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CROI 2016: Tenofovir HIV Treatment Raises Risk of Broken Bones

Treatment containing tenofovir is associated with a higher risk of bone fractures in people living with HIV, but a single infusion of zoledronic acid -- a drug used in the treatment of osteoporosis -- can protect against bone loss, a pair of studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston show.

[Produced in collaboration with Aidsmap.com]

In a related study, bone loss associated with the use of tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) was shown to reverse quickly after the use of tenofovir ceased.

HIV causes bone loss, and a large case-controlled study in Denmark has shown that HIV infection increases the risk of fractures. There is also evidence of a loss of bone mineral density in the first year after starting antiretroviral therapy (ART).

Tenofovir use is associated with bone mineral loss, although in most people the extent of bone loss is modest, occurs mainly during the first year of treatment, and its long-term consequences are unclear. In particular, previous studies which have identified bone loss in people taking tenofovir have not been able to show whether this results in a higher risk of fractures.

Since tenofovir is one of the most widely-prescribed antiretrovirals (contained in Truvada and the single-tablet regimens Atripla, Complera, and Stribild) and because many people will take the drug for prolonged periods, it is important to know more about fractures and a more serious complication of bone mineral loss and osteonecrosis, in which bone dies.

Tenofovir and Fracture Risk in EuroSIDA Study

To address the question of whether tenofovir or other drugs are associated with a higher risk of fracture and osteonecrosis, investigators carried out an analysis of fracture risk and osteonecrosis in the EuroSIDA cohort, which follows people with HIV in Europe and Argentina.

Patients followed in the EuroSIDA cohort after 2004 were included in the study. The end-points were fracture, osteonecrosis, death or last follow-up. A series of analyses were conducted to determine the risk factors associated with fracture and osteonecrosis. Use of individual antiretroviral drugs (ever, current, and cumulative exposure) was included in the final multivariate analysis.

The 11,820 patients recruited to the study were followed for a total of 86,118 person years. Patients had a median age of 41 years and 86% were white. Median CD4 cell count at baseline was 440 cells/mm³ and 70% of patients at enrollment had an undetectable viral load.

During follow-up 618 fractures (incidence 7.2 per 1000 person-years) and 89 cases of osteonecrosis (incidence 1 per 1000 person-years) were recorded. Fractures most commonly occurred in the arms (122), legs (135), and ribs (44), although 202 reported fractures occurred at unrecorded sites. Of the fractures, 132 were recorded as osteoporotic, or considered to have occurred as a result of reduced bone mineral density.

The incidence of fractures was highest in people with current CD4 cell counts below 200 cells/mm³ (8.9 per 1000 person-years of follow up) and lowest in people with CD4 cell counts above 500 (5.5 per 1000 person-years).

After adjusting for possible confounders, factors associated with an increased risk of fracture included older age, body mass index (BMI) <18, injection drug use, lower baseline CD4 cell count, coinfection with hepatitis C virus, previous osteonecrosis, a history of fracture, non-AIDS-related cancer, and cardiovascular disease in the previous 12 months.

The incidence of osteonecrosis was much lower, at 1 case per 1000 person-years of follow-up, in people with CD4 counts below 200 cells/mm³ and 0.8 cases per 1000 person-years in people with CD4 counts above 500 cells/mm³, a non-significant difference. Risk factors for osteonecrosis were the same as those for fracture, with the exception of non-AIDS-related cancer.

Overall incidence of fractures among patients ever exposed to tenofovir was 8.1 per 1000 person-years. This compared to an incidence of 4.7 per 1000 person-years for people never treated with this drug. Incidence among patients currently taking tenofovir was 7.8 per 1000 person-years, compared to 5.6 for patients currently off this drug.

The association between tenofovir use and fracture risk persisted in multivariate analysis. Patients who had ever used tenofovir (1.40; 95% CI 1.15-1.70) and also individuals currently taking tenofovir (1.25; 95% CI 1.05-1.49) had a significantly increased risk of fractures. There was no association between longer use of tenofovir and increased fracture risk. No other antiretrovirals increased the risk of fracture.

Asked why cumulative tenofovir exposure did not increase the risk of fracture, presenter Alvaro Borges from the University of Copenhagen suggested that the findings were consistent with the observation that bone mineral loss due to tenofovir treatment occurs in the first year of treatment and does not worsen with prolonged treatment.

No antiretrovirals -- including tenofovir -- were associated with an increased risk of osteonecrosis.

A number of factors -- HIV-related and non-HIV-related -- increase the risk of fracture and osteonecrosis, concluded the investigators. Tenofovir was the only anti-HIV drug associated with an increased risk of fracture.

Zoledronic Acid

Zoledronic acid is a biphosphonate drug licensed for the treatment of bone-related cancers along with chemotherapy and for the treatment of osteoporosis in men and women at increased risk of fractures. It is administered as an infusion once a year. The drug slows down the loss of calcium from the bones, reducing the risk of fractures.

Reduced bone mineral density is common in people living with HIV, and as previously noted, modest bone mineral loss is a common occurrence during the first year of antiretroviral therapy. Investigators from Emory University School of Medicine in Atlanta designed a study to investigate whether a single infusion of zoledronic acid could limit bone mineral loss during the first year of antiretroviral therapy.

This was a single-center, randomized, double-blind, placebo-controlled Phase 2 study. Patients starting HIV therapy for the first time with no history of bone loss were eligible for inclusion. All participants received an antiretroviral regime of atazanavir (Reyataz) with tenofovir/emtricitabine (Truvada). Patients were randomized to receive a single 5 mg infusion of zoledronic acid or placebo. The study lasted 48 weeks with assessment of bone turnover and bone mineral density at baseline and weeks 12, 24, and 48.

A total of 63 patients were enrolled. The majority (84%) were black and a fifth were women. Mean age at baseline was 40 years.

Therapy with zoledronic acid was associated with a 74% reduction in bone loss by week 12. The benefits persisted through to week 24 and 48 (65% and 56% reduction, respectively, relative to placebo).

By week 12, patients in the treatment arm had a 8% increase in lumbar spine bone mineral density relative to placebo, the difference increasing to 11% at weeks 24 and 48. At week 48, lumbar spine bone mineral density had increased by 2% in patients treated with zoledronic acid; this compared to a 4% decrease among patients who received the placebo. Lumbar spine T-scores and Z-scores were significantly higher among patients who received zoledronic acid versus placebo at all follow-up points (all p<0.05). Similar trends were also observed at the hip and femoral neck.

Zoledronic acid was well tolerated with no major adverse events reported. Rates of viral suppression and CD4 cell increase were similar between the treatment and placebo arms.

The investigators conclude that a single infusion of zoledronic acid at the time HIV therapy was started prevented antiretroviral-induced bone resorption and bone loss at key fracture-prone body sites. The benefits of therapy were present at week 12 and persisted through 48 weeks of follow-up. The researchers suggest that zoledronic acid could be used as a prophylaxis against bone mineral loss during the first year of antiretroviral treatment and call for a multicenter randomized trial to confirm their findings.

2/23/16

Reference

AH Borges, J Hoy, E Florence, et al. Antiretrovirals, Fractures, and Osteonecrosis in a Large European HIV Cohort
. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 46.

I Ofotokun, KTitanji, A Vunnava, et al. A Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 47.