Herpes simplex virus type 1 typically causes diseases of the mouth, face, skin, esophagus, or brain. HSV-2 usually causes infections of the genitals, rectum, skin, hands, or meninges. Both cause serious infections in neonates. Agents used in treating HSV work by several mechanisms to inhibit viral DNA replication in the host cell (Figure 62–1; Table 62–1).
Acyclovir and Valacyclovir
Acyclovir is an acyclic guanine nucleoside analogue that lacks the 2′ and 3′ positions normally supplied by ribose. Valacyclovir is the L-valyl ester prodrug of acyclovir. Acyclovir is the prototype of a group of antiviral agents that are nucleoside congeners (see Figure 62–2) that are phosphorylated intracellularly by a viral kinase and subsequently by host cell enzymes to become inhibitors of viral DNA synthesis. Related agents include penciclovir and ganciclovir.
Chemical structures of some antiherpes drugs. Many antiherpes agents are nucleoside congeners that are phosphorylated sequentially by viral and host kinases to become triphosphate inhibitors of viral DNA synthesis (see Figure 62–3). Foscarnet is a pyrophosphate analogue that selectively blocks the pyrophosphate binding site on viral DNA polymerases, thereby inhibiting chain elongation.
Mechanisms of Action and Resistance
Acyclovir inhibits viral DNA synthesis via a mechanism outlined in Figure 62–3. Its selectivity of action depends on interaction with HSV TK (thymidine kinase) and DNA polymerase. The initial phosphorylation of acyclovir is facilitated by HSV TK and thus occurs only in cells infected with the virus. The affinity of acyclovir for HSV TK is about 200 times greater than for the mammalian enzyme. Cellular enzymes convert the monophosphate to acyclovir triphosphate, which competes for endogenous dGTP. The immunosuppressive agent mycophenolate mofetil (see Chapter 35) potentiates the antiherpes activity of acyclovir and related agents by depleting intracellular dGTP pools. Acyclovir triphosphate competitively inhibits viral DNA polymerases and, to a much lesser extent, cellular DNA polymerases. Acyclovir triphosphate also is incorporated into viral DNA, where it acts as a chain terminator because of the lack of a 3′-hydroxyl group. By a mechanism termed suicide inactivation, the terminated DNA template containing acyclovir binds the viral DNA polymerase and leads to its irreversible inactivation.
Acyclovir inhibits DNA synthesis by HSV DNA polymerase. After penetrating the membrane of a susceptible mammalian host cell, an HSV virion releases its capsid, which delivers viral DNA into the host cell, initiating viral DNA synthesis. Acyclovir, a guanine analogue, inhibits viral but not mammalian DNA polymerase. A. DNA synthesis with mammalian DNA polymerase (insensitive to acyclovir). In the presence of acyclovir, human DNA synthesis proceeds normally. Here, mammalian DNA polymerase removes pyrophosphate (PPi) PPi (----) from dGTP and uses dGTP to add a dGMP to the 3′ end of a growing nucleic acid polymer, the guanine base pairing with a cytosine and dGMP’s 5′PO4 bonding to the 3′OH group on the ribose of the preceding base, thymine. A 3′OH on the sugar of the added dGMP is available to form a 3′-5′ bond with the next nucleotide added. B. DNA synthesis in host cell by HSV DNA polymerase (sensitive to acyclovir). The guanine analogue acyclovir inhibits viral DNA polymerase by acting as a terminal substrate, but to do so, acyclovir must be phosphorylated to acyclovir triphosphate. The first phosphate group is added by the HSV TK, which has an affinity for acyclovir that is about 200 times that of the mammalian enzyme for acyclovir. Host cell enzymes add the second and third phosphates, producing acyclovir triphosphate, which concentrates 40- to 100-fold in HSV-infected cells over the concentrations in uninfected cells. Thus, acyclovir triphosphate competes well for endogenous dGTP. HSV DNA polymerase cleaves PPi (----) from acyclovir triphosphate and adds acyclovir monophosphate to the 3′ end of the growing DNA strand. Acyclovir lacks a hydroxyl group in the 3′ position (indeed, it lacks that 3′ position), and further addition to the polymer by HSV DNA polymerase is not possible. Furthermore, a viral exonuclease activity associated with viral DNA polymerase cannot remove the acyclovir moiety. Compare the actions of acyclovir to those of ganciclovir and penciclovir, which have 3′OH groups, and to foscarnet, which binds avidly at the PPi cleavage site of HSV DNA polymerase, preventing cleavage of PPi from nucleoside triphosphates.
Acyclovir resistance in HSV can result from impaired production of viral TK, altered TK substrate specificity (e.g., phosphorylation of thymidine but not acyclovir), or altered viral DNA polymerase. Alterations in viral enzymes are caused by point mutations and base insertions or deletions in the corresponding genes. Resistant variants are present in native virus populations and in isolates from treated patients. The most common resistance mechanism in clinical HSV isolates is absent or deficient viral TK activity; viral DNA polymerase mutants are rare. Phenotypic resistance typically is defined by in vitro inhibitory concentrations of more than 2–3 μg/mL, which predict failure of therapy in immunocompromised patients. Acyclovir resistance in VZV isolates is caused by mutations in VZV TK and less often by mutations in viral DNA polymerase.
The oral bioavailability of acyclovir is about 10%–30% and decreases with increasing dose (Wagstaff et al., 1994). Delivery of an oral dose can be enhanced by administration of the the prodrug form, valacyclovir. Valacyclovir is an esterified version with higher bioavailability (55%–70%) than acyclovir (Steingrimsdottir et al., 2000); deesterification occurs rapidly and nearly completely following oral administration. Unlike acyclovir, valacyclovir is a substrate for intestinal and renal peptide transporters. Acyclovir distributes widely in body fluids, including vesicular fluid, aqueous humor, and CSF. Compared with plasma, salivary concentrations are low, and concentrations in vaginal secretion vary widely. Acyclovir is concentrated in breast milk, amniotic fluid, and placenta. Newborn plasma levels are similar to maternal ones. Percutaneous absorption of acyclovir after topical administration is low. Renal excretion of unmetabolized acyclovir by glomerular filtration and tubular secretion is the principal route of elimination. The elimination t1/2 of acyclovir is about 2.5 h (range 1.5–6 h) in adults with normal renal function. In neonates, the elimination t1/2 of acyclovir is about 4 h and increases to 20 h in anuric patients.
Acyclovir’s clinical use is limited to herpesviruses. Acyclovir is most active against HSV-1 (effective CP range: 0.02–0.9 μg/mL), approximately half as active against HSV-2 (0.03–2.2 μg/mL), a tenth as potent against VZV (0.8–4.0 μg/mL) and EBV, and least active against CMV (generally > 20 μg/mL) and HHV-6. Uninfected mammalian cell growth generally is unaffected by high acyclovir concentrations (> 50 μg/mL).
In immunocompetent persons, the clinical benefits of acyclovir and valacyclovir are greater in initial HSV infections than in recurrent ones. These drugs are particularly useful in immunocompromised patients because these individuals experience both more frequent and more severe HSV and VZV infections. Because VZV is less susceptible than HSV to acyclovir, higher doses must be used for treating VZV infections. Oral valacyclovir is as effective as oral acyclovir in HSV infections and more effective for treating herpes zoster. Acyclovir is ineffective therapeutically in established CMV infections, but ganciclovir is effective for CMV prophylaxis in immunocompromised patients. EBV-related oral hairy leukoplakia may improve with acyclovir. Oral acyclovir in conjunction with systemic corticosteroids appears beneficial in treating Bell palsy; valacyclovir is ineffective in acute vestibular neuritis.
Herpes Simplex Virus Infections
In initial genital HSV infections, oral acyclovir (200 mg five times daily or 400 mg three times daily for 7–10 days) and valacyclovir (1000 mg twice daily for 7–10 days) are associated with significant reductions in virus shedding, symptoms, and time to healing (Kimberlin and Rouse, 2004). Intravenous acyclovir (5 mg/kg every 8 h) has similar effects in patients hospitalized with severe primary genital HSV infections. Topical acyclovir is much less effective than systemic administration. None of these regimens reproducibly reduces the risk of recurrent genital lesions. Acyclovir (200 mg five times daily or 400 mg three times daily for 5 days or 800 mg three times daily for 2 days) or valacyclovir (500 mg twice daily for 3 or 5 days) shortens the manifestations of recurrent genital HSV episodes by 1–2 days. Frequently recurring genital herpes can be suppressed effectively with chronic oral acyclovir (400 mg twice daily or 200 mg three times daily) or with valacyclovir (500 mg or, for very frequent recurrences, 1000 mg once daily). During use, the rate of clinical recurrences decreases by about 90%, and subclinical shedding is markedly reduced, although not eliminated. Valacyclovir suppression of genital herpes reduces the risk of transmitting infection to a susceptible partner by about 50% over an 8-month period (Corey et al., 2004). Chronic suppression may be useful in those with disabling recurrences of herpetic whitlow or HSV-related erythema multiforme.
Oral acyclovir is effective in primary herpetic gingivostomatitis (600 mg/m2 four times daily for 10 days in children) but provides only modest clinical benefit in recurrent orolabial herpes. Short-term, high-dose valacyclovir (2 g twice over 1 day) shortens the duration of recurrent orolabial herpes by about 1 day (Elish et al., 2004). The FDA has approved an acyclovir/hydrocortisone combination (Lipsovir) for early treatment of recurrent herpes cold sores. Topical acyclovir cream is modestly effective in recurrent labial (Spruance et al., 2002) and genital herpes simplex virus infections. Preexposure acyclovir prophylaxis (400 mg twice daily for 1 week) reduces the overall risk of recurrence by 73% in those with sun-induced recurrences of HSV infections. Acyclovir during the last month of pregnancy reduces the likelihood of viral shedding and the frequency of cesarean delivery in women with primary or recurrent genital herpes (Corey and Wald, 2009).
In immunocompromised patients with mucocutaneous HSV infection, intravenous acyclovir (250 mg/m2 every 8 h for 7 days) shortens healing time, duration of pain, and the period of virus shedding. Oral acyclovir (800 mg five times per day) and valacyclovir (1000 mg twice daily) for 5–10 days are also effective. Recurrences are common after cessation of therapy and may require long-term suppression. In those with very localized labial or facial HSV infections, topical acyclovir may provide some benefit. Intravenous acyclovir may be beneficial in viscerally disseminating HSV in immunocompromised patients and in patients with HSV-infected burn wounds.
Systemic acyclovir prophylaxis is highly effective in preventing mucocutaneous HSV infections in seropositive patients undergoing immunosuppression. Intravenous acyclovir (250 mg/m2 every 8–12 h) begun prior to transplantation and continuing for several weeks prevents HSV disease in bone marrow transplant recipients. For patients who can tolerate oral medications, oral acyclovir (400 mg five times daily) is effective, and long-term oral acyclovir (200–400 mg three times daily for 6 months) also reduces the risk of VZV infection (Steer et al., 2000). In HSV encephalitis, acyclovir (10 mg/kg every 8 h for a minimum of 10 days) reduces mortality by more than 50% and improves overall neurologic outcome compared with vidarabine. Higher doses (15–20 mg/kg every 8 h) and prolonged treatment (up to 21 days) are recommended by many experts. Intravenous acyclovir (20 mg/kg every 8 h for 21 days) is more effective than lower doses in viscerally invasive neonatal HSV infections (Kimberlin et al., 2001). In neonates and immunosuppressed patients and, rarely, in previously healthy persons, relapses of encephalitis following acyclovir may occur. The value of continuing long-term suppression with valacyclovir after completing intravenous acyclovir is under study.
An ophthalmic formulation of acyclovir (not available in the U.S.) is at least as effective as topical vidarabine or trifluridine in herpetic keratoconjunctivitis.
Infection owing to resistant HSV is rare in immunocompetent persons; however, in immunocompromised hosts, acyclovir-resistant HSV isolates can cause extensive mucocutaneous disease and, rarely, meningoencephalitis, pneumonitis, or visceral disease. Resistant HSV can be recovered from 4% to 7% of immunocompromised patients receiving acyclovir treatment. Recurrences after cessation of acyclovir usually are due to sensitive virus but may be due to acyclovir-resistant virus in patients with AIDS. In patients with progressive disease, intravenous foscarnet therapy is effective, and vidarabine is considered only when all other therapies have failed (Chilukuri and Rosen, 2003).
Acyclovir generally is well tolerated. Chronic acyclovir suppression of genital herpes has been used safely for up to 10 years. No excess frequency of congenital abnormalities has been recognized in infants born to women exposed to acyclovir during pregnancy (Ratanajamit et al., 2003). Topical acyclovir in a polyethylene glycol base may cause mucosal irritation and transient burning when applied to genital lesions. Oral acyclovir has been associated infrequently with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Valacyclovir also may be associated with headache, nausea, diarrhea, nephrotoxicity, and CNS symptoms (confusion, hallucinations). Uncommon side effects include severe thrombocytopenic syndromes, sometimes fatal, in immunocompromised patients. Acyclovir has been associated with neutropenia in neonates. The principal dose-limiting toxicities of intravenous acyclovir are renal insufficiency and CNS side effects. Nephrotoxicity usually resolves with drug cessation and volume expansion. Hemodialysis may be useful in severe cases. Severe somnolence and lethargy may occur with combinations of zidovudine (see Chapter 59) and acyclovir. Concomitant cyclosporine and probably other nephrotoxic agents enhance the risk of nephrotoxicity. Probenecid decreases the acyclovir renal clearance and prolongs the elimination t1/2. Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion, such as methotrexate.
Cidofovir is a cytidine nucleotide analogue with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses.
Because cidofovir is a phosphonate that is phosphorylated by cellular but not viral enzymes, it inhibits acyclovir-resistant TK-deficient or TK-altered HSV or VZV strains, ganciclovir-resistant CMV strains with UL97 mutations (but not those with DNA polymerase mutations), and some foscarnet-resistant CMV strains. Cidofovir synergistically inhibits CMV replication in combination with ganciclovir or foscarnet.
Mechanisms of Action and Resistance
Cidofovir inhibits viral DNA synthesis by slowing and eventually terminating chain elongation. Cidofovir is metabolized to its active diphosphate form by cellular enzymes; the levels of phosphorylated metabolites are similar in infected and uninfected cells. The diphosphate acts as both a competitive inhibitor with respect to dCTP and as an alternative substrate for viral DNA polymerase.
Cidofovir resistance in CMV is due to mutations in viral DNA polymerase. Low-level resistance to cidofovir develops in up to about 30% of patients with retinitis by 3 months of therapy. Highly ganciclovir-resistant CMV isolates that possess DNA polymerase and UL97 kinase mutations are resistant to cidofovir, and prior ganciclovir therapy may select for cidofovir resistance. Some foscarnet-resistant CMV isolates show cross-resistance to cidofovir, and triple-drug-resistant variants with DNA polymerase mutations occur.
Cidofovir has very low oral bioavailability. Penetration into the CSF is low. Topical cidofovir gel may result in low plasma concentrations (<0.5 μg/mL) in patients with large mucocutaneous lesions. Plasma levels after intravenous dosing decline in a biphasic pattern with a terminal t1/2 that averages 2.6 h. The active form, cidofovir diphosphate, has a prolonged intracellular t1/2 and competitively inhibits CMV and HSV DNA polymerases at concentrations one-eighth to one six-hundredth of those required to inhibit human DNA polymerases (Hitchcock et al., 1996). A phosphocholine metabolite also has a long intracellular t1/2 (about 87 h) and may serve as an intracellular reservoir of drug. The prolonged intracellular t1/2 of cidofovir diphosphate allows infrequent (weekly or biweekly) dosing regimens. Cidofovir is cleared by the kidney via glomerular filtration and tubular secretion. Over 90% of the dose is recovered unchanged in the urine. Probenecid blocks tubular transport of cidofovir and reduces renal clearance and associated nephrotoxicity. Elimination relates linearly to creatinine clearance; the t1/2 increases to 32.5 h in patients on CAPD. Hemodialysis removes more than 50% of the administered dose.
Intravenous cidofovir is approved for the treatment of CMV retinitis in HIV-infected patients. Intravenous cidofovir has been used for treating acyclovir-resistant mucocutaneous HSV infection, adenovirus disease in transplant recipients, and extensive molluscum contagiosum in HIV patients. Reduced doses without probenecid may be beneficial in BK virus nephropathy in patients with a renal transplant. Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been used in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neoplasia in women. Intralesional cidofovir induces remissions in adults and children with respiratory papillomatosis.
Nephrotoxicity is the principal dose-limiting side effect of intravenous cidofovir. Concomitant oral probenecid and saline prehydration reduce the risk of renal toxicity; however, probenecid alters renal clearance of many agents, albeit not of cidofovir. For example, probenecid alters zidovudine pharmacokinetics such that zidovudine doses should be reduced when probenecid is present, as should the doses of other drugs whose renal secretion probenecid inhibits (e.g., β-lactam antibiotics, NSAIDs, acyclovir, lorazepam, furosemide, methotrexate, theophylline, and rifampin). On maintenance doses of 5 mg/kg every 2 weeks, up to 50% of patients develop proteinuria, 10%–15% show an elevated serum creatinine concentration, and 15%–20% develop neutropenia. Anterior uveitis that is responsive to topical corticosteroids and cycloplegia occurs commonly, and low intraocular pressure occurs infrequently with intravenous cidofovir. Administration with food and pretreatment with antiemetics, antihistamines, or acetaminophen may improve tolerance. Concurrent nephrotoxic agents are contraindicated, and at least 7 days should elapse before initiation of cidofovir treatment is recommended after prior exposure to aminoglycosides, intravenous pentamidine, amphotericin B, foscarnet, NSAID, or contrast dye. Cidofovir and oral ganciclovir are poorly tolerated in combination at full doses.
Topical application of cidofovir is associated with dose-related application site reactions (e.g., burning, pain, and pruritus) in up to one-third of patients and occasionally ulceration. Cidofovir is considered a potential human carcinogen. It may cause infertility and is classified as pregnancy category C.
Famciclovir and Penciclovir
Famciclovir is the diacetyl ester prodrug of 6-deoxy penciclovir and lacks intrinsic antiviral activity. Penciclovir is an acyclic guanine nucleoside analogue. Penciclovir is similar to acyclovir in its spectrum of activity and potency against HSV and VZV. It also is inhibitory for HBV.
Mechanisms of Action and Resistance
Penciclovir is an inhibitor of viral DNA synthesis. In HSV- or VZV-infected cells, penciclovir is phosphorylated initially by viral TK. Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase (see Figure 62–3). Although penciclovir triphosphate is approximately a one-hundredth as potent as acyclovir triphosphate in inhibiting viral DNA polymerase, it is present in infected cells at much higher concentrations and for more prolonged periods. The prolonged intracellular t1/2 of penciclovir triphosphate, 7–20 h, is associated with prolonged antiviral effects. Because penciclovir has a 3′-hydroxyl group, it is not an obligate chain terminator but does inhibit DNA elongation. Resistance during clinical use is low. TK-deficient, acyclovir-resistant herpesviruses are cross-resistant to penciclovir.
Oral penciclovir has low (<5%) bioavailability. In contrast, famciclovir is well absorbed orally (bioavailability ~75%) and is converted rapidly to penciclovir by deacetylation of the side chain and oxidation of the purine ring during and following absorption. Food slows absorption but does not reduce overall bioavailability. The plasma elimination t1/2 of penciclovir averages about 2 h, and more than 90% is excreted unchanged in the urine. Following oral famciclovir administration, nonrenal clearance accounts for about 10% of each dose, primarily through fecal excretion, but penciclovir (60% of dose) and its 6-deoxy precursor (<10% of dose) are eliminated primarily in the urine. The plasma t1/2 averages 9.9 h in renal insufficiency (Clcr < 30 mL/min); hemodialysis efficiently removes penciclovir.
Oral famciclovir, topical penciclovir, and intravenous penciclovir are approved for managing HSV and VZV infections.
Oral famciclovir (250 mg three times a day for 7–10 days) is as effective as acyclovir in treating first-episode genital herpes (Kimberlin and Rouse, 2004). In patients with recurrent genital HSV, patient-initiated famciclovir treatment (125 or 250 mg twice daily for 5 days) reduces healing time and symptoms by about 1 day. Famciclovir (250 mg twice daily for up to 1 year) is effective for suppression of recurrent genital HSV, but single daily doses are less effective. Higher doses (500 mg twice daily) reduce HSV recurrences in HIV-infected persons. Intravenous penciclovir (5 mg/kg every 8 or 12 h for 7 days) (not available in the U.S.) is comparable to intravenous acyclovir for treating mucocutaneous HSV infections in immunocompromised hosts. In immunocompetent persons with recurrent orolabial HSV, topical 1% penciclovir cream (applied every 2 h while awake for 4 days) shortens healing time and symptoms by about 1 day (Raborn et al., 2002).
In immunocompetent adults with herpes zoster of 3 days’ duration or less, famciclovir (500 mg three times a day for 10 days) is at least as effective as acyclovir (800 mg five times daily) in reducing healing time and zoster-associated pain, particularly in those 50 years or older. Famciclovir is comparable with valacyclovir in treating zoster and reducing associated pain in older adults (Tyring et al., 2000). Famciclovir (500 mg three times a day for 7–10 days) also is comparable with high-dose oral acyclovir in treating zoster in immunocompromised patients and in those with ophthalmic zoster (Tyring et al., 2001).
Famciclovir is associated with dose-related reductions in HBV DNA and transaminase levels in patients with chronic HBV hepatitis but is less effective than lamivudine (Lai et al., 2002). Famciclovir is also ineffective in treating lamivudine-resistant HBV infections owing to emergence of multiply resistant variants.
Oral famciclovir is associated with headache, diarrhea, and nausea. Urticaria, rash, and hallucinations or confusional states (predominantly in the elderly) have been reported. Topical penciclovir (~1%) rarely is associated with local reactions. The short-term tolerance of famciclovir is comparable with that of acyclovir. Penciclovir is mutagenic at high concentrations. Long-term administration (1 year) does not affect spermatogenesis in men. Safety during pregnancy has not been established.
Ganciclovir and Valganciclovir
Ganciclovir is an acyclic guanine nucleoside analogue that is similar in structure to acyclovir. Valganciclovir is the L-valyl ester prodrug of ganciclovir. Ganciclovir has inhibitory activity against all herpesviruses and is especially active against CMV.
Mechanisms of Action and Resistance
Ganciclovir inhibits viral DNA synthesis. It is monophosphorylated intracellularly by viral TK during HSV infection and by a viral phosphotransferase encoded by the UL97 gene during CMV infection. Ganciclovir diphosphate and ganciclovir triphosphate are formed by host enzymes. At least 10-fold higher concentrations of ganciclovir triphosphate are present in CMV-infected than in uninfected cells. The triphosphate is a competitive inhibitor of dGTP incorporation into DNA and preferentially inhibits viral rather than host cellular DNA polymerases. Incorporation into viral DNA causes eventual cessation of DNA chain elongation (see Figures 62–1A and 62–3).
Cytomegalovirus can become resistant to ganciclovir by either of two mechanisms: reduced intracellular ganciclovir phosphorylation owing to mutations in the viral phosphotransferase and mutations in viral DNA polymerase. Highly resistant variants with both mutations are cross-resistant to cidofovir and variably to foscarnet. Ganciclovir also is much less active against acyclovir-resistant TK-deficient HSV strains.
The oral bioavailability of ganciclovir is low, only 6%–9% following ingestion with food. On the other hand, oral doses of the prodrug valganciclovir are well absorbed and hydrolyzed rapidly to ganciclovir; thus, valganciclovir provides greater bioavailability of the vanciclovir moiety, about 60%. Food further increases the bioavailability of valganciclovir by about 25%. Following intravenous administration of ganciclovir, vitreous fluid levels are similar to or higher than those in plasma and decline with a t1/2 of 23–26 h. Intraocular sustained-release ganciclovir implants provide vitreous levels of about 4.1 μg/mL. The plasma elimination t1/2 is about 2–4 h. Intracellular ganciclovir triphosphate concentrations are 10-fold higher than those of acyclovir triphosphate and decline much more slowly, with an intracellular elimination t1/2 longer than 24 h. These differences may account in part for ganciclovir’s greater anti-CMV activity and provide the rationale for single daily doses in suppressing human CMV infections. Over 90% of ganciclovir is eliminated unchanged by renal excretion. Plasma t1/2 increases in patients with severe renal insufficiency.
In CMV retinitis, initial induction treatment (5 mg/kg IV every 12 h for 10–21 days) is associated with improvement or stabilization in about 85% of patients (Faulds and Heel, 1990). Reduced viral excretion is usually evident by 1 week, and funduscopic improvement is seen by 2 weeks. Because of the high risk of relapse, patients with AIDS with retinitis require suppressive therapy with high doses of ganciclovir (5 mg/kg/d). Oral ganciclovir (1000 mg three times daily) is effective for suppression of retinitis after initial intravenous treatment but has been replaced in practice by oral valganciclovir. Oral valganciclovir (900 mg twice daily for 21 days of initial treatment) is comparable with intravenous dosing for initial control and sustained suppression (900 mg daily) of CMV retinitis (Schreiber et al., 2009). Intravitreal ganciclovir injections have been used in some patients, and an intraocular sustained-release ganciclovir implant is more effective than systemic dosing in suppressing retinitis progression.
Ganciclovir therapy (5 mg/kg every 12 h for 14–21 days) may benefit other CMV syndromes in patients with AIDS or recipients of solid-organ transplants (Kotton et al., 2010). Ganciclovir has been used for both prophylaxis and preemptive therapy of CMV infections in transplant recipients (Schreiber et al., 2009).
A ganciclovir ophthalmic gel formulation (Zirgan) is effective in treating HSV keratitis (Colin et al., 1997). Oral ganciclovir also reduces HBV DNA levels and aminotransferase levels in chronic hepatitis B virus infection (Hadziyannis et al., 1999), but the drug is not approved for this indication.
Myelosuppression is the principal dose-limiting toxicity of ganciclovir. Neutropenia occurs in about 15%–40% of patients and is observed most commonly during the second week of treatment and usually is reversible within 1 week of drug cessation. Persistent fatal neutropenia has occurred. Recombinant G-CSF (filgrastim, lenograstim) may be useful in treating ganciclovir-induced neutropenia (see Chapter 41). Thrombocytopenia occurs in 5%–20% of patients. Zidovudine and probably other cytotoxic agents increase the risk of myelosuppression, as do nephrotoxic agents that impair ganciclovir excretion. Probenecid and possibly acyclovir reduce renal clearance of ganciclovir. Oral ganciclovir increases the absorption and peak plasma concentrations of didanosine by approximately 2-fold and that of zidovudine by about 20%. CNS side effects (5%–15%) range in severity from headache to behavioral changes to convulsions and coma. About one-third of patients must interrupt or prematurely stop intravenous ganciclovir therapy because of bone marrow or CNS toxicity. Infusion-related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities, nausea or vomiting, and eosinophilia also have been described. Ganciclovir is classified as pregnancy category C (risk not ruled out).
Foscarnet (trisodium phosphonoformate) is an inorganic pyrophosphate analogue that is inhibitory for all herpesviruses and HIV.
Mechanisms of Action and Resistance
Foscarnet inhibits viral nucleic acid synthesis by interacting directly at HSV DNA polymerase or HIV reverse transcriptase (see Figures 62–1A and 62–3). Foscarnet reversibly blocks the pyrophosphate binding site of the viral DNA polymerase, inhibiting cleavage of pyrophosphate from deoxynucleotide triphosphates and thereby inhibiting chain elongation (deoxynucleotide triphosphate + DNAn → diphosphate + DNAn+1). Foscarnet has about 100-fold greater inhibitory effects against herpesvirus DNA polymerases than against cellular DNA polymerase α. Herpesviruses resistant to foscarnet have point mutations in the viral DNA polymerase.
Foscarnet is poorly soluble in aqueous solutions and requires large volumes for administration; in addition, the drug’s oral bioavailability is low. Vitreous levels approximate those in plasma; CSF levels average 66% of those in plasma at steady state. Over 80% of foscarnet is excreted unchanged in the urine. Dose adjustments are necessary for small decreases in renal function. Plasma elimination has initial bimodal half-lives totaling 4–8 h and a prolonged terminal elimination t1/2 of 3–4 days. Sequestration in bone with gradual release accounts for the fate of an estimated 10%–20% of a given dose. Foscarnet is cleared efficiently by hemodialysis (~50% of a dose).
Intravenous foscarnet is effective for treatment of CMV retinitis, including ganciclovir-resistant infections, other types of CMV infection, and acyclovir-resistant HSV and VZV infections.
In CMV retinitis in patients with AIDS, foscarnet (60 mg/kg every 8 h or 90 mg/kg every 12 h for 14–21 days followed by chronic maintenance at 90 to 120 mg/kg every day in one dose) is associated with clinical stabilization in about 90% of patients. In CMV retinitis in patients with AIDS, foscarnet (60 mg/kg every 8 h or 90 mg/kg every 12 h for 14–21 days followed by chronic maintenance at 90 to 120 mg/kg every day in one dose) is associated with clinical stabilization in about 90% of patients. When used for preemptive therapy of CMV viremia in bone marrow transplant recipients, foscarnet (60 mg/kg every 12 h for 2 weeks followed by 90 mg/kg daily for 2 weeks) is as effective as intravenous ganciclovir and causes less neutropenia (Reusser et al., 2002). When used for CMV infections, foscarnet may reduce the risk of Kaposi sarcoma in HIV-infected patients. Intravitreal injections of foscarnet also have been used. In acyclovir-resistant mucocutaneous HSV infections, lower doses of foscarnet (40 mg/kg every 8 h for ≥ 7 days) are associated with cessation of viral shedding and with complete healing of lesions in about three-quarters of patients. Foscarnet also appears to be effective in acyclovir-resistant VZV infections. Topical foscarnet cream is ineffective in treating recurrent genital HSV in immunocompetent persons but appears to be useful in chronic acyclovir-resistant infections in immunocompromised patients.
Major dose-limiting toxicities are nephrotoxicity and symptomatic hypocalcemia. Increases in serum creatinine occur in up to one-half of patients but are generally reversible after cessation. High doses, rapid infusion, dehydration, prior renal insufficiency, and concurrent nephrotoxic drugs are risk factors. Saline loading may reduce the risk of nephrotoxicity. Foscarnet is highly ionized at physiological pH, and metabolic abnormalities are very common. These include increases or decreases in Ca2+ and phosphate, hypomagnesemia, and hypokalemia. Concomitant intravenous pentamidine administration increases the risk of symptomatic hypocalcemia. CNS side effects include headache (25%), tremor, irritability, seizures, and hallucinosis. Other reported side effects are generalized rash, fever, nausea or emesis, anemia, leukopenia, abnormal liver function tests, electrocardiographic changes, infusion-related thrombophlebitis, and painful genital ulcerations. Topical foscarnet may cause local irritation and ulceration, and oral foscarnet may cause GI disturbance. Preclinical studies indicate that high foscarnet concentrations are mutagenic. Safety in pregnancy or childhood is uncertain.
Fomivirsen, a 21-base phosphorothioate oligonucleotide, provides antisense therapy. The drug is complementary to the mRNA sequence for the major immediate-early transcriptional region of CMV and inhibits CMV replication through sequence-specific and nonspecific mechanisms, including inhibition of virus binding to cells. Fomivirsen is active against CMV strains resistant to ganciclovir, foscarnet, and cidofovir. Fomivirsen is given by intravitreal injection in the treatment of CMV retinitis for patients intolerant of or unresponsive to other therapies. Following injection, it is cleared slowly from the vitreous (t1/2 ~ 55 h) through distribution to the retina and probable exonuclease digestion. In HIV-infected patients with refractory, sight-threatening CMV retinitis, fomivirsen injections (330 μg weekly for 3 weeks and then every 2 weeks or on days 1 and 15 followed by monthly) significantly delay time to retinitis progression. Ocular side effects include iritis in up to one-quarter of patients, which can be managed with topical corticosteroids; vitritis; cataracts; and increases in intraocular pressure in 15%–20% of patients. Recent cidofovir use may increase the risk of inflammatory reactions. This drug is no longer available in the U.S.
Docosanol is a long-chain saturated alcohol that is approved as an over-the-counter 10% cream for the treatment of recurrent orolabial herpes. Docosanol inhibits the in vitro replication of many lipid-enveloped viruses, including HSV. It does not inactivate HSV directly but appears to block fusion between the cellular and viral envelope membranes and inhibits viral entry into the cell. Topical treatment beginning within 12 h of prodromal symptoms or lesion onset reduces healing time by about 1 day and is well tolerated. Treatment initiation at papular or later stages provides no benefit.
Idoxuridine is an iodinated thymidine analogue that inhibits the in vitro replication of various DNA viruses, including herpesviruses and poxviruses. Idoxuridine lacks selectivity, in that low concentrations inhibit the growth of uninfected cells. The triphosphate inhibits viral DNA synthesis and is incorporated into both viral and cellular DNA. In the U.S., idoxuridine is approved only for topical (ophthalmic) treatment of HSV keratitis. Idoxuridine formulated in dimethylsulfoxide is available outside the U.S. for topical treatment of herpes labialis, genitalis, and zoster. Adverse reactions include pain, pruritus, inflammation, and edema of the eye or lids; allergic reactions are rare.
Trifluridine is a fluorinated pyrimidine nucleoside that has in vitro inhibitory activity against HSV types 1 and 2, CMV, vaccinia, and to a lesser extent, certain adenoviruses. Trifluridine inhibits replication of herpesviruses, including acyclovir-resistant strains, and also inhibits cellular DNA synthesis at relatively low concentrations. Trifluridine monophosphate irreversibly inhibits thymidylate synthase, and trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA; trifluridine is incorporated into viral and cellular DNA. Trifluridine-resistant HSV has been described.
Trifluridine currently is used for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis owing to HSV types 1 and 2. Topical trifluridine is more active than idoxuridine and comparable with vidarabine in HSV ocular infections. Adverse reactions include discomfort on instillation and palpebral edema. Hypersensitivity reactions and irritation are uncommon. Topical trifluridine also appears to be effective in some patients with acyclovir-resistant HSV cutaneous infections.