August 10, 2017
For HIV-positive men with osteopenia, bisphosphonate therapy with zoledronic acid is more effective at increasing bone mineral density (BMD) than switching from tenofovir disoproxil fumarate (TDF, Viread), according to the results of a randomized control trial reported at the 9th International AIDS Society (IAS) Conference on HIV Science in Paris. Andrew Carr, M.B.B.S., M.D., of St Vincent's Hospital in Sydney said that the results showed that, if a patient required intervention for low BMD, just switching from TDF would not be enough.
Several randomized trials have shown that TDF lowers BMD and could also have an impact on fractures. In addition, a number of studies have shown that, in HIV-positive people with low BMD, switching from a TDF regimen to abacavir (Ziagen), an integrase inhibitor or the newer formulation tenofovir alafenamide (TAF, Vemlidy) has benefits. An alternative strategy in this scenario is to use zoledronic acid, but this is the first study to examine whether zoledronic acid or switching from TDF is superior.
Zoledronic acid is a bisphosphonate drug licensed for the treatment of osteoporosis in people with increased risk of fracture. It is usually administered as an infusion once a year. The drug slows down the loss of calcium from the bones, reducing the risk of fractures. Zoledronic acid was examined in a study last year of antiretroviral treatment (ART)-naïve individuals with no history of bone loss who began an ART regimen containing TDF. People randomized to receive a single infusion of zoledronic acid were protected against loss of BMD up to 48 weeks.
The current study enrolled patients who were stable on a TDF regimen and who had osteopenia (a T score at or below -1 at the spine or left femoral neck by dual-energy x-ray absorptiometry (DXA). Exclusion criteria included prior virological failure, resistance, contraindications to proposed switch drugs, prior use of bisphosphonate therapy and needing therapy for a low BMD (e.g., a fragility fracture).
Participants were randomized either to receive 5 mg of zoledronic acid at the beginning of the study and one year later, or to switch from TDF to an alternative ART regimen (determined before randomization).
Participants in both arms also received supplements of calcium and vitamin D, with the latter's dose adjusted for each patient's degree of vitamin D deficiency.
The study's primary outcome measure was the mean percentage change in BMD at the lumbar spine (L1-L4), as measured by DXA. Spine BMD was chosen as it responds more rapidly than hip BMD to pharmaceutical intervention.
Recruited at clinics in Sydney, Melbourne and Barcelona, 43 participants took part in the zoledronic acid arm and 42 in the TDF switch arm. Almost all were men, their mean age was 50, three-quarters were white and they had been taking TDF for around six years.
At baseline, median T scores at the spine were -1.7 in the zoledronic acid arm and -1.6 in the TDF switch arm. At the hip, T scores were -1.4 and -1.1, respectively.
In the TDF switch arm, the most common regimens to switch to contained abacavir (26 participants) or an integrase inhibitor (12 participants).
In terms of the primary outcome, participants in the zoledronic acid arm had a 6.1% increase in spine BMD at 12 months and 7.4% increase at 24 months. This was significantly superior to the results for those in the TDF switch arm, which were 2.9% and 2.9%, respectively. Results were similar for the hip, and they showed that the greatest improvement for both interventions occurred during the first 12 months.
While the study was not powered to detect a difference in the rate of fractures, there was one fracture in the zoledronic acid arm, compared with seven fractures in four patients in the TDF switch arm. During his IAS presentation, Andrew Carr said that much larger and longer duration studies would be needed to determine the impact on fracture outcomes.
There was no difference in serious adverse events between the two arms, and none were considered related to any study intervention. As could be expected, kidney function as measured by eGFR improved in the TDF switch arm.
The study is collecting further data up to 36 months, which will be reported in due course. Carr said that one limitation of the study was that it did not include switching to TAF, as the drug was not available when the study was established. Nonetheless, he could not imagine that switching to TAF would be superior to switching to abacavir or an integrase inhibitor.
He concluded that, in adult men with low BMD, zoledronic acid in combination with calcium and vitamin D supplementation is more effective at increasing BMD than switching from a regimen containing TDF. During questions and answers, he acknowledged that the two strategies could in fact be combined.
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