Intravenous Cidofovir Research Articles

Valganciclovir

Valganciclovir (Valcyte) is an orally administered prodrug of the standard anti-cytomegalovirus (CMV) drug ganciclovir. Valganciclovir is as effective as intravenous ganciclovir for the treatment of AIDS-related CMV retinitis, and oral ganciclovir for the prophylaxis of CMV infection and disease in high-risk solid organ transplant recipients. The drug is generally well tolerated and has a similar tolerability profile to that of oral or intravenous ganciclovir, but is devoid of adverse events related to intravenous or indwelling catheter access associated with the use of intravenous ganciclovir, cidofovir and foscarnet. The simple and convenient once-daily valganciclovir regimen offers potential for improved patient compliance. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients. Furthermore, the use of valganciclovir instead of intravenous ganciclovir may provide significant cost savings, based on data comparing oral versus intravenous regimens for the treatment of AIDS-related CMV retinitis. Overall, valganciclovir appears to have some advantages over ganciclovir. Therefore, when used as prophylaxis against CMV infection and disease in high-risk solid organ transplant recipients or as induction and maintenance therapy of CMV retinitis in patients with AIDS, oral valganciclovir is an attractive alternative to other available anti-CMV drugs.

Successful use of intralesional and intravenous cidofovir in association with indole‐3‐carbinol in an 8‐year‐old girl with pulmonary papillomatosis

We report the history of an 8-year-old girl who was treated for suspected lung lesions of respiratory papillomatosis with Indole-3-Carbinol, local and intravenous injections of Cidofovir for 27 months. This is the first report where a complete cure of the lung lesions occurred in a child, and was sustained for at least 24 months.

Antiviral prophylaxis of smallpox.

Proof-of-concept studies suggest that current defences against smallpox could be strengthened by supplementing vaccination with antiviral drug prophylaxis, based on aerosolized or orally available forms of the long-acting medication cidofovir. Delivery of aerosolized cidofovir to mice results in its prolonged retention in respiratory tissues and protection against lethal intranasal or aerosol poxviral challenge. Although cidofovir itself is not orally available, the addition of an alkoxyalkanol ether side-chain allows it to be absorbed from the gastrointestinal tract. This also markedly increases its antiviral activity and lengthens its intracellular half-life from roughly 3 to 8-10 days. Oral treatment also protected mice against lethal poxviral challenge. These results suggest that a single aerosol dose of cidofovir (or an alkoxyalkanol-ether derivative) could provide prolonged protection against initiation of smallpox infection, whereas oral treatment could prevent both initiation of infection and internal dissemination of virus. Both approaches may avoid the nephrotoxicity that occasionally results from intravenous cidofovir therapy.

PROGRESSIVE OUTER RETINAL NECROSIS CAUSED BY VARICELLA-ZOSTER VIRUS IN CHILDREN WITH ACQUIRED IMMUNODEFICIENCY SYNDROME

We report three HIV-infected children with bilateral progressive outer retinal necrosis caused by varicella-zoster virus. All three lost vision in both eyes. Aggressive treatment strategies with combination intravenous antiviral therapy in addition to intravitreal antiviral therapy and appropriate surgical management may prevent blindness. Rapid recognition of this distinct clinical syndrome is essential to improve visual outcome.

Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults.

BK virus (BKV)-associated nephropathy (BKVAN) has been increasingly recognized as an important cause of renal transplant dysfunction. We report the role of quantitative viral load monitoring in the management of BKVAN. We developed a real-time quantitative polymerase chain reaction (PCR) assay for BKV detection in urine and plasma. Four renal allograft recipients, including two children, with BKVAN were treated with low-dose cidofovir and followed prospectively. The PCR assay showed a detection limit of 10 viral copies with an intra-assay coefficient of variation of 19%. All four patients with BKVAN demonstrated intranuclear inclusions on allograft biopsy and a progressive rise in serum creatinine; three patients underwent multiple biopsies before the diagnosis of BKVAN was made. Three of the patients experienced a "viral syndrome" before the onset of renal dysfunction. One child also demonstrated an echogenic renal mass. All of the patients demonstrated strongly positive urinary PCR values (>100,000 copies/microL). BKV DNA was also detected in the plasma of three patients. All the patients were treated with intravenous low-dose cidofovir (0.25-1 mg/kg per dose, every 2-3 weeks, without probenecid). BK viruria resolved within 4 to 12 weeks (after 1-4 doses) of the cidofovir therapy, and all patients remain with stable renal function 6 to 26 months posttherapy. Quantitative PCR for BKV is a sensitive and reliable method for following the course of the infection in renal transplant patients. In addition, cidofovir therapy may be useful in the treatment of some of these patients, and its role needs to be investigated further.

Challenges and options in the management of viral infections after stem cell transplantation.

During the period of profound combined immunodeficiency after bone marrow or peripheral blood stem cell transplantation (SCT), patients are at increased risk for serious viral disease. Recent advances in rapid diagnostic methods and the introduction of potent antiviral compounds have made it possible to establish efficient management strategies for several herpesviruses. Acyclovir, valaciclovir, and famciclovir are widely used for the treatment of herpes simplex virus or varicella zoster virus disease. Intravenous ganciclovir, foscarnet, and cidofovir are available for prevention or therapy of cytomegalovirus disease, and oral valganciclovir could become a valuable alternative to intravenous treatment if shown to be effective and safe after SCT. Preliminary data on pleconaril for therapy of picornaviral disease are promising. Future investigations may help to clarify the role of the neuraminidase inhibitors zanamivir and oseltamivir in the management of influenza in SCT recipients. The emergence of viruses resistant to antiviral drugs is of concern, and alternative treatment strategies need to be defined.

Successful treatment of varicella zoster virus retinitis with aggressive intravitreal and systemic antiviral therapy

Aims : To describe the successful treatment of varicella zoster virus retinitis (VZVR) using intravenous cidofovir as part of an aggressive management strategy. Case reports : Two patients with bilateral VZVR were treated with a combination of intravenous cidofovir and ganciclovir with adjuvant intravitreal foscarnet or ganciclovir. Both patients maintained good vision in the less severely affected eye. Retinal detachment did not occur in either patient. Conclusions : VZVR should be treated aggressively with a combination of intravenous and intravitreal therapy to improve visual prognosis. Intravenous cidofovir, in the absence of contra-indications, should be considered as part of this aggressive therapeutic approach, especially in patients with AIDS in whom the prognosis is particularly poor.

Viral skin infections in the elderly: diagnosis and management.

Over the past several years, there have been advances in the diagnosis and treatment of cutaneous viral diseases in elderly patients. Herpes zoster is caused by reactivation in adults of the varicella-zoster virus (VZV) that causes chickenpox in children. For many years, aciclovir was the gold standard of antiviral therapy for the treatment of herpes zoster. Famciclovir and valaciclovir are newer antivirals, which offer less frequent administration. Postherpetic neuralgia (PHN) refers to pain lasting 2 months or more after an acute attack of herpes zoster. The pain may be constant or intermittent. The treatment of established PHN may include topical anaesthetics, analgesics, tricyclic antidepressants and anticonvulsants, and nonpharmacological therapy may be used to complement such treatment. Therapeutic strategies to prevent PHN include the use of oral corticosteroids, nerve blocks, and treatment with standard antiviral therapy. The three most recently discovered human herpes viruses (HHV-6, HHV-7 and HHV-8), in common with the other members of the family, may cause a primary infection, establish latent infection in a specific set of cells in their host, and then reactivate if conditions of altered immunity develop. These viruses have been associated with an array of disorders, which are important for the clinician to recognise. Cytomegalovirus (CMV) is a member of the herpesvirus family that is very prevalent worldwide. More than 80% of primary infections and 20% of reactivation-producing symptoms occur in transplant populations. Treatment options include intravenous administration of ganciclovir, foscarnet or cidofovir. Herpes simplex virus (HSV) most commonly affects the genital and perioral regions. In the elderly, HSV infection is typically manifest at the vermilion border of the lip. The main concern of recurrent herpes labialis in the elderly is related to potential autoinoculation of the eye or genital area. Treatment with aciclovir, famciclovir or valaciclovir is indicated for these infections. Molluscum contagiosum is caused by a poxvirus, which produces cutaneous lesions that appear as small, firm, umbilicated papules. Immunocompromised patients often do not respond to the usual destructive therapies, and intravenous or topical cidofovir may be useful in these patients.

The ganciclovir implant plus oral ganciclovir versus parenteral cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: The Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial

PURPOSE: To compare the regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis. METHODS: Sixty-one patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis were randomized either to the regimen of the ganciclovir implant plus oral ganciclovir, 1 gm three times daily, or intravenous cidofovir, 5 mg/kg once weekly for two doses, followed by 5 mg/kg every other week. RESULTS: Mortality was similar between the two treatment groups. Mortality rates were 0.41 per person-year in patients assigned to the ganciclovir regimen and 0.49 per person-year in patients assigned to cidofovir ( P = .59). Ocular outcomes were similar between the two groups. Retinitis progression occurred at a rate of 0.67 per person-year in the ganciclovir group and 0.71 per person-year in the cidofovir group ( P = .72). A loss of visual acuity of 15 letters or more occurred at a rate of 0.78 per person-year in the ganciclovir group and 0.47 per person-year in the cidofovir group ( P = .28). The rate of loss of visual field was 7 degrees per month in the ganciclovir group and 2 degrees per month in the cidofovir group ( P = .048). Vitreous hemorrhage was more common in the ganciclovir implant group (0.13 per person-year) than in the cidofovir group (no cases, P = .014), whereas uveitis appeared to be more common in the cidofovir group (0.35 per person-year) than in the ganciclovir group (0.09 per person-year, P = .066). Nephrotoxicity (serum creatinine 1.6 mg/dL or greater) occurred at a rate of 0.18 per person-year in the ganciclovir group and 0.48 per person-year in the cidofovir group ( P = .10). CONCLUSIONS: Although the small number of patients in this study limits definitive interpretation, these data suggest that in the era of highly active antiretroviral therapy, the regimens of the ganciclovir implant plus oral ganciclovir and of intravenous cidofovir are similar for controlling cytomegalovirus retinitis and preventing visual loss but have different side effects.

Failure of Cidofovir to Reduce CMV-Antigenemia in a Child Transplanted from a Matched Unrelated Donor

Viral infections represent an important cause of morbidity and mortality in patients receiving allogeneic bone marrow transplantation (BMT), especially from a matched unrelated donor 1,2. An 8-year-old boy transplanted from a matched unrelated donor for relapsing acute lymphoblastic leukemia, was admitted at day +103 from BMT to receive foscarnet because of posit ive pp65-CMV-antigenemia (18/ 200,000 harvested cells), during ganciclovir prophylaxis. At the same time the patient presented watery diarrhea and adenovirus was detected in his stools. In the following days, while diarrhea persisted with the presence of adenovirus, an increase in transaminase level was observed (AST 52 IU/L, ALT 186 IU/L) and the patient developed dyspnea associated with abnormal respiratory sounds in both lungs, in absence of relevant radiological abnormalities. All these symptoms were considered as due to spreading adenovirus infection. Therefore, treatment with intravenous cidofovir at 5 mg/kg was decided, hoping to control both CMV and adenovirus 3,4. Foscarnet was Journal of Chemotherapy Vol. 13 n. 1 (100-101) 2001

Economic evaluation of systemic treatments for cytomegalovirus retinitis in patients with AIDS.

To determine the cost of using systemic therapy to treat newly diagnosed cytomegalovirus (CMV) retinitis in persons with AIDS. Incidence-based simulation model of CMV treatment from a government payer perspective. Swiss healthcare system. Patients with AIDS and newly diagnosed CMV retinitis. Patients were assigned to 1 of 4 treatment regimens for induction and maintenance therapy: (i) intravenous (IV) cidofovir induction and maintenance (cidofovir IV/IV); (ii) IV foscarnet induction and maintenance (foscarnet IV/IV); (iii) IV ganciclovir induction and maintenance (ganciclovir IV/IV); and (iv) IV ganciclovir induction and oral (PO) ganciclovir maintenance (ganciclovir IV/PO). Following a second relapse, patients were assigned to one of the other regimens. Time to first and subsequent progression, duration of maintenance treatment and direct medical expenditures [1998 Swiss francs (SwF)] . The median time to first progression was longest for cidofovir IV/IV, followed by foscarnet IV/IV, ganciclovir IV/IV and ganciclovir IV/PO. Mean survival was 13 months and mean costs for this period in the base case were lowest in those initially treated with cidofovir (SwF146,742), followed by initial treatment with foscarnet IV/IV (SwF194,809), ganciclovir IV/PO (SwF195,190) and ganciclovir IV/IV (SwF243,964). Costs were most sensitive to changes in efficacy estimates. Of the regimens studied, initiation of treatment with systemic cidofovir appears least costly over a 13-month period.

Treatment of cowpox virus respiratory infections in mice with ribavirin as a single agent or followed sequentially by cidofovir.

To better understand the potential of ribavirin in the treatment of orthopoxvirus infections (such as those acquired through bioterrorist activities), the efficacy of the drug was studied in a cowpox respiratory infection model in mice under varying disease severity. Mice did not survive a high intranasal cowpox virus challenge [3 x 10(6) plaque forming units (pfu)/animal] treated with subcutaneous ribavirin (100 mg/kg/day for 5 days), but lived 3.9 days longer than placebos. In contrast, 100% of animals receiving the same dose of drug survived a 3 x 10(5) pfu challenge compared with 0% survival of those that received placebo. Survival rates of 50 and 30% occurred with ribavirin doses of 50 and 25 mg/kg/day, respectively. At the 100 mg/kg/day dose, ribavirin reduced lung virus titres 40-fold on day 6 of the infection relative to titres in the placebo group. Weight loss resulting from illness and mean lung weights of mice treated with ribavirin were also significantly reduced. Mice were infected intranasally with the high 3 x 10(6) pfu virus challenge dose and treated with 100 mg/kg/day ribavirin for 5 days, followed by single injections of 75 mg/kg cidofovir on day 6, 7, 8 or 9. Cidofovir alone (without ribavirin) administered on day 6 had no beneficial effect on disease outcome. Ribavirin alone increased the mean time to death by 3.7 days. Ribavirin treatment for 5 days followed by cidofovir treatment on days 6 and 7 significantly increased the mean time to death beyond that achieved with ribavirin alone by 8.2 and 4.4 days, respectively, with 30 and 40% of mice surviving the infection. These results suggest that many individuals infected with an orthopoxvirus by aerosol route would benefit by a course of ribavirin therapy. Later, the fewer number of very sick individuals could be treated with intravenous cidofovir.

Long-term follow-up of patients with AIDS treated with parenteral cidofovir for cytomegalovirus retinitis: the HPMPC Peripheral Cytomegalovirus Retinitis Trial

To evaluate patients with cytomegalovirus (CMV) retinitis treated with intravenous cidofovir for long-term outcomes.Patients with CMV retinitis enrolled in a randomized, controlled clinical trial of intravenous cidofovir as treatment for retinitis were followed for long-term outcomes, including 21 patients initially enrolled in the deferral group who received cidofovir therapy after progression of retinitis.Thirteen tertiary care clinics specializing in AIDS care and ophthalmology.Fifty-eight patients with AIDS and small peripheral CMV retinitis lesions.Cidofovir 5 mg/kg once weekly for 2 weeks followed by low-dose maintenance cidofovir therapy (3 mg/kg) in 35 patients or high-dose maintenance (5 mg/kg) in 23 patients.Time to progression of retinitis, drug toxicities.Median time to progression of retinitis was 2.5 months. Median time to discontinuation of cidofovir because of intolerance was 6.6 months, and did not differ significantly between the two maintenance doses. Median time to discontinuation of cidofovir for intolerance other than probenecid reaction was 16.3 months for patients treated with low-dose maintenance and 5.0 months for patients treated with high-dose maintenance (P = 0.021). Proteinuria of 2+ or more occurred at a rate of 1.22/person-year. In patients with sufficient follow-up to determine resolution of proteinuria, 89.9% of episodes resolved, and the median time to resolution was 20 days. Rates of probenecid intolerance and of cidofovir-associated uveitis were 0.35/person-year, and 0.20/person-year, respectively.Although effective for the treatment of CMV retinitis, cidofovir has potential toxicity. Toxicity typically resolves with discontinuation of therapy, but careful attention to both concomitant therapy and monitoring for toxicity is required.

Intravenous cidofovir for compassionate use in AIDS patients with cytomegalovirus retinitis. Spanish Cidofovir Study Group.

We report the compassionate use of intravenous cidofovir for the treatment of cytomegalovirus retinitis in 51 patients with AIDS who were receiving highly active antiretroviral therapy (HAART). After a median of 9 doses, 49 patients showed no retinitis activity. However, treatment was stopped in 17 patients because of adverse reactions and in 5 patients for other reasons. Two deaths were considered related to the drug. Iritis developed in 21 patients (41.2%), a frequency higher than that reported during the pre-HAART era. Patients with iritis had median CD4 cell counts-both at nadir and at the initiation of cidofovir therapy-approximately 3 times higher than those for patients without iritis (P=.003 and P=.05, respectively). Our study confirms the efficacy of cidofovir therapy for AIDS-associated cytomegalovirus retinitis. Our data suggest that the risk of iritis may be higher for patients with better immunological status, probably because of their enhanced ability to mount an inflammatory response.

Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis

AIMIntravenous cidofovir is used to treat cytomegalovirus (CMV) retinitis, and has been reported to cause anterior uveitis. Relations were sought between this complication and patient characteristics that might help predict...

Ocular complications of intravenous cidofovir for cytomegalovirus retinitis in patients with AIDS.

To describe the frequency of anterior uveitis and ocular hypotony in cidofovir-treated patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis. A retrospective review was performed of all patients with AIDS-related CMV retinitis during a 12-month period. The CMV retinitis activity, concurrent illnesses and medications, and CD4+ lymphocyte count were recorded in addition to the degree of anterior chamber inflammation and intraocular pressure at each visit. The frequency of uveitis and ocular hypotony in cidofovir-treated patients was determined and the possible influence of other ocular and systemic factors considered. Eight of 9 patients on cidofovir developed anterior uveitis. The cellular anterior chamber activity resolved with topical corticosteroid administration in all eyes with uveitis but significant flare persisted despite topical steroids in 3 patients. Posterior synechiae responded poorly to topical mydriatic therapy, resulting in inadequate mydriasis which significantly limited the fundal view. One patient developed a visually significant unilateral hypotonous maculopathy. Patients treated with intravenous cidofovir for AIDS-related CMV retinitis are at significant risk of ocular adverse effects. Prompt treatment with topical corticosteroids and mydriatics may control uveitis and in some cases cidofovir treatment may be cautiously continued. In the event of ocular hypotony cidofovir should be discontinued in favour of an alternative anti-cytomegaloviral agent.

Complications of Therapy with Intravenous Cidofovir: Severe Nephrotoxicity and Anterior Uveitis

Complications of Therapy with Intravenous Cidofovir: Severe Nephrotoxicity and Anterior Uveitis

Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS.

Cidofovir is an antiviral nucleotide analogue with significant activity against cytomegalovirus (CMV) and other herpesviruses. The drug is indicated for the treatment of CMV retinitis, a sight-threatening condition, in patients with AIDS. Cidofovir has a long intracellular half-life which allows for a prolonged interval (2 weeks) between maintenance doses. In contrast, other intravenous treatment options for patients with CMV retinitis (i.e. ganciclovir and foscarnet) must be administered on a daily basis. The efficacy of intravenous cidofovir has been demonstrated in patients with AIDS and previously untreated CMV retinitis in multicentre randomised trials, and in a dose-finding study of cidofovir in patients with AIDS and previously treated relapsing CMV retinitis. Clinical trials have been relatively small (n < or = 100 patients) and no studies have been conducted directly comparing intravenous cidofovir with the more established intravenous agents, ganciclovir or foscarnet. Indirect comparisons of clinical trial data suggest that intravenous cidofovir may have similar efficacy to intravenous ganciclovir or foscarnet in delaying progression of CMV retinitis. However, such comparisons must be made with caution because of potential differences in patient populations, data analysis techniques and interobserver variability in the masked assessment of retinal photographs. Nevertheless, intravenous cidofovir offers a less intrusive administration regimen than intravenous ganciclovir or foscarnet because of its prolonged dosage interval. Since therapy is life-long, patients receiving daily intravenous ganciclovir or foscarnet (but not cidofovir) usually require an indwelling central venous catheter and are therefore at increased risk of serious infection. The relatively long dosage interval for cidofovir may also have favourable implications in terms of overall treatment costs and patient quality of life, although specific data are very limited. Potentially irreversible nephrotoxicity is the major treatment-limiting adverse event associated with intravenous cidofovir in patients with AIDS-related CMV retinitis. Anterior uveitis/iritis has been reported frequently with intravenous cidofovir in postmarketing reports and a small number of patients have developed hypotony. Other treatment options for CMV retinitis are also associated with serious adverse events, and selection of pharmacotherapy will depend on a number of factors including retinitis lesion characteristics, patient quality-of-life issues and efficacy and tolerability profiles of available therapies. Although the extent of its use may be limited by its adverse event profile, cidofovir offers a useful addition to the limited number of drugs available for the treatment of CMV retinitis in patients with AIDS.

Uveitis in patients treated with intravenous cidofovir

PURPOSE: To study the characteristics of uveitis occurring during intravenous cidofovir treatment for CMV retinitis in patients with AIDS. PATIENTS AND METHODS: We retrospectively studied ten cases (16 eyes) of uveitis in patients with CMV retinitis treated with intravenous cidofovir. All the patients had ophthalmologic examinations and, if required, fundus angiographies. The median follow-up was eight months. RESULTS: Uveitis occurred after a mean of 8.5 infusions of cidofovir (range 2-17). All ten patients were on protease inhibitors. The mean CD4+ cell count was 92 ± 51/µl and the median viral load was 3.9 log. All the eyes with uveitis had healed CMV retinitis. The first examination of the involved eyes showed inflammation of the anterior chamber (100%), vitritis (50%), posterior synechiae (75%), and low intraocular pressure (94%). Uveitis did not relapse in the seven patients who stopped cidofovir, whereas it relapsed in two of the three patients who did not stop treatment. At the end of follow-up, permanent posterior synechiae were present in 69% of the involved eyes. COMMENTS: Cidofovir therapy necessitates slit-lamp surveillance, especially in patients on HAART. Cidofovir-related uveitis requires a local steroid treatment, but if possible, cidofovir should be withdrawn.

Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir.

Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir and adefovir are dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of both drugs are independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and both drugs are cleared by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir and adefovir from serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For both drugs, > 90% of an intravenous dose is recovered unchanged in the urine over 24 hours. Metabolism does not contribute significantly to the total clearance of either drug. Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity, presumably by blocking its active tubular secretion. This is the basis of the clinical use of concomitant probenecid as a nephroprotectant during cidofovir therapy. Subcutaneous administration produces exposure equivalent to that following intravenous administration. Drug interaction studies with cidofovir are ongoing, but there is no evidence of an interaction between zidovudine and either cidofovir or adefovir. Clearance of cidofovir in patients with renal impairment showed a linear relationship to creatinine clearance. The low oral bioavailability of adefovir has led to the development of an oral prodrug, adefovir dipivoxil, currently in development for the treatment of HIV and hepatitis B infections.