.
Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is approximately 3 hours in patients with normal renal function and 20 hours in patients with anuria.
Acyclovir is readily cleared by hemodialysis but not by peritoneal dialysis. Acyclovir diffuses into most tissues and body fluids to produce concentrations that are 50–100% of those in serum. Cerebrospinal fluid concentrations are 50% of serum values.
Clinical Uses
Oral acyclovir has multiple uses (Table 49–1). In primary genital herpes, oral acyclovir shortens by approximately 5 days the duration of symptoms, the time of viral shedding, and the time to resolution of lesions; in recurrent genital herpes, the time course is shortened by 1–2 days.
Treatment of primary genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term chronic suppression of genital herpes with oral acyclovir decreases the frequency both of symptomatic recurrences and of asymptomatic viral shedding in patients with frequent recurrences, thus decreasing sexual transmission. However, outbreaks may resume upon discontinuation of suppressive acyclovir. In recurrent herpes labialis, oral acyclovir reduces the mean duration of pain but not the time to healing. Oral acyclovir decreases the total number of lesions and duration of varicella (if begun within 24 hours after the onset of rash) and cutaneous zoster (if begun within 72 hours). However, because VZV is less susceptible to acyclovir than HSV, higher doses are required (Table 49–1). A meta-analysis suggested that acyclovir was superior to placebo in reducing the duration of “zoster-associated pain,” a continuous variable combining acute and chronic pain. When given prophylactically to patients undergoing organ transplantation, oral acyclovir (200 mg every 8 hours or 800 mg every 12 hours) or intravenous acyclovir (5 mg/kg every 8 hours) prevents reactivation of HSV infection. The benefit of acyclovir for prevention of CMV infections in transplant patients is controversial.
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 zoster, intravenous acyclovir reduces the incidence of cutaneous and visceral dissemination.
Topical acyclovir is much less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrences.
Resistance
Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase. Infections that are clinically resistant to acyclovir 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.
Adverse Reactions
Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible tremors, delirium, seizures); however, these renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects.
High doses of acyclovir cause testicular atrophy in rats, but there has beeo evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir.
Valacyclovir
Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration, resulting in serum levels three to five times greater than those achieved with oral acyclovir and approximating those resulting from intravenous acyclovir administration. Oral bioavailability is about 48%. As with acyclovir, uses of valacyclovir include treatment of first atacks or recurrences of genital herpes, suppression of frequently recurrent genital herpes, treatment of herpes zoster infection, and, recently, as a 1-day treatment for orolabial herpes (Table 49–1).
Valacyclovir has also been shown to be effective in preventing cytomegalovirus disease after organ transplantation when compared with placebo. In general, comparative studies have shown similar or slightly improved efficacy of valacyclovir versus acyclovir for all indications; furthermore, valacyclovir therapy was associated with a shorter duration of zoster-associated pain than acyclovir in one study, as well as a lower frequency of postherpetic neuralgia. Once-daily dosing of valacyclovir (500 mg) as chronic suppression in persons with recurrent genital herpes has recently been shown to markedly decrease the risk of sexual transmission. Valacyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. AIDS patients receiving high-dosage valacyclovir chronically (ie, 8 g/d) had an increased incidence of gastrointestinal intolerance as well as thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolyticuremic syndrome. In transplant patients receiving valacyclovir (8 g/d), non-dose-limiting confusion and hallucinations were the most frequent side effects.
Famciclovir
Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (Figure 49–2). After oral administration, famciclovir is rapidly converted by first-pass metabolism to penciclovir, which shares many features with acyclovir. It is active in vitro against HSV-1, HSV- 2, VZV, EBV, and HBV. 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, 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 and has a more prolonged intracellular effect in experimental systems. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient and are cross-resistant to acyclovir and famciclovir.
Pharmacokinetics
The bioavailability of penciclovir from orally administered famciclovir is 70%; less than 20% is plasma protein-bound. A peak serum concentration of 2 g/mL is achieved following a 250 mg oral dose. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in VZV-infected cells in vitro. Penciclovir is excreted primarily in the urine.
Clinical Uses
Oral famciclovir is effective for the treatment of first and recurrent genital herpes attacks and for chronic daily suppression (Table 49–1). It is also used to treat acute herpes zoster (shingles). In controlled trials in immunocompetent patients with zoster, famciclovir was similar to acyclovir in rates of cutaneous healing but was associated with a shorter duration of postherpetic neuralgia.
Comparison of famciclovir to valacyclovir for treatment of herpes zoster in immunocompetent patients showed similar rates of cutaneous healing and pain resolution. However, neither drug decreased the incidence of postherpetic neuralgia.
Adverse Reactions
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) had no changes in sperm morphology or motility. The incidence of mammary adenocarcinoma was also increased in female rats receiving famciclovir for 2 years.
Penciclovir
The guanosine analog penciclovir is the active metabolite of famciclovir (see above). Topical application of 1% penciclovir cream is effective for the treatment of recurrent herpes labialis in immunocompetent adults.
When therapy was initiated within 1 hour after the onset of signs or symptoms and continued every 2 hours during waking hours for 4 days, treatment with topical penciclovir resulted in a shortening of the mean duration of lesions, lesion pain, and virus shedding by approximately one-half day compared with placebo. Side effects are uncommon.
Trifluridine
Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis. The compound has in vitro activity against HSV-1, HSV-2, vaccinia, and some adenoviruses. It is phosphorylated intracellularly to its active form by cellular enzymes, then competes with thymidine triphosphate for incorporation by the viral DNA polymerase.
Incorporation of trifluridine triphosphate into both viral and cellular DNA prevents its systemic use. Application of a 1% solution is effective in treating primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2. Topical application of trifluridine solution, alone or in combination with interferon alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.
Ganciclovir
Ganciclovir is an acyclic guanosine analog ерat requires triphosphorylation for activation prior to 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. Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.
Pharmacokinetics
Ganciclovir may be administered intravenously, orally, or via intraocular implant. A 5 mg/kg dose of ganciclovir administered intravenously over 1 hour produces serum concentrations averaging 6–10 g/mL, with trough levels of approximately 1 g/mL. Cerebrospinal fluid concentrations are approximately 50% of those in serum. Intravitreal concentrations following intravenous administration average 1 g/mL. The half-life is 2–4 hours with normal renal function.
Clearance of the drug is linearly related to creatinine clearance. Ganciclovir is readily cleared by hemodialysis. The bioavailability of oral ganciclovir is poor (6–9% when taken with food). In patients with an intraocular implant, ganclovir is released into the vitreous cavity at a rate of approximately 1.4 g/h.
Clinical Uses
Intravenous ganciclovir has been shown to delay progression of CMV retinitis in patients with AIDS when compared with no treatment (Table 49–2). 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, below), although side effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis and esophagitis. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipients. Use of intravenous ganciclovir to treat CMV pneumonitis in immunocompromised patients may be beneficial, particularly in combination with intravenous cytomegalovirus immunoglobulin. Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis following induction. Although less effective than intravenous ganciclovir, the risk of myelosuppression and of catheter-related complications is diminished.
Ganciclovir may also be administered intraocularly to treat CMV retinitis, either by direct intravitreal administration or via an intraocular implant. The implant, which achieves high and prolonged intraocular levels of ganciclovir, has been shown to delay progression of retinitis to a greater degree than systemic therapy with ganciclovir. Surgical replacement is required at intervals of 5–8 months. Owing to the lack of systemic protection against end-organ CMV disease (eg, colitis, esophagitis, ventriculitis) in patients treated with the ganciclovir implant alone—as well as the absence of protection against contralateral retinal CMV infection—concurrent therapy with a systemic anti-CMV agent is recommended. A recent study showed that the combination of either intravenous or oral ganciclovir and the ganciclovir intraocular implant in AIDS patients with CMV retinitis resulted in a decreased incidence of Kaposi’s sarcoma over 6 months compared with those treated with the implant alone.
Resistance
Sporadic cases of ganciclovir-resistant CMV infection have been reported since the introduction of ganciclovir in the late 1980s; clinical manifestations may include progressive disease or prolonged viremia. Until recently, the majority of resistant cases were in patients with AIDS receiving prolonged therapy with ganciclovir.
However, with the advent of more widespread use of oral ganciclovir, often in combination with more intensive immunosuppressive therapies, an increased frequency of ganciclovir-resistant CMV infection has beeoted in organ transplant recipients. The most common mechanisms of resistance are mutations in UL97, resulting in decreased levels of the triphosphorylated (ie, active) form of ganciclovir; mutations in UL54, which result in a mutant DNA polymerase, occur less frequently. Isolates with mutations in UL97 are not cross-resistant with cidofovir or foscarnet, while mutations in UL54 may confer cross-resistance to cidofovir (and, less frequently, foscarnet). Performance of antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically, as is the substitution of alternative therapies (eg, foscarnet), and concomitant reduction in immunosuppressive therapies, if possible. The addition of
CMV hyperimmune globulin may also be considered.
Adverse Reactions & Drug Interactions
The most common side effect of systemic ganciclovir treatment (more common with intravenous than with oral administration) is myelosuppression, particularly neutropenia (20–40% of patients).
Myelosuppression may be additive in patients receiving ganciclovir in combination with zidovudine, azathioprine, or mycophenolate mofetil. Central nervous system toxicity (headache, changes in mental status, seizures) has been rarely reported. Other potential adverse effects include fever, rash, abnormal liver function, and retinal detachment in patients with CMV retinitis. The drug is mitogenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical significance of these preclinical data is unclear. The primary potential adverse effects associated with the intraocular implant are vitreous hemorrhage and retinal detachment.
Levels of ganciclovir may rise in patients taking concurrent probenecid. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.
Valganciclovir
Mechanism of Action
Valganciclovir is a monovalyl ester prodrug that is rapidly hydrolyzed to the active compound ganciclovir (see Ganciclovir) by intestinal and hepatic esterases when administered orally.
Pharmacokinetics
Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of oral valganciclovir is 60%, and steady state AUC increases by 30% with a high-fat meal. The AUC0–24hr resulting from valganciclovir (900 mg once daily) is similar to those noted after 5 mg/kg/d of intravenous ganciclovir. As with ganciclovir, the major route of elimination is renal, through glomerular filtration and active tubular secretion.
Plasma concentrations of valganciclovir are reduced by approximately 50% by hemodialysis.
Clinical Uses
Valganciclovir is indicated for the treatment of CMV retinitis in patients with AIDS (Table 49–2). A randomized, open-label study demonstrated similar efficacy of oral valganciclovir and intravenous ganciclovir for induction therapy. Although clinical data assessing maintenance therapy with valganciclovir are not yet available, the pharmacokinetic profile would suggest similarity with intravenous ganciclovir. Potential side effects and drug interactions are those associated with ganciclovir (see Ganciclovir).
Cidofovir
Cidofovir is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes. After phosphorylation, cidofovir 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. Isolates with resistance to cidofovir have been selected in vitro; these isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscarnet. Clinically significant resistance to cidofovir has not been reported to date.
Pharmacokinetics
Although the terminal half-life of cidofovir is about 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17–65 hours, thus allowing widely spaced administration. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Peak serum concentrations when administered with probenecid (see Clinical Uses) are about 19 g/mL. Cerebrospinal fluid penetration is poor after intravenous administration. Elimination involves active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%.
Clinical Uses
Intravenous cidofovir is effective for the treatment of CMV retinitis. Intravenous cidofovir must be administered with probenecid (
Other potential uses of cidofovir that are currently under investigation include treatment of the polyomavirus-associated progressive multifocal leukoencephalopathy syndrome in patients with AIDS, postexposure prophylaxis against smallpox, and topical treatment of molluscum contagiosum. Topical cidofovir is not currently available in a standardized preparation.
Adverse Reactions
The primary adverse effect of intravenous cidofovir is a dose-dependent nephrotoxicity. 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 side effects include uveitis, decreased intraocular pressure, and probenecid-related hypersensitivity reactions. Neutropenia and metabolic acidosis are rare. The drug caused mammary adenocarcinomas in rats and is embryotoxic.
Foscarnet
Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate compound (Figure 49–2) that inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without requiring activation by phosphorylation. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV. 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, activity is usually maintained against ganciclovir- and cidofovir-resistant isolates of CMV.
Pharmacokinetics
The drug is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Peak serum concentrations averaging 80–100 g/mL are achieved following an infusion of 60 mg/kg. Cerebrospinal fluid concentrations are 43–67% of steady state serum concentrations. Although the mean plasma half-life is 4.5–6.8 hours, up to 30% of the drug may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown.
Clearance of foscarnet is primarily by the kidney and is directly proportionate to creatinine clearance. Serum drug concentrations are reduced by approximately 50% following a 3-hour hemodialysis.
Clinical Uses
Foscarnet is effective treatment for CMV retinitis, with an efficacy approximately equal to that of ganciclovir (Table 49–2). Foscarnet is also used for treatment of CMV colitis, CMV esophagitis, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection. The dose of foscarnet must be titrated according to the patient’s calculated creatinine clearance prior to each infusion. Use of an infusion pump to control the rate of infusion is important to avoid toxicity, and relatively 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 as monotherapy in delaying progression of retinitis. Foscarnet has been administered intravitreally for the treatment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are lacking.
As with ganciclovir, a decrease in the incidence of Kaposi’s sarcoma has been observed in patients who have received foscarnet. However, treatment of patients with Kaposi’s sarcoma using antiherpes agents has not been successful.
Adverse Reactions
Potential adverse effects of foscarnet include renal insufficiency, hypo- or hypercalcemia, and hypo- or hyperphosphatemia. 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 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, 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. The drug caused chromosomal damage in preclinical studies.
Fomivirsen
Fomivirsen is an oligonucleotide that inhibits human CMV through an antisense mechanism. Binding of fomivirsen to target mRNA results in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Although resistant isolates have been induced under selection pressure in vitro, clinical resistance has not been observed to date. Cross-resistance between fomivirsen and other anti-CMV agents (ganciclovir, cidofovir, foscarnet) would not be expected. Fomivirsen is injected intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. The drug is slowly cleared from vitreous with a half-life of approximately 55 hours in humans and is subsequently cleared from the retina. Measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Immediate therapy of CMV retinitis with fomivirsen was more effective in delaying progression than deferred treatment in a recent clinical trial. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include iritis and vitreitis as well as increased intraocular pressure and changes in vision. An interval of at least 2–4 weeks is recommended between cidofovir administration and use of fomivirsen because of the risk of ocular inflammation.
AIDS TREATMENT
A large and increasing number of antiretroviral agents are currently available for treatment of HIV- 1-infected patients (Table 49–3). When to initiate therapy is controversial, but it is clear that monotherapy with any one agent should be avoided because of the need for maximal potency to durably inhibit virus replication and to avoid premature development of resistance. A combination of agents (highly active antiretroviral therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naïve patients. Also important in selection of agents is optimization of adherence, tolerability, and convenience. Given that many patients will ultimately experience at least one treatment failure, close monitoring of viral load and CD4 cell counts is critical to trigger appropriate changes in therapy. The judicious use of drug resistance testing should be considered in selecting an alternative regimen for a patient who is not responding to therapy.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1. Lactic acidemia and severe hepatomegaly with steatosis have been reported with the use of NRTI agents, alone or in combination with other antiretroviral drugs. Obesity, prolonged nucleoside exposure, and risk factors for liver disease have been described as factors that increase risk for lactic acidemia; however, cases have also been reported in patients with no known risk factors.
NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic or lactic acidosis of unknown cause. Given their similar mechanism of action, it is probable that these cautions should be applied to treatment with nucleotide inhibitors as well (see Nucleotide Inhibitors).
Zidovudine
Zidovudine (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–4) that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Plasma protein binding is approximately 35%. The serum half-life averages 1 hour, and the intracellular half-life of the phosphorylated compound is 3.3 hours. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency.
As the first licensed antiretroviral agent, zidovudine has been well studied. Zidovudine 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, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from As with other NRTI agents, resistance may limit clinical efficacy. 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 in the case of didanosine and M184V in the case of lamivudine) seems to enhance 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 anemia or neutropenia. Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Less frequent side effects include thrombocytopenia, hyperpigmentation of the nails, and myopathy. Very high doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no humn cases of genital neoplasms have been reported to date. 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, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents. Hematologic toxicity may be increased during coadministration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. (See Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge.)
Didanosine
Didanosine (ddI) is a synthetic analog of deoxyadenosine. At acid pH, hydrolysis of the glycosidic bond between the sugar and the base moieties of ddI will inactivate the compound.
Didanosine’s AUC is reduced by 55% if it is ingested within 2 hours after a meal. Peak serum concentrations average 1 g/mL after a 300 mg dose. Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. Plasma protein binding is low (< 5%). The elimination half-life is 0.6–1.5 hours, but the intracellular half-life of the activated compound is as long as 12–24 hours. The drug is eliminated by glomerular filtration and tubular secretion. Dosage reduction is therefore required for low creatinine clearance, after hemodialysis or during continuous ambulatory peritoneal dialysis, and for low body weight (Table 49–3).
The original formulation, a buffered powder, has been replaced by chewable and dispersible buffered tablets with greater bioavailability (30–40%); a new enteric-coated formulation further improves patient convenience and tolerability. Since the chewable tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those taking sodium-restricted diets. Didanosine should be taken on an empty stomach and, because of the buffered formulation, should be administered at least 2 hours after administration of drugs requiring acidity for optimal absorption (eg, ketoconazole, itraconazole, dapsone).
Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date.
The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis should be avoided. Other reported adverse effects include painful peripheral distal neuropathy, diarrhea, hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). 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—indicate the utility of periodic retinal examinations.
Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine in order to avoid decreased antibiotic plasma concentrations due to chelation. Coadministration with ganciclovir results in an increased AUC of didanosine and a decreased AUC of ganciclovir, while coadministration with methadone results in decreased didanosine serum levels.
Lamivudine
Lamivudine (3TC) is a cytosine analog (Figure 49–4) 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 (see Anti-Hepatitis Agents). Oral bioavailability exceeds 80% and is not food-dependent. Peak serum levels after standard doses are 1.5 ± 0.5 g/mL, and protein binding is less than 36%. In children, the mean CSF:plasma ratio of lamivudine was 0.2. Mean elimination half-life is 2.5 hours, while the intracellular half-life of the active 5′-triphosphate metabolite in HIV-1-infected cell lines is 10.5–15.5 hours. The majority of lamivudine is eliminated unchanged in the urine, and the dose should be reduced in patients with renal insufficiency or low body weight (Table 49–3). No supplemental doses are required after routine hemodialysis. Lamivudine therapy rapidly selects—both in vitro and in vivo—for M184V-resistant mutants of HIV, which show high-level resistance to lamivudine and a reduction in susceptibility to abacavir, didanosine, and zalcitabine. Thus, lamivudine, like other antiretroviral agents, is best used in combination therapies that are fully suppressive of viral replication to reduce the generation of resistant mutants. The M184V mutation may restore phenotypic susceptibility to zidovudine, indicating that these two drugs in combination regimens may be particularly beneficial. However, HIV-1 strains resistant to both lamivudine and zidovudine have been isolated.
Potential side effects are headache, insomnia, fatigue, and gastrointestinal discomfort, though these are typically mild. Lamivudine’s AUC increases when it is coadministered with trimethoprimsulfamethoxazole. Peak levels of zidovudine increase when the drug is administered with lamivudine, though this effect is not felt to have clinical significance.
Zalcitabine
Zalcitabine (ddC) is a cytosine analog (Figure 49–4) that has synergistic anti-HIV-1 activity with a variety of antiretroviral agents against both zidovudine-sensitive and zidovudine-resistant strains of HIV-1.
Zalcitabine has a relatively long intracellular half-life of 10 hours (despite its elimination half-life of 2 hours) and high oral bioavailability (> 80%). However, plasma levels decrease by 25–39% when the drug is administered with food or antacids. Plasma protein binding is low (< 4%). 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 (eg, T69D, K65R, M186V), phenotypic resistance appears to be rare, particularly in combination regimens.
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 renal clearance caused by amphotericin B, foscarnet, and aminoglycosides may increase the risk of zalcitabine neuropathy. The other major reported toxicity is oral and esophageal ulcerations. Pancreatitis occurs less frequently than with didanosine administration, but coadministration 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. Cardiomyopathy has rarely been reported. Zalcitabine causes thymic lymphomas in rodents, but no clinical correlates have been observed in humans. Potential drug interactions include an increased AUC of zalcitabine when administered in combination with probenecid or cimetidine and decreased bioavailability when zalcitabine is coadministered with antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy.
Stavudine
The thymidine analog stavudine (D4T) (Figure 49–4) has high oral bioavailability (86%) that is not food-dependent. The plasma half-life is 1.22 hours; the intracellular half-life is 3.5 hours; and mean cerebrospinal fluid concentrations are 55% of those of plasma. Plasma protein binding is negligible. Excretion is by active tubular secretion and glomerular filtration. The dosage of stavudine should be reduced in patients with renal insufficiency, in those receiving hemodialysis, and for low bodyweight (Table 49–3).
V75T and I50T mutations are associated with decreased in vitro susceptibility to stavudine; the former also confers decreased susceptibility to didanosine and zalcitabine. Clinically significant resistance to stavudine has been rare. The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy. The frequency of neuropathy may be increased when stavudine is administered with other neuropathy-inducing drugs such as zalcitabine and didanosine. Symptoms typically resolve completely upon discontinuation of stavudine; in such cases, a reduced dosage may be cautiously restarted. Potential adverse effects other thaeuropathy include pancreatitis, arthralgias, and elevation in serum aminotransferases.
Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should generally not be used together.
Abacavir
In contrast to earlier NRTIs, abacavir is a guanosine analog. It is well absorbed following oral administration (83%), is unaffected by food, and is about 50% bound to plasma proteins. In singledose studies, the elimination half-life was 1.5 hours. Cerebrospinal fluid levels are approximately one-third those of plasma. The drug is metabolized by alcohol dehydrogenase and glucuronosyltransferase to inactive metabolites that are eliminated primarily in the urine. High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, M184V, L74V), and for that reason it tends to develop slowly. Although cross-resistance to lamivudine, didanosine, and zalcitabine has beeoted in vitro in recombinant strains with abacavir-associated mutations, the clinical significance is unknown.
Hypersensitivity reactions, occasionally fatal, have been reported in 2–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, involve multiple organ systems and include fever, malaise, and gastrointestinal complaints. Skin rash may or may not be present. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels are not specific for this reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir following discontinuation results in return of symptoms within hours and may be fatal. Other adverse events may include rash, nausea and vomiting, diarrhea, headache, and fatigue. Adverse effects that appear to be infrequent include pancreatitis, hyperglycemia, and hypertriglyceridemia. Clinically significant adverse drug interactions have not been reported to date, though coadministration of alcohol and abacavir may result in an increase in abacavir’s AUC.
Nucleotide Inhibitors
Tenofovir
Tenofovir disoproxilfumarate is a prodrug that is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine. Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. The oral bioavailability of tenofovir from tenofovir disopoxilfumarate, a water-soluble diester prodrug of the active ingredient tenofovir, in fasted patients is approximately 25%. Oral bioavailability is increased if the drug is ingested following a high-fat meal (increased AUC by
about 40%); therefore, taking the drug along with a meal is recommended. Maximum serum concentrations are achieved in about 1 hour after taking the medication. Elimination occurs by a combination of glomerular filtration and active tubular secretion. However, only 70–80% of the dose is recovered in the urine, allowing for the possibility of hepatic metabolism as well as alteration in hepatic insufficiency; the latter has not been studied.
Tenofovir is indicated for use in combination with other antiretroviral agents. Initial studies demonstrated potent HIV-1 suppression in treatment-experienced adults with evidence of viral replication despite ongoing antiretroviral therapy; similar benefit in antiretroviral-naive patients has yet to be demonstrated. The once-daily dosing regimen of tenofovir lends added convenience.
Varying degrees of cross-resistance to tenofovir by preexisting zidovudine-associated mutations (eg, M41L, L210W) may occur and diminish virologic response; these appear to depend on the number of specific mutations present. Presence of the 65R mutation also reduces virologic response. However, virologic response to tenofovir is not diminished in the lamivudine-abacavirassociated M184V mutation. Cross-resistance with protease inhibitor agents is unlikely.
Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, and flatulence) are the most common side effects but rarely require discontinuation of therapy. Preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia); however, to date there has beeo evidence of bone toxicity in humans. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Tenofovir is not metabolized by the cytochrome P450 system, so drug interactions with agents metabolized by this system are unlikely. As with the NRTIs, lactic acidosis and hepatomegaly with steatosis should be watched for.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
The NNRTIs bind directly to a site on the HIV-1 reverse transcriptase, resulting in blockade of RNA- and DNA-dependent DNA polymerase activities. The binding site is near to but distinct from that of the NRTIs. Unlike the latter group of agents, the NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. Resistance to an NNRTI is generally rapid with monotherapy and is associated with the K103N mutation as well as the less critical Y181C/I mutation; cross-resistance among this class of agents, although observed in vitro, is of unknown clinical significance. There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.
A syndrome of drug hypersensitivity has been described in patients receiving NNRTIs as well as in those receiving amprenavir or abacavir. Serious rashes, including Stevens-Johnson syndrome, have occurred.
Nevirapine
The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic, approximately 60% protein-bound, and achieves cerebrospinal fluid levels that are 45% of those in plasma. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.
Nevirapine is typically used as a component of a combination antiretroviral regimen. In addition, a single dose of nevirapine (200 mg) has recently been shown to be 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 given to the neonate within 3 days after delivery.
Severe and life-threatening skin rashes have occurred during nevirapine therapy, including Stevens- Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with rash accompanied by constitutional symptoms. Rash occurs in approximately 17% of patients, most typically in the first 4–8 weeks of therapy, and is dose-limiting in about 7% of patients. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the frequency of rash. Fulminant hepatitis may occur in association with rash and fever, typically within the first 6 weeks of initiation of therapy, or may occur without a concomitant rash. Therefore, serial monitoring of liver function tests is strongly recommended. Other frequently reported adverse effects associated with nevirapine therapy are fever, nausea, headache, and somnolence.
Nevirapine is both a substrate and a moderate inducer of CYP3A metabolism, thus resulting in a 1.5-fold to twofold increase in oral clearance of itself and a corresponding decrease in the terminal phase half-life with repeated dosing—as well as decreased levels of indinavir and saquinavir if administered concurrently (see Table 49–4). Owing to an increase ievirapine and a decrease in
ketoconazole levels during coadministration, these two agents should not be given together.
Nevirapine levels may increase during coadministration with inhibitors of CYP3A metabolism, such as cimetidine and the macrolide agents, and decrease in the presence of CYP3A inducers such as rifabutin and rifampin (see Table 4–2). Such agents should be coadministered cautiously and only if good alternatives are lacking.
Delavirdine
Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids. It is extensively bound (about 98%) to plasma proteins. Cerebrospinal fluid levels average only 0.4% of the corresponding plasma concentrations, representing about 20% of the fractioot bound to plasma proteins. Caution should be used when administering delavirdine to patients with hepatic insufficiency because clinical experience in this situation is limited. Skin rash occurs in about 18% of patients receiving delavirdine; it typically occurs during the first month of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other adverse effects may include 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 exposures 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. However, it also inhibits CYP3A and thus inhibits its own metabolism. In addition to its interactions with other antiretroviral agents (see Table 49–4), delavirdine will result in increased levels of numerous agents (Table 49–3). Dose reduction of indinavir and saquinavir should be considered if they are administered concurrently with delavirdine. Delavirdine plasma concentrations are reduced in the presence of antacids, phenytoin, phenobarbital, carbamazepine, rifabutin, and rifampin; concentrations are increased during coadministration with clarithromycin, fluoxetine, dexamethasone, and ketoconazole.
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%), and bioavailability is increased to about 65% following a high-fat meal. Peak plasma concentrations are seen 3–5 hours after administration of daily doses; steady state plasma concentrations are reached in 6–10 days. 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%).
Cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels; these are approximately three times higher than the free fraction of efavirenz in the plasma. Because there is limited experience to date, caution is advised with use in patients with hepatic impairment.
The principal adverse effects of efavirenz involve the central nervous system (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria); these may occur in up to 50% of patients. They tend to occur during the first days of therapy and may resolve while medication is continued; administration at bedtime may be helpful. However, psychiatric symptoms may be severe. Skin rash has also been reported early in therapy in up to 28% of patients, is usually mild to moderate, and typically resolves despite continuation. Other potential adverse reactions include nausea and 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 of 600 mg/d. Therefore, pregnancy should be avoided in women receiving efavirenz.
Efavirenz is a substrate, an inhibitor, and a moderate inducer of CYP3A4, thus inducing its own metabolism and interacting with the metabolism of many other drugs. Decreased plasma concentrations would be expected if efavirenz is administered concurrently with agents that induce CYP3A4 activity, including phenobarbital, rifampin, and rifabutin. The AUC of ethinyl estradiol is increased if coadminstered with efavirenz, and levels of clarithromycin are decreased.
Efavirenz may reduce plasma methadone levels by 50% and thus should not be concurrently used. Coadministration of efavirenz with drugs that are highly dependent on CYP3A for clearance is contraindicated (see Table 4–2). Interactions with other antiretroviral agents are summarized in Table 49–4. The dose of indinavir should be increased if coadministered with efavirenz. Coadministration of efavirenz with saquinavir is to be avoided because of decreases in saquinavir plasma concentrations.
Protease Inhibitors
During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then 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 cleavage of the Gag-Pol polyprotein, protease inhibitors result in the production of immature, noninfectious viral particles. Unfortunately, specific genotypic alterations that confer phenotypic resistance is fairly common with these agents, thus contraindicating monotherapy. The issue of cross-resistance among agents in this class of drugs is complex and requires further investigation; it appears to require a minimum of four substitutions in the gene. A syndrome of redistribution and accumulation of body fat that includes 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.
Although controversial, these abnormalities appear to be particularly associated with the use of protease inhibitors. Concurrent increases in triglyceride and LDL levels, along with glucose intolerance and insulin resistance, have beeoted as well. The cause is not yet known. Protease inhibitors have also been associated with increased spontaneous bleeding in patients with hemophilia A or B.
All of the antiretroviral protease inhibitors are substrates of the CYP3A4 isoenzyme. As such, there is a potential for drug-drug interactions. In addition, however, certain of the protease inhibitors are CYP3A4 inhibitors as well (eg, amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), thus having the potential to cause decreased clearance and increased plasma concentrations of other substrate drugs. For this reason, the CYP3A4 inhibitors should not be administered concurrently with agents that are heavily metabolized by CYP3A (see Table 4–2).
Ritonavir also functions as a CYP3A4 inducer, such that potential drug-drug interactions may be clinically beneficial (see Ritonavir).
Saquinavir
In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S; Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with lowdose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents.
Both formulations of saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir has a large volume of distribution but is 98% protein-bound; penetration into the cerebrospinal fluid is negligible. The elimination half-life is 12 hours. Excretion is primarily in the feces. Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia; these are more common with Fortovase) and rhinitis. Although refrigeration is recommended for storage, the capsules are stable at room temperature for up to 3 months. Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate; thus, it should be used with the same precautions regarding drugdrug interactions as the other protease inhibitors. Coadministration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because inhibition of first-pass metabolism of saquinavir by ritonavir can result in higher—and thus more efficacious—levels of saquinavir (see Table 49–3 and Table 49–4). Liver function tests should be monitored if saquinavir is coadministered with delavirdine.
The most common critical mutations are L90M and G48V, conferring an approximately tenfold decrease in susceptibility.
Ritonavir
Ritonavir is an inhibitor of HIV-1 and HIV-2 proteases with high bioavailability (about 75%) that increases when the drug is given with food. 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. Capsules (but not the oral solution) should be refrigerated for storage. Resistance is associated with mutations at positions 84, 82, 71, 63, and 46, of which the I84V mutation appears to be the most critical.
The most common adverse effects of ritonavir are gastrointestinal disturbances, paresthesias (circumoral and peripheral), elevated serum aminotransferase levels, altered taste, and hypertriglyceridemia. Nausea, vomiting, and abdominal pain typically occur during the first few weeks of therapy, and patients should be told to expect them. Slow dose escalation over 4–5 days is recommended to decrease the frequency of 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.
Ease of administration is limited by ritonavir’s numerous drug interactions. Ritonavir is both a substrate and an inhibitor of CYP3A4; as such, coadministration with agents heavily metabolized by CYP3A must be approached with the same precautions discussed above. In addition, since ritonavir is an inhibitor of the CYP3A4 isoenzyme, concurrent administration with other PIs results in increased plasma levels of the latter drugs; these interactions have been exploited to permit more convenient dosing (see Table 49–3 and Table 49–4).
Lopinavir/Ritonavir
Several studies have shown enhanced efficacy or improved tolerability of two protease inhibitors administered together. Lopinavir 100/ritonavir 400 is a licensed combination in which subtherapeutic doses of ritonavir inhibit the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. Trough levels of lopinavir are greater than the median HIV-1 wild type 50% inhibitory concentration, thus maintaining potent viral suppression as well as providing a pharmacologic barrier to the emergence of resistance. In addition to improved patient compliance because of the reduced pill burden with twice-daily dosing, lopinavir/ritonavir is generally well tolerated.
Absorption is enhanced with food. Lopinavir is 98–99% protein-bound and is extensively metabolized by the CYP3A isozyme of the hepatic cytochrome P450 system, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.
The most common adverse effects are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Potential drug-drug interactions are extensive (see Ritonavir and Table 49–4). Drugs that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations may be serious or clinically significant—including those listed in Table 49–4 as well as those listed in Table 4–2—should not be given with lopinavir/ritonavir. Coadministration with rifampin, carbamazepine, phenobarbital, phenytoin, dexamethasone, or
Fusion Inhibitors
Enfuvirtide
Enfuvirtide (formerly called T-20) is a newly approved antiretroviral agent of a novel class, ie, a fusion inhibitor that blocks entry into the cell. Enfuvirtide, a synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.
Resistance to enfuvirtide can occur, and the frequency and mechanisms of this phenomenon are currently being investigated. However, enfuvirtide completely lacks cross-resistance to the other currently approved antiretroviral drug classes. The drug is administered subcutaneously in combination with other antiretroviral agents in treatment-experienced patients with persistent HIV-1 replication despite ongoing therapy. Protein binding is high (92%), and metabolism appears to be by proteolytic hydrolysis without involvement of the cytochrome p450 system. Elimination half-life is 3.8 hours, and time to peak concentration is 8 hours. The most common side effects associated with enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions may occur, are of varying severity, and may recur on rechallenge. Eosinophilia has also beeoted. No interactions have been identified that would require alteration of other antiretroviral drugs.
Investigational Antiretroviral Agents
New therapies are being sought offering the advantages of once-daily dosing, smaller pill size, lower incidences of adverse effects, new viral targets, and activity against virus that is resistant to other agents. Agents under evaluation or reformulation for once-daily dosing include stavudine and nevirapine. The NRTI agents amdoxovir and emtricitabine, the NNRTI agents DPC-083 and TMC- 125, and the protease inhibitors atazanavir, tipranavir, and fosamprenavir (the prodrug of amprenavir) are among the new agents currently in development. In addition, new drug classes such as entry inhibitors and integrase inhibitors are under clinical investigation.
Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge
In addition to knowledge about the clinical efficacy, adverse effect profile, and likelihood of emergence of resistance, the physician caring for an HIV-infected patient must be well versed in basic pharmacokinetics as well. Such patients are frequently taking multiple medications, including combinations of antiretroviral agents, prophylaxis or treatment for opportunistic infections, and opioid pain medications or methadone for maintenance therapy.
For example, an HIV-infected patient receiving ganciclovir for treatment of cytomegalovirus retinitis may be unable to tolerate concomitant therapies with the potential for additive myelosuppression, including zidovudine, ribavirin, or the interferons. Addition of colonystimulating factor therapy for cytopenias or substitution of a different, nonmyelodepressant drug for ganciclovir may ultimately be necessary. In a patient taking didanosine (ddI), the ingestion of manyother antiretroviral agents that may comprise their combination regimen, including delavirdine, indinavir, amprenavir, and tenofovir, must be separated by 2 or more hours in order to avoid interference with their absorption. Prescription of abacavir may be complicated by the fact that alcohol decreases the AUC of abacavir by 41%; the patient should be made aware of this potentially harmful interaction. The NNRTI agents and protease inhibitors for treatment of HIV infection are all metabolized by the cytochrome P450 enzyme system, primarily the 3A4 isoform. Many are also either inducers or inhibitors of CYP3A4 as well. Their myriad potential drug-drug interactions necessitate great caution during the treatment of AIDS patients. For example, an increased incidence of rifabutin-associated uveitis due to increased levels when given in combination with ritonavir is an important consideration when considering the addition of an agent for the prophylaxis or treatment against Mycobacterium avium complex (MAC) infection in a patient already on an effective HAART regimen. Similarly, the addition of clarithromycin for prophylaxis against MAC could potentially increase serum levels of delavirdine, ritonavir, and indinavir; conversely, levels of clarithromycin increase in the presence of indinavir and ritonavir but decrease with efavirenz. Most recently, however, these interactions have been used to advantage in the form of dual protease inhibitor regimens, based upon resultant increased plasma concentrations (Cmax, Cmin, and AUC ) of the substrate (eg, saquinavir) when coadministered with an inducer (eg, ritonavir). Improved drug exposure, increased antiviral potency, more convenient dosing, and improved tolerability due to the use of lower doses are some of the benefits, thus improving patient adherence to the regimen. A newly licensed coformulation of lopinavir with ritonavir takes advantage of this phenomenon, known as “protease inhibitor boosting.” Thus, a thorough working knowledge of potential drug-drug interactions is essential in the care of patients.
Agents effective against hepatitis B virus (HBV) and hepatitis C virus (HCV) are now available (see Table 49–5). Although treatment is suppressive rather than curative, the high prevalence of these infections worldwide, with their concomitant morbidity and mortality, reflect a critical need for improved therapeutics.
Lamivudine
The pharmacokinetics and safety profile of lamivudine are described above (see Lamivudine). The more prolonged intracellular half-life in HBV cell lines (17–19 hours) than in HIV-infected cell lines (see above) allows for lower doses, administered less frequently, for hepatitis. Lamivudine can be safely administered to patients with decompensated liver disease.
Lamivudine achieves almost universal HBV DNA suppression, with decreases in viral replication by about 3-4 log copies in most patients. Response to lamivudine is more rapid than to interferon (see below), with HBV DNA levels decreasing by approximately 97% after 2 weeks of therapy and 98% by 1 year. However, evidence of viral replication recurs in over 80% upon discontinuation of therapy. Seroconversion of HBeAg antigen from positive to negative occurs in only about 20% of patients; yet in patients who do achieve seroconversion with lamivudine, the response is typically sustained. Progression to liver fibrosis is less frequent in patients treated with lamivudine compared with placebo. The height of the pretreatment serum ALT level may be the best predictor of HBeAg seroconversion.
Chronic therapy with lamivudine in patients with hepatitis may ultimately be limited by the emergence of lamivudine-resistant HBV isolates with YMDD mutation. Emergence of this mutation, which typically occurs within 8–9 months of therapy, is associated with reappearance of detectable levels of HBV DNA. The estimated rate of YMDD mutation is about 20% per year. In the doses used for HBV infection, lamivudine has an excellent safety profile. No evidence of mitochondrial toxicity has been reported.
Adefovir
Although initially and abortively developed for treatment of HIV infection, adefovir has been recently approved, at lower and less toxic doses, for treatment of HBV infection. Like tenofovir (see Antiretroviral Agents), adefovir is a nucleotide analog. As an analog of adenosine monophosphate, adefovir is phosphorylated by cellular kinases to the active disphosphate metabolite; it then competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA.
Oral bioavailability is about 59% and is unaffected by meals. Peak serum levels occur at a median of 1.75 hours after dosing, and the terminal elimination half-life is approximately 7.5 hours. Protein binding is less than 4%. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. Dosing interval should be modified in patients with impaired renal function. Approximately 35% of the adefovir dose is removed during a 4-hour hemodialysis. Recent placebo-controlled trials showed that adefovir resulted in significant suppression of HBV replication and improvement in liver histology and fibrosis at 1 year. However, as with lamivudine, serum HBV DNA reappeared following cessation of therapy.
Adefovir maintains activity against lamivudine-resistant strains of HBV, and no resistance to adefovir was detected in patients who had received continuous treatment for up to 1 year. Adefovir is associated with a dose-dependent nephrotoxicity. The risk is low for treatment durations of up to 1 year at its recommended dosage for HBV but may rise in patients with preexisting renal dysfunction or in those treated for longer durations. Also, as with the antiretroviral nucleoside analogs (see Nucleoside Reverse Transcriptase Inhibitors), lactic acidosis and severe hepatomegaly with steatosis may occur. When coadministered with ibuprofen, the AUC of adefovir is increased by about 23%, apparently due to higher oral bioavailabilty.
Interferon Alfa
Interferons are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving synthesis of both RNA and protein. They appear to function by binding to specific membrane receptors on the cell surface and initiating a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of virus replication.
They are classified according to the cell type from which they were derived, and each of the three immunologically distinct major classes of human interferons has unique physicochemical characteristics and different producer cells, inducers, and biologic effects.
Interferon alfa preparations are available for treatment of both HBV and HCV virus infections. Interferon alfa-2b is the only preparation licensed for treatment of HBV infection and for acute hepatitis C. Interferon alfa-2b leads to loss of HBeAg, normalization of serum aminotransferases, and sustained histologic improvement in approximately one-third of patients with chronic hepatitis B, thus reducing the risk of progressive liver disease.
In acute hepatitis C, the rate of clearance of the virus without therapy is estimated to be 15–30%. No therapy has yet been proved effective in the treatment of acute hepatitis C; however, a recent study suggested that interferon alfa-2b, in doses higher than those used for treatment of chronic hepatitis C (see Table 49–5), resulted in a sustained rate of clearance of 98%.
Several interferon alfa preparations are available for the treatment of patients with chronic hepatitis C infection, including interferon alfa-2a, interferon alfa-2b, interferon alfacon-2, pegylated interferon alfa-2a, and pegylated interferon alfa-2b, as described below. 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. For all agents, combination therapy with oral ribavirin in patients with chronic hepatitis C is more effective than monotherapy with either interferon or ribavirin alone, increasing the percentage of previously untreated patients with a sustained virologic response from approximately 16% to approximately 40%. Therefore, monotherapy is recommended only in patients who cannot tolerate ribavirin. The time to maximal response may range from 24 weeks to 48 weeks of therapy.
Interferon alfa-2a and interferon alfa-2b may be administered subcutaneously or intramuscularly, while interferon alfacon-1 is administered subcutaneously (see Table 49–5). Maximum serum concentrations occur approximately 4 hours after intramuscular administration and approximately 7 hours after subcutaneous administration; 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-
Typical side effects are constitutional iature, including a flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration. Other potential adverse effects include thrombocytopenia, granulocytopenia, elevation in serum aminotransferase levels, induction of autoantibodies, nausea, fatigue, headache, arthralgias, rash, alopecia, anorexia, hypotension, and edema. Severe neuropsychiatric side effects may occur.
Absolute contraindications to therapy are psychosis, severe depression, neutropenia, thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and a history of organ transplantation (other than liver). Alfa interferons are abortifacient in primates and should not be administered in pregnancy.
Pegylated Interferon Alfa
Pegylated interferon alfa-2a (peginterferon alfa-2a) and pegylated interferon alfa-2b (peginterferon alfa-2b) have recently been introduced for the treatment of patients with chronic hepatitis C infection. In these agents, a linear or branched polyethylene glycol (PEG) moiety is attached to interferon by a covalent bond. Reduced clearance and sustained absorption results in an increased half-life and steadier drug concentrations, allowing for less frequent dosing.
In comparison with the nonpegylated interferon alfa compounds, the pegylated products have substantially longer terminal half-lives and slower clearance. Maximum serum concentrations occur between 15 hours and 44 hours after dosing and are sustained for up to 48–72 hours.
For pegylated interferon alfa-2a, maximum serum concentrations occur at 72–96 hours after dosing and are sustained for up to 168 hours. In patients with chronic hepatitis C, the mean terminal half-life was 80 hours for pegylated interferon alfa-2a (versus 5.1 hours for interferon alfa-2a) and was about 40 hours for pegylated interferon alfa-2b (versus 2–3 hours for interferon alfa-2b). Renal elimination accounts for about 30% of clearance, and clearance is reduced by approximately half in subjects with impaired renal function. Although dose reduction in renal insufficiency is not specifically recommended, caution is advised in this setting.
Efficacy appears to be superior to therapy with nonpegylated interferons in controlled clinical trials, particularly as regards the proportion of patients with sustained virologic responses. As with the nonpegylated interferon alfa agents, combination therapy of the pegylated interferon alfa compounds with ribavirin is more effective than monotherapy.
Adverse events are similar to those of the interferon alfa agents described above. The PEG molecule is a nontoxic polymer that is readily excreted in the urine.
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 RNA 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 about 64%, increases with high-fat meals, and decreases with coadministration of antacids. Since elimination is mostly through the urine, clearance is decreased in patients with creatinine clearances less than 30 mL/min. Ribavirin capsules in combination with subcutaneous interferon alfa-2b are effective for the treatment of chronic hepatitis C infection in patients with compensated liver disease (see Anti- Hepatitis Agents, above). Monotherapy with ribavirin alone is not effective.
Approximately 10–20% of patients experience a dose-dependent hemolytic anemia that may be dose-limiting.
Other side effects are depression, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Absolute contraindications to ribavirin therapy include anemia, end-stage renal failure, severe heart disease, and pregnancy. Ribavirin is both teratogenic in animals and mutagenic in mammalian cells.
Investigational Agents
The nucleoside analogs entecavir and clevudine, the nucleotide analog emtricitabine, and the immunologic modulators theradigm-HBV and thymosin alpha-1 are new agents under evaluation for the treatment of HBV infection.
Anti-Influenza Agents
Amantadine & Rimantadine
Amantadine (1-aminoadamantane hydrochloride) and its -methyl derivative, rimantadine, are cyclic amines that inhibit uncoating of the viral RNA of influenza A within infected host cells, thus preventing its replication. Rimantadine is four to ten times more active than amantadine in vitro.
Steady state peak plasma levels in healthy young adults average 0.5—0.8 g/mL for amantadine; elderly persons require only one half of the weight-adjusted dose for young adults to achieve equivalent trough plasma levels of 0.3 g/mL. While amantadine is excreted unmetabolized in the urine, rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly, in renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency. No supplemental doses of either agent are required after hemodialysis. Plasma half-life is 12–18 hours for amantadine and 24–36 hours for rimantadine.
Both amantadine and rimantadine, in doses of 100 mg twice daily or 200 mg once daily, are approximately 70–90% protective in the prevention of clinical illness by influenza A. The effectiveness of postexposure prophylaxis is inconsistent. When begun within 1–2 days after the onset of clinical symptoms of influenza, both drugs reduce the duration of fever and systemic complaints by 1–2 days.
The primary target for both agents is the M2 protein within the viral membrane; this target incurs both specificity against influenza A (since influenza B contains a different protein in its membrane) and a mutation-prone site, causing the rapid development of resistance in up to 50% of treated individuals. Transmission of resistant virus to household contacts has been documented. Crossresistance to zanamivir and oseltamivir does not occur.
The most common adverse effects are gastrointestinal intolerance and central nervous system complaints (eg, nervousness, difficulty in concentrating, lightheadedness); the latter are less frequent with rimantadine than with amantadine. The central nervous system toxicity of amantadine may be increased with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Serious neurotoxic reactions, occasionally fatal, may occur in association with high amantadine plasma concentrations (1–5 g/mL).
Acute amantadine overdose is associated with anticholinergic effects. Amantadine is teratogenic and embrytoxic in rodents, and birth defects have been reported after exposure during pregnancy.
Zanamivir & Oseltamivir
Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36– 48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease.
Oseltamivir is an orally administered prodrug that is activated in the gut and liver. Dosage is 75 mg twice daily. The half-life of oseltamivir is 6–10 hours, and excretion is primarily in the urine. Inaddition to treatment of influenza, prophylaxis once daily may be effective in preventing influenza.
Potential side effects include nausea and vomiting, which may be decreased by administration with food. Decreased susceptibility to zanamivir and oseltamivir in vitro is associated with mutations in viral neuraminidase or hemagglutinin. A resistant virus was recovered from an immunocompromised patient who had received zanamivir for 2 weeks. However, the incidence and clinical significance of resistance are not yet known.
Other Antiviral Agents
Interferons
Interferons have been studied for numerous clinical indications. In addition to HBV and HCV infections (see Anti-Hepatitis Agents, above), intralesional injection of interferon alfa-2b or alfa-n3 may be used for treatment of condylomata acuminata.
Ribavirin
In addition to oral administration for hepatitis C infection in combination with interferon alfa (see above), aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12–18 hours per day for 3–7 days) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia, reducing the severity and duration of illness. Aerosolized ribavirin has also been used to treat influenza A and B infection but has not gained widespread use. Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation. Health care workers should be protected against extended inhalation exposure.
Intravenous ribavirin decreases mortality in Lassa fever and other viral hemorrhagic fevers if started early. Clinical benefit has been reported in cases of severe measles pneumonitis, and continuous infusion of ribavirin decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. Peak plasma concentrations are approximately tenfold higher than with oral administration and occur earlier (ie, at 0.5 hours after dosing). At steady state, cerebrospinal fluid levels are about 70% of those in plasma.
Palivizumab
Palivizumab is a humanized monoclonal antibody directed against the F glycoprotein on the surface of RSV. It was recently approved for the prevention of RSV infection in high-risk infants and children such as premature infants and those with bronchopulmonary dysplasia. A placebocontrolled trial utilizing 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. The major observed adverse effect has been 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. The mechanism of action against these human papillomavirus (HPV)-induced lesions is unknown. The 5% cream is to be applied three times weekly. Local skin reactions are the most common side effect.
Antiviral Agents >
Preparations Available
Abacavir(Ziagen)
Oral: 300 mg tablets; 20 mg/mL solution
Oral (Trizir): 300 mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine
Acyclovir(generic, Zovirax)
Oral: 200 mg capsules; 400, 800 mg tablets; 200 mg/5 mL suspension
Parenteral: 50 mg/mL; powder to reconstitute for injection (500, 1000 mg/vial)
Topical: 5% ointment
Adefovir(Hepsera)
Oral: 10 mg tablets
Amantadine(generic, Symmetrel)
Oral: 100 mg capsules, tablets; 50 mg/5 mL syrup
Amprenavir(Agenerase)
Oral: 50, 150 mg capsules; 15 mg/mL solution
Cidofovir(Vistide)
Parenteral: 375 mg/vial (75 mg/mL) for IV injection
Delavirdine(Rescriptor)
Oral: 100, 200 mg tablets
Didanosine(dideoxyinosine, ddI)
Oral (Videx): 25, 50, 100, 150, 200 mg tablets; 100, 167, 250 mg powder for oral solution; 2,
powder for pediatric solution
Oral (Videx-EC): 125, 200, 250, 400 mg delayed release capsules
Efavirenz(Sustiva)
Oral: 50, 100, 200 mg capsules; 600 mg tablets
Enfuvirtide(Fuzeon)
Parenteral: 90 mg/mL for injection
Famciclovir(Famvir)
Oral: 125, 250, 500 mg tablets
Fomivirsen(Vitravene)
Intravitreal: 6.6 mg/mL for injection
Foscarnet(Foscavir)
Parenteral: 24 mg/mL for IV injection
Ganciclovir(Cytovene)
Oral: 250, 500 mg capsules
Parenteral: 500 mg/vial for IV injection
Intraocular implant (Vitrasert): 4.5 mg ganciclovir/implant
Idoxuridine (Herplex)
Ophthalmic: 0.1% solution
Imiquimod(Aldera)
Topical: 5% cream
Indinavir(Crixivan)
Oral: 100, 200, 333, 400 mg capsules
Interferon alfa-2a(Roferon-A)
Parenteral: 3, 6, 9, 36 million IU vials
Interferon alfa-2b(Intron-A)
Parenteral: 3, 5, 10, 18, 25, and 50 million IU vials
Interferon alfa-2b(Rebetron)
Parenteral: 3 million IU vials (supplied with oral ribavirin, 200 mg capsules)
Interferon alfa-n3(Alferon N)
Parenteral: 5 million IU/vial
Interferon alfacon-1 (Infergen)
Parenteral: 9 and
Lamivudine(Epivir)
Oral (Epivir): 150, 300 mg tablets; 10 mg/mL oral solution
Oral (Epivir-HBV): 100 mg tablets; 5 mg/mL solution
Oral (Combivir): 150 mg tablets in combination with 300 mg zidovudine
Oral (Trizir): 300 mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine
Lopinavir/ritonavir (Kaletra)
Oral: 133.3 mg/33.3 mg capsules; 400 mg/100 mg per 5 mL solution
Nelfinavir(Viracept)
Oral: 250 mg tablets; 50 mg/g powder
Nevirapine(Viramune)
Oral: 200 mg tablets; 50 mg/5 mL suspension
Oseltamivir(Tamiflu)
Oral: 75 mg capsules; powder to reconstitute as suspension (12 mg/mL)
Palivizumab(Synagis)
Parenteral: 50, 100 mg/vial
Peginterferon alfa-2a(pegylated interferon-alfa 2a, Pegasys)
Parenteral: 180 g/mL
Peginterferon alfa-2b(pegylated interferon-alfa 2b, PEG-Intron)
Parenteral: powder to reconstitute as 100, 160, 240, 300 g/mL injection
Penciclovir(Denavir)
Topical: 1% cream
Ribavirin
Aerosol (Virazole): powder to reconstitute for aerosol; 6 gm/100 mL vial
Oral (Rebetol): 200 mg capsules
Oral (Rebetron): 200 mg in combination with 3 million units interferon alfa-2b (Intron-A)
Rimantadine(Flumadine)
Oral: 100 mg tablets; 50 mg/5 mL syrup
Ritonavir(Norvir)
Oral: 100 mg capsules; 80 mg/mL oral solution
Saquinavir
Oral (Invirase): 200 mg hard gel capsules
Oral (Fortovase): 200 mg soft gel capsules
Stavudine(Zerit)
Oral: 15, 20, 30, 40 mg capsules; powder for 1 mg/mL oral solution
Tenofovir(Viread)
Oral: 300 mg tablets
Trifluridine(Viroptic)
Topical: 1% ophthalmic solution
Valacyclovir(Valtrex)
Oral: 500, 1000 mg tablets
Valgancyclovir (Valcyte)
Oral: 450 mg capsules
Zalcitabine(dideoxycytidine, ddC) (Hivid)
Oral: 0.375, 0.75 mg tablets
Zanamivir(Relenza)
Inhalational: 5 mg/rotadisk
Zidovudine(azidothymidine, AZT) (Retrovir)
Oral: 100 mg capsules, 300 mg tablets, 50 mg/5 mL syrup
Oral (Combivir): 300 mg tablets in combination with 150 mg lamivudine
Oral (Trizir): 300 mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine
Parenteral: 10 mg/mL
Antifungal Agents
Antifungal Agents: Introduction
Human fungal infections have increased dramatically in incidence and severity in recent years, due mainly to advances in surgery, cancer treatment, and critical care accompanied by increases in the use of broad-spectrum antimicrobials and the HIV epidemic. These changes have resulted in increased numbers of patients at risk for fungal infections.
Pharmacotherapy of fungal disease has been revolutionized by the introduction of the relatively nontoxic oral azole drugs and the echinocandins. Combination therapy is being reconsidered, and new formulations of old agents are becoming available. Unfortunately, the appearance of azoleresistant organisms, as well as the rise in the number of patients at risk for mycotic infections, has created new challenges. The antifungal drugs presently available fall into several categories: systemic drugs (oral or parenteral) for systemic infections, oral drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections.
Systemic Antifungal Drugs for Systemic Infections
Amphotericin B
Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use.
Chemistry Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds;
macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water, and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system (see Table 48–1 and Liposomal Amphotericin B).
Pharmacokinetics
Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. The intravenous injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 g/mL; the drug is more than 90% bound by serum proteins. While it is mostly metabolized, some amphotericin B is excreted slowly in the urine over a period of several days. The serum t1/2 is approximately 15 days. Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations and therefore no dose adjustment is required. The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.
Mechanism of Action
Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B-associated pores in the cell membrane. As suggested by its chemistry, amphotericin B combines avidly with lipids (ergosterol) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.
Resistance to amphotericin B occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug.
Adverse Effects
The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly.
Infusion-Related Toxicity
These reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypotension. They can be ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, antihistamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and
premedication strategy.
Slower Toxicity
Renal damage is the most significant toxic reaction. Renal impairment occurs iearly all patients treated with clinically significant doses of amphotericin. The degree of azotemia is variable and often stabilizes during therapy, but can be serious enough to necessitate dialysis. A reversible component is associated with decreased renal perfusion and represents a form of prerenal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction. The irreversible form of amphotericin nephrotoxicity usually occurs in the setting of prolonged administration (>
Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae.
Antifungal Activity
Amphotericin B remains the antifungal agent with the broadest spectrum of action. It has activity against the clinically significant yeasts, including Candida albicans and Cryptococcus neoformans; the organisms causing endemic mycoses, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis; and the pathogenic molds, such as Aspergillus fumigatus and mucor. Some fungal organisms such as Candida lusitaniae and Pseudallescheria boydii display intrinsic amphotericin B resistance.
Clinical Use
Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains the drug of choice for nearly all life-threatening mycotic infections. It is often used as the initial induction regimen for serious fungal infections and is then replaced by one of the newer azole drugs (see Azoles) for chronic therapy or prevention of relapse. Such induction therapy is especially important for immunosuppressed patients and those with severe fungal pneumonia, cryptococcal meningitis with altered mental status, or sepsis syndrome due to fungal infection. Once a clinical response has been elicited, these patients will then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse. Amphotericin has also been used as empiric therapy for selected patients in whom the risks of leaving a systemic fungal infection untreated are high. The most common such patient is the cancer patient with neutropenia who remains febrile on broad-spectrum antibiotics.
For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1 mg/kg/d. It is usually continued to a defined total dose (eg, 1–2 g), rather than a defined time span, as used with other antimicrobial drugs.
Intrathecal therapy for fungal meningitis is poorly tolerated and fraught with difficulties related to maintaining cerebrospinal fluid access. Thus, intrathecal therapy with amphotericin B is being increasingly supplanted by other therapies but remains an option in cases of fungal central nervous system infections that have not responded to other agents.
Local administration of amphotericin B has been used with success. Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival injection. Fungal arthritis has been treated with adjunctive local injection directly into the joint. Candiduria responds to bladder irrigation with amphotericin B, and this route has been shown to produce no significant systemic toxicity.
Flucytosine
Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. While devoid of anticancer properties, it became apparent that it was a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B.
Pharmacokinetics
Flucytosine is currently available in
Mechanism of Action
Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively. Human cells are unable to convert the parent drug to its active metabolites.
Synergy with amphotericin B has been demonstrated in vitro and in vivo. It may be related to enhanced penetration of the flucytosine through amphotericin-damaged fungal cell membranes. In vitro synergy with azole drugs has also been seen, although the mechanism is unclear. Resistance is thought to be mediated through altered metabolism of flucytosine, and, while uncommon in primary isolates, it develops rapidly in the course of flucytosine monotherapy.
Adverse Effects
The adverse effects of flucytosine result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently. A form of toxic enterocolitis can occur. There seems to be a narrow therapeutic window, with an increased risk of toxicity at higher drug levels and resistance developing rapidly at subtherapeutic concentrations. The use of drug concentration measurements may be helpful in reducing the incidence of toxic reactions, especially when flucytosine is combined with nephrotoxic agents such as amphotericin B.
Clinical Use
The spectrum of activity of flucytosine is restricted to Cryptococcus neoformans, some candida species, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis.
Azoles
Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring as indicated below. The imidazoles consist of ketoconazole, miconazole, and clotrimazole (Figure 48–1). The latter two drugs are now used only in topical therapy. The triazoles include itraconazole, fluconazole, and voriconazole.
Pharmacology
The pharmacology of each of the azoles is unique and accounts for some of the variations in clinical use. Table 48–2 summarizes the differences among four of the theirazoles.
Mechanism of Action
The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects. Resistance to azoles occurs via multiple mechanisms. Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance in certain settings.
Clinical Use
The spectrum of action of these medications is quite broad, ranging from many candida species, Cryptococcus neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole and voriconazole, even aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as Pseudallescheria boydii.
Adverse Effects
As a group, the azoles are relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. Adverse effects specific to individual agents are discussed below.
Drug Interactions
All azole drugs affect the mammalian cytochrome P450 system of enzymes to some extent, and consequently they are prone to drug interactions. The most significant reactions are indicated below.
Liposomal Amphotericin B
Therapy with amphotericin B is often limited by toxicity, especially drug-induced renal impairment. This has led to the development of lipid drug formulations on the assumption that lipid-packaged drug will bind to the mammalian membrane less readily, permitting the use of effective doses of the drug with lower toxicity. Liposomal amphotericin preparations package the active drug in lipid delivery vehicles, in contrast to the colloidal suspensions currently in use. Amphotericin binds to the lipids in these vehicles with an affinity between that for fungal ergosterol and that for human cholesterol. The lipid vehicle then serves as an amphotericin reservoir, reducing nonspecific binding to human cell membranes. This preferential binding allows for a reduction of toxicity without sacrificing efficacy and permits use of larger doses. Furthermore, some fungi contain lipases that may liberate free amphotericin B directly at the site of infection.
Three such formulations are now available and have differing pharmacologic properties as summarized in Table 48–1. While clinical trials have demonstrated different renal and infusionrelated toxicities for these preparations compared with regular amphotericin B, there are no trials comparing the different formulations with each other. Limited studies have suggested at best a moderate improvement in the clinical efficacy of the lipid formulations compared to conventional amphotericin B. Because the lipid preparations are much more expensive, their use is usually restricted to patients intolerant to, or not responding to, conventional amphotericin treatment.
Systemic Antifungal Drugs for Mucocutaneous Infections
Griseofulvin
Griseofulvin is a very insoluble fungistatic drug derived from a species of penicillium. It is administered in a microcrystalline form at a dosage of 1 g/d. Absorption is improved when it is given with fatty foods. Griseofulvin’s mechanism of action at the cellular level is unclear, but it is deposited iewly forming skin where it binds to keratin, protecting the skin from new infection. Since its action is to prevent infection of these new skin structures, it must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse. Adverse effects include an allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital. Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine.
Terbinafine
Terbinafine is a synthetic allylamine that is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses, especially onychomycosis. Like griseofulvin, it is a keratophilic medication, but unlike griseofulvin, it is fungicidal. Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase. This leads to the accumulation of the sterol squalene, which is toxic to the organism.
One tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis and is more effective than griseofulvin or itraconazole. Adverse effects are rare, consisting primarily of gastrointestinal upset and headache. Terbinafine does not seem to affect the P450 system and has demonstrated no significant drug interactions to date.
Nystatin
Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration and is only used topically. It is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. Nystatin is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, it has little toxicity, though oral use is often limited by the unpleasant taste.
Nystatin is active against most candida species and is most commonly used for suppression of local candidal infections. Some common indications include oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal infections.
1. http://www.youtube.com/watch?v=LM-ynizbdFQ&feature=related
2. http://www.youtube.com/watch?v=0wK1127fHQ4&feature=related
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5. http://www.apchute.com/moa.htm
6. http://www.apchute.com/moa.htm
7. http://www.apchute.com/moa.htm
8. http://www.youtube.com/watch?v=Btqlf6Rs_Ek&feature=related
9. http://www.youtube.com/watch?v=2uehdqZzKEM&feature=related
10. http://www.youtube.com/watch?v=07Tr__R_koE&feature=related
11. http://www.youtube.com/watch?v=8zYIEiXvSZY&feature=related
12. http://www.youtube.com/watch?v=0qGNuAUy-Dc&feature=related
13. http://www.youtube.com/watch?v=xiuWdJYyIKs
14. http://www.apchute.com/moa.htm
