Tenofovir toxicity

Therapies not recommended for initial treatment due to poor potency or significant toxicity include delavirdine, nevirapine in patients with moderate to high CD4+ T-cell counts, indinavir or saquinavir used without ritonavir ( unboosted ), ritonavir used without another protease inhibitor, and tenofovir plus didanosine with an NNRTI. 

Bone toxicity It is not known if long-term administration of tenofovir (more than 1 year) will cause bone abnormalities. If bone abnormalities are suspected, obtain appropriate consultation. 

Tenofovir is taken once daily and is generally well tolerated, perhaps because it produces less mitochondrial toxicity than the NRTIs. Nausea, vomiting, flatulence, and diarrhea occur in 10% or fewer patients. Resistance to tenofovir has been documented, and cross-resistance to NRTIs may occur. 

Tenofovir should not be given to patients with renal insufficiency. Its coadministration with didanosine results in increased plasma levels of didanosine that can produce toxicity. Because lactic acidosis and severe hepatomegaly with steatosis have been reported with NRTIs, it is important to monitor patients with known risk factors during treatment with tenofovir. 

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

As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great (Tables 49-3 and 49-4). Atazanavir AUC is reduced by 76% when combined with omeprazole thus, the combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as indinavir and irinotecan, is contraindicated because of enhanced toxicity. Tenofovir and efavirenz should not be -administered with atazanavir unless ritonavir is added to boost levels. 

Allopurinol increases didanosine plasma concentrations and their coadministration is not recommended. Ganciclovir, tenofovir and disoproxil also increase didanosine plasma concentrations, and dose reduction is recommended. Conversely, methadone decreases didanosine plasma concentrations, and appropriate doses for the combination have not been established. Didanosine should not be administered with drugs that cause pancreatic or neurotoxicity. Ribavirin increases its risk of toxicity and should not be coadministered. 

Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002 46 716-23. 

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. 

VANCOMYCIN NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS-TENOFOVIR, ZIDOVUDINE t adverse effects with zidovudine and possibly tenofovir Additive toxicity Monitor FBC and renal function closely (at least weekly)... 

AMPHOTERICIN NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS - TENOFOVIR, ZIDOVUDINE Possibly T adverse effects with tenofovir and zidovudine Additive toxicity Avoid if possible otherwise monitor FBC and renal function (weekly). 1 doses as necessary... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS GANCICLOVIRAfALGANCIC LOVIR 1. T adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly 1 efficacy of ganciclovir 1. Uncertain possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain L bioavailability 1. Avoid if possible otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance if in doubt, consider alternative cytomegalovirus prophylaxis... 

Tenofovir disoproxil fumarate is hydrolyzed rapidly to tenofovir and then is phosphorylated by cellular kinases to its active metabohte, tenofovir diphosphate the active moiety is, in fact, a triphosphate compound because the parent drug starts out as the monophosphate. The intracellular diphosphate is a competitive inhibitor of viral reverse transcriptases and is incorporated into HIV DNA to cause chain termination because it has an incomplete ribose ring. Although tenofovir diphosphate has broad-spectrum activity against viral DNA polymerases, it has low affinity for human DNA polymerases-a, -P, and -y, which is the basis for its selective toxicity. 

FOSCARNET SODIUM NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS-LAMIVUDINE, TENOFOVIR, ZALCITABINE t adverse effects with tenofovir and possibly lamivudine and zalcitabine Uncertain possibly additive toxicity via competition for renal excretion Avoid if possible otherwise monitor EBC and renal function weekly... 

In a study in 13 healthy subjects receiving methadone, tenofovir 300 mg daily for 2 weeks did not alter the pharmacokinetics of methadone, and no symptoms of opioid toxicity or opioid withdrawal were detected. ... 

Some combinations of NRTIs are potentially antagonistic (stavudine with zidovudine, lamivudine with zalcitabine) and some are expected to result in additive toxicity (didanosine with stavudine or zalcitabine, and possibly stavudine with zalcitabine). Some do not appear to result in additional benefits (emtricitabine with lamivudine), and some are considered inferior to other combinations (stavudine with lamivudine, zidovudine with zalcitabine or didanosine). None of these combinations are recommended. Combinations that are specifically recommended (with other antiretrovirals) include lamivudine with abacavir, didanosine or zidovudine, or didanosine with emtricitabine. Sole use of all triple NRTI regimens should generally be avoided, with the possible exception of abacavir or tenofovir , (p.806) with zidovudine and lamivudine. 

Ivfertinez E, Milinkovic A de Lazzari E, Ravasi G, Blanco JL, Larrousse M, Mallolas J, Garcia F, Miro JM, Gatell JM I creatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults Lancet (2004) 364,65-7... 

Tenofovir absorption is increased by high-fat food. Caution is recommended with drugs causing renal toxicity. Tenofovir did not alter the pharmacokinetics of ribavirin, and there was no clinically significant pharmacokinetic interaction with rifampicin (rifampin). 

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