Recent Studies Show Concerns With The Use of Tenofovir (Viread), Popular Drug in HIV Treatment

Tenofovir impairs enzyme that stops cells aging

This study let us know that NRTI drugs, already known for causing the damage to mitochondrial DNA that leads to peripheral neuropathy, fat loss and some other side-effects, also exert an effect on cellular DNA, and that in this case tenofovir may be the drug to keep an eye on.

Telomerase shortening is, by definition, a side-effect that won’t start causing symptoms for many years, and the study does provide a cautionary note in discussions about the possibility of very long-term side-effects associated with the use of tenofovir, both in HIV treatment and in pre-exposure prophylaxis.

More information here


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Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir+Lamivudine or Tenofovir DF+ Emtricitabine With Atazanavir-Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202

"In conclusion, we have shown significant perturbation in mitochondrial indices after 96 weeks of nonthymidine NRTI containing regimens which were assigned randomly. In the TDF/FTC group, changes in oxidative phosphorylation complex I and complex IV activity levels consistently were inversely correlated with changes in several objective measures of body fat, including in both subcutaneous and visceral compartments"

  Patients with human immunodeficiency virus type 1 (HIV-1) infection receiving thymidine nucleoside reverse-transcriptase inhibitors (NRTIs) experience a high rate of metabolic abnormalities, including lipoatrophy. Depletion of adipose tissue mitochondrial DNA (mtDNA) and impairment of the oxidative phosphorylation system are associated with lipoatrophy induced by thymidine NRTI containing regimens. Mitochondrial oxidative phosphorylation enzymes nicotinamide adenine dinucleotide (reduced; NADH) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) contain polypeptides of mtDNA-encoded subunits and so are affected by mtDNA depletion.
In the current era of nonthymidine NRTI containing regimens, lipoatrophy incidence has significantly decreased but has not been completely prevented . In addition, subjects who have established lipoatrophy while taking thymidine NRTI containing regimens experience only a slow and incomplete resolution of lipoatrophy after switching to nonthymidine NRTI based therapy , putting into question the mitochondrial toxicity.

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Fortunately, 10 year observational data on the use of TDF show encouraging results in stabilization of reduced creatinine clearance

Association Between Tenofovir Exposure and Reduced Kidney Function in a Cohort of HIV-Positive Patients: Results From 10 Years of Follow-up

 "In this cohort, TDF exposure was associated with reduced kidney function, but the loss in eGFR attributable to TDF is relatively mild in a long-term perspective.

There has been debate about the association between TDF exposure and renal dysfunction and about the clinical impact of the loss in eGFR due to TDF exposure. Our study shows that the association was not of a high magnitude and that the quantified loss in eGFR attributable to TDF is relatively modest after many years of exposure. Importantly, the loss attributable to TDF seems to occur during the first year of exposure and stabilizes after that. Although the loss is maintained, it does not seem to further deteriorate with additional years of exposure. The clinical impact of this association need to be analyzed, taking into account the efficacy of TDF, but it is highly plausible that TDF exposure, although associated with reduced kidney function, has no severe adverse effects over the long term for most HIV-positive patients.”

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Tenofovir Dosing for patients with kidney dysfunction

I have seen some confusion about Tenofovir (Viread, which is in Truvada and Atripla) dosing in those with kidney problems in my pozhealth at yahoogroups.com list, so I am posting this information.

So far, most of the problems with tenofovir and kidney function have been reported in treatment experienced patients on boosted protease inhibitors, african americans, people with diabetes, or those using other medications that may affect the kidneys. Naive patients on Atripla seem to be doing just fine.

By the way, for those of you who have not calculated your creatinine clearance, ask your doctor if that value is included in your lab report. If not , ask him or her to include it. You can also calculate it here:

http://cpsc.acponline.org/enhancements/212creatinineCalc.html


From
http://www.medscape.com/druginfo/monograph?cid=med&drugid=22106&drugname=Viread+Oral&monotype=monograph&secid=3


Special Populations
Dosage of tenofovir should be adjusted in adults with creatinine clearances less than 50 mL/minute. The manufacturer and some experts recommend that adults with creatinine clearances of 30 to 49 mL/minute should receive 300 mg of tenofovir once every 48 hours and those with clearances of 10 to 29 mL/minute should receive 300 mg twice weekly. Adults undergoing hemodialysis should receive 300 mg of tenofovir once every 7 days (based on 3 hemodialysis sessions per week, each lasting approximately 4 hours) or 300 mg after a total of approximately 12 hours of dialysis; the dose should be administered following completion of a dialysis session. Because safety and efficacy of these dosages have not been evaluated in clinical studies, clinical response to treatment and renal function should be closely monitored. The manufacturer states that dosage recommendations cannot be made for adults with creatinine clearances less than 10 mL/minute who are not undergoing hemodialysis since the pharmacokinetics of the drug have not been studied in such patients.
The usual dosage of the fixed-combination preparation containing emtricitabine and tenofovir disoproxil fumarate (Truvada®) can be used in adults with creatinine clearances of 50 mL/minute or greater. The manufacturer of the fixed-combination preparation recommends a dosage of one tablet (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) every 48 hours in adults with creatinine clearances of 30–49 mL/minute; response to therapy and renal function should be monitored in these patients since this dosing recommendation has not been evaluated in clinical studies. The fixed-combination preparation should not be used in adults with creatinine clearances less than 30 mL/minute, including those undergoing dialysis.

The usual dosage of the fixed-combination preparation containing tenofovir disoproxil fumarate, emtricitabine, and efavirenz (Atripla®) can be used in adults with creatinine clearances of 50 mL/minute or greater. The fixed-combination preparation should not be used in adults with creatinine clearances less than 50 mL/minute.

Dosage adjustment is not necessary in patients with hepatic impairment

HIV Lipodystrophy: Where are We After 10 Years?

http://f1.grp.yahoofs.com/v1/EFLdR5ilPaVxAGznd1_SkpO6x-gEAJhwMccdRiItI3tZhDrmSZ-UkqTqOJLUFWeYHpDdtENW6uery9Kibf9Z/lipoupdateGMHCMAR08.pdf