The derivatives of nucleosides that are monophosphorylated belong to the nucleotide analogs. Those with antiviral properties include cidofovir, adefovir, and tenofovir. Tenofovir is used to treat HIV infection and is discussed in Chapter 2, page 62.
Phosphorylation of nucleosides occurs within the cyto- plasm of cells that are beginning mitotic division. The synthe- sis of bases that contribute to DNA chain elongation is limited by the inclusion of nucleotide analogs. Mitochondrial DNA- polymerase may also be affected.
Cidofovir has received much attention as a therapy for many viral diseases (Fig. 3.21). Although preemptive antiviral ther- apy for CMV infection following allogenic stem cell transplan- tation is recommended as an effective strategy for preventing CMV disease, some studies do not support this hypothesis (211). Cidofovir is considered an option for the treatment of acyclovir-resistant HSV although it has not been FDA- approved for this purpose. However, there is an increasing need for additional therapies as more herpes viral strains
become acyclovir-resistant. Cidofovir shows promise as a ther- apy against TK-deﬁcient strains of HSV. As the ﬁrst acyclic phosphonate nucleotide approved for use in the United States, cidofovir can be used to treat CMV retinitis inpatients with AIDS. AIDS patients treated with cidofovir for CMV retinitis often report an improvement in AIDS-related Kaposi’s sarcoma.
Cidofovir is the most effective anti-orthopoxvirus agent currently under preclinical investigation (212). Other diseases for which cidofovir is used include VZV, CMV, HPV, polyoma viruses, adenoviruses, and other poxviruses (213). Cidofovir shows efﬁciency against JC virus in vitro (214). Cidofovir is considered to be the second-line therapy for CMV disease after the ﬁrst antiviral failed (215). Anogenital warts respond to cidofovir topical gel (216).
Mechanism of Action
Cidofovir is considered to be an acyclic phosphonate nucle- otide. Cidofovir is similar to foscarnet in that it does not require thymidine kinase for phophorylation (Fig. 3.22). To become activated, the drug is phosphorylated by cellular kinase to cidofovir diphosphate (217–219), which makes it effective against TK-deﬁcient strains of HSV. HHV-8 replication is sen- sitive to cidofovir. Although cidofovir is poorly absorbed by mouth, aerosolized cidofovir may help create a barrier against aerosolized virus infections. Cidofovir acts as a chain termina- tor for viral DNA polymerase. After intracellular phosphoryla- tion to a diphosphate form, activity occurs at the 3′ end of the viral DNA with termination at the end of two sequences.
Clinical Studies and Reports that Support the Use of Cidofovir
Several studies document the treatment of acyclovir-resistant and normal strains of HSV with topical cidofovir. Representa- tive studies are highlighted in Table 3.19 (213,215,220–251). The FDA did not approve the use of cidofovir gel for acyclovir- resistant herpesvirus infection due to a lack of sufﬁcient phase- three data (229). However, the manufacturer has reported suc- cessful treatment of HSV with compounded cidofovir cream (230). Cidofovir delays the progression of CMV retinitis in
patients with AIDS (220–224). The use of cidofovir alone may not change the course of progressive multifocal leukoencepha- lopathy in non-HIV-positive patients (249).
Cidofovir has shown to be effective against HHV-8 (in vitro). HAART therapy usually beneﬁts KS lesions, but a case report indicates cidofovir treatment may be considered for the control of KS lesions and to reduce HHV-8 replication (250).
Genital warts and common warts can be effectively treated with cidofovir, although it is not currently FDA-approved for this purpose. Table 3.20 highlights other treatments. Dosages may vary with little effect on toxicity. For patients receiving 3 mg/kg vs 5 mg/kg of cidofovir, the only toxic con- dition deemed signiﬁcant (p < 0.04) was an increase in base- line creatinine. Other conditions included nausea and vomiting. Cidofovir must be used with caution if combined with other known nephrotoxic drugs or used concomitant with cyclosporin (215).
A number of side effects have been reported with the use of cidofovir (211–251).
Skin changes. May cause localized ﬁbrosis if cidofovir is injected.
Erythema. Some HPV (condylomata acuminata) HIV- positive patients experience transient erythema from cidofovir use with no long-term side effects (248).
Nephrotoxicity. Occurs as serum creatinine levels rise to 1.5–2 times normal. Some patients develop tubular toxicity. Pretreatment with intravenous normal saline and probenecid is mandatory to decrease the risk of nephotoxicity.
Metabolic acidosis. Ocular hypotony. Uveitis. (250).
Probenecid. Probenecid can be used with intravenous normal saline to reduct the risk of nephrotoxicity (213). Other nephrotoxic agents. Concomitant use is con-
Cidofovir gel availability. Compounding of the drug is expensive.
Smallpox vaccination study. Currently, smallpox vac- cinations are being tested. Should volunteers develop complications of vaccinia, cidofovir will be the drug of choice for antiviral therapy.
Adefovir dipivoxil is a diester prodrug of adefovir with speciﬁc activity against the human hepatitis B virus (HBV). Adefovir was approved in September 2002. Those who take the oral drug have experienced improved liver histology and have a
Fig. 3.23 Associated names, structure, and applicability of adefovir dipivoxil.
reduced serum HBV DNA concentration if they were infected with the precore mutant strain of the virus (252). With precore mutant HBV, the virus’ ability to produce “e” antigen is destroyed by the viral genome. Precore mutant virus is associ- ated with more severe liver disease and is more commonly found in Asian and Mediterranean countries. The wild type also responds favorably to adefovir. Brand name, chemical structure, and antiviral uses of adefovir are shown in Fig. 3.23.
Mechanisms of Action
Adefovir is a nucleotide analog of adenosine monophosphate that is acyclic. Nucleotide analogs block HBV DNA polymere- ase, the enzyme involved in correct replication of the virus in cells. Adefovir is actually adefovir dipivoxil, a diester prodrug of adefovir. Adefovir is phosphorylated to the active metabo- lite, adefovir diphosphate, by host cellular kinases. The diphosphate form inhibits the reverse transcriptase of the DNA polymerase by competing with the normal DNA sub- strate, deoxyadenosine triphosphate. Once the adefovir com- pound is incorporated into the viral DNA, the DNA chain ceases to elongate. This mechanism is shown in Fig. 3.24.
Studies to Support the use of Adefovir
A variety of studies were performed on adefovir before the
FDA gave approval, and are shown in Table 3.21 (252–255).
Adefovir is administered as an oral tablet. Each table contains
10 mg of adefovir dipivoxil and a number of inactive ingredi- ents. In laboratory studies, 0.2–0.25 µM of adefovir achieved a
50% reduction in viral DNA synthesis. Adefovir is excreted by glomular ﬁltration and active tubular secretion by the kid- neys. The potential for CYP 450 interactions with adefovir as a inhibitor or substrates with other medicinal products is neg- ligible given the renal elimination of adefovir. Adefovir may be taken without regard to food.
In initial clinical trials, a number of adverse events were reported, such as asthenia, headache, abdominal pain, nau- sea, ﬂatulence, diarrhea, and dyspepsia. However the reports between those receiving adefovir and the placebo were not sig- niﬁcantly different. Pre- and post-liver transplant patients reported some additional concerns that may be important on
a case-by-case basis: changes in serum creatinine and serum phosphorus, pruritus and rash, abnormal liver functions, and some respiratory complications.
Discontinuation of adefovir treatment. Once patients who have been on adefovir or other anti-HBV therapy discontinue therapy, severe acute exacerbation of hepa- titis has occurred. Monitoring of hepatic function of pa- tients who discontinue anti-HBV therapy should continue over time. Resumption of anti-HBV therapy may be needed if alanine aminotransferase (ALT) lev- els rise signiﬁcantly. Patients with poor liver function (hepatitis or cirrhosis) may be at higher risk. Deaths have occurred, so patients should be closely monitored.
Nephrotoxicity. Patients with normal renal function have a low risk of nephrotoxicity. However, for patients with or at risk of renal dysfunction, chronic administration of the standard dosage of adefovir may cause nephrotoxicity.
Coadministration with nephrotoxic agents. Coad- ministration of cyclosporine, tacrolimus, aminoglyco- sides, vancomycin, and non-steroidal anti-inﬂammatory drugs with adefovir may increase the chances that nephrotoxicity may occur.
Coadministration with ibuprofen. Ibuprofen at a dosage of 800 mg three times /day increased adefovir exposure by 23% although the signiﬁcance of this ob- servation is unknown.
Pregnancy. No adequate or well-controlled studies on pregnant women have been conducted. Fetal malfor- mations occurred in pregnant rats when administered doses 38 times human systemic exposure, although there is no indication that this would be predictive of human response. Adefovir should be administered to pregnant women only after careful consideration of the risks and beneﬁts and only if clearly needed.
Pediatric and geriatric use. Insufﬁcient studies have been done to establish safety and effectiveness.
Overdosage. Doses of adefovir of 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated
with gastrointestinal side effects. In case of overdose, the patient should be monitored for evidence of toxicity and standard supportive treatment used, as necessary.
HIV. For those with HIV, adefovir may interfere with the efﬁcacy of usual HIV medications. Patients should have an HIV test prior to administration of adefovir.
Lactic acidosis. Nucleoside analog medications, such as adefovir, may cause a build-up of acid in the blood called lactic acidosis, which should be treated as a med- ical emergency. Symptoms of lactic acidosis are weak- ness or tiredness, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, cold extremities, dizziness or light-headedness, or a fast or irregular heartbeat.
Renal impairment. Patients with moderately or severely impaired renal function or undergoing dialysis for end- stage renal disease may experience decreased half-life and clearance rates for adefovir. The dosing interval of adefovir may need to be adjusted for these patients.
Hepatic impairment. In non-chronic HBV patients, the pharmacokinetics remains the same in patients with moderate and severe hepatic impairment compared with unimpaired patients. No change in dosage is an- ticipated for these patients.
Antisense oligonucleotides containing locked (poorly binding) nucleic acids are a new class of therapeutic agents for viral infections, cancer, inﬂammatory, and cardiovascular diseases. Some drawbacks of antisense drugs include low-binding to active sites and toxic side effects (256). Oligonucleotides may be inhibitors of HIV (257). It still remains a challenge for oli- gonucleotides to provide efﬁcient and speciﬁc antisense activ- ity with reduced toxicity. Fomivirsen is an example of an antisense drug.
Fig. 3.25 Associated names, structure, and applicability of fomivirsen.
Fomivirsen, an antisense drug, is the ﬁrst in this group to be FDA-approved. Patients who have CMV retinitis as a result of their AIDS infection may be treated with fomivirsen, particularly if they have a contraindication to, or an intolerance for, other CMV retinitis treatments (Fig. 3.25). Fomivirsen is effective when certain CMV strains are known to be ganciclo- vir, foscarnet, and cidofovir resistant.
Mechanism of Action
Fomivirsen is a DNA analogue that complements a unique sequence of nucleotides with the mRNA of CMV. Formivirsen is a single-stranded antisense oligonucleotide (Fig. 3.26). This region of mRNA is responsible for the regulation of viral gene expression that is necessary to produce infectious CMV. As the CMV genetic material begins to reproduce, messenger RNA is used to encode a speciﬁc protein. Fomivirsen is a complemen- tary (antisense) sequence that binds to the messenger RNA sequences and prohibits the development of new CMV pro- teins. Because it is more speciﬁc to CMV, fomivirsen produces few side effects. Because fomivirsen interferes with CMV rep- lication, CMV may not be able to develop resistance as it has to ganciclovir and other antivirals.
Clinical Studies and Reports of Fomivirsen Usage
Most clinical studies have involved the use of fomivirsen in the treatment of CMV retinitis (258–260) (Table 3.22).
Treatment for CMV-retinitis is shown in Table 3.23.
In AIDS patients, pigmentary retinopathy, alterations in the electro-retinogram, rings of over-or under-pigmented retinal epithelium around the cornea (bull’s-eye maculopathy), and cat- aracts have been reported. Other common adverse effects are:
Ocular inﬂammation. Vitreitis and/or iritis may occur.
Intraocular pressure. Elevation of intraocular pres- sure occurs in 10–20% of cases.
Fomivirsen has a narrow therapeutic index. It can cause toxic effects in some patients when the same dose is safe for others. Widespread retinal epithelial charge can occur, causing severe peripheral loss (261,262).