The approved tenofovir / Viread label lists not only standard nucleoside-class side effects but also – since an update in 2012 – makes mention of diminished bone mineral density (BMD) in the Warnings / Precautions section.
Demonstrating that a particular drug affects BMD in patients who are already at an increased risk of bone fractures due to HIV-related osteoporosis is not easy.
This is what Mulligan and colleagues did in a large (N=498) pre-exposure prophylaxis (PrEP) trial of Truvada (TDF/FTC) [1]. The groups were well matched by demographics, initial BMD and HIV risk factors. The study was double-blinded, with a placebo comparison arm. Results showed a clear and statistically significant decrease in BMD in the TDF group by ITT analysis. Even more pronounced differences were noted in the group of study participants (approx. 50% of the entire cohort) that had detectable drug levels at the time of BMD measurements. In contrast, placebo patients had a slight increase in BMD at both spine and hip at 24, 48 and 72 weeks (see graph).
Since the original launch of tenofovir, the drug’s use has expanded significantly and now includes an earlier treatment start for HIV-positive patients as well as pre-exposure prophylaxis (PrEP) for high-risk individuals. As a result, the duration of tenofovir exposure is now many years, f not decades longer compared to its original labeling.
What may have been considered an acceptable side effect with more limited exposure and the more limited population of HIV patients with advanced disease (CD<350 cells/mL) now should be reevaluated.
The time has come to monitor kidney function more regularly for tenofovir recipients. Reduced glomerular filtration and proximal tubular damage caused by adefovir, cidofovir, and tenofovir is well described. Commonly referred to as partial or complete Fanconi syndrome, it results in glucosuria, aminoaciduria, phosphate and bicarb wasting [2]. Urinary phosphate loss can certainly contribute to osteopenia and a decreased BMD.
This has short- and long-term consequences. Short-term, reduction in creatinine clearance is a concern. Even if progression to overt renal failure seems to be a rare event in prospective clinical trials, substantial elevations in serum creatinine are not rare in clinical practice. Long-term, the effect of tenofovir on BMD is indisputable but underreported and inadequately studied. Publications addressing renal impairment, Fanconi syndrome and how tenofovir impacts BMD have increased in recent years but Gilead is probably sitting on tons of additional data not yet shared with the public.
A search on the FDA web site for Post-Market Drug Safety Evaluations comes back empty for tenofovir [3]. Surprisingly, the FDA label for Viread is quite benign. It specifies that creatinine clearance should be assessed prior to treatment. There is no recommendation for monitoring kidney function unless a patient is considered ‘at risk’ for renal dysfunction. Which amounts to no f/u monitoring for 95% of tenofovir recipients.
Maybe a renewed risk/benefit assessment is in order. Interestingly, the recommendations from the Spanish AIDS and ID societies, updated in 2014, [4] have done just that. They advocate yearly monitoring of renal function for all HIV-infected in general, and more frequent checks for those receiving tenofovir specifically.
Solid and timely advice. An FDA or Cochrane safety review should be encouraged.
References:
[1] Mulligan CID May 2015
[2] A Hall Q J Med 2014; 107:261
[3] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.htm#postmarket_summaries
[4] Enferm Infecc Microbiol Clin. 2014;32:583
