Switching from TDF to TAF associated with improvements in bone mineral density in people over 60

Switching tenofovir formulation was associated with increases in bone mineral density among older people with HIV, an international team of investigators report in The Lancet HIV. The study involved people with HIV over the age of 60 who had an undetectable viral load while taking an antiretroviral combination containing tenofovir disoproxil fumarate (TDF). Two-thirds were randomised to change to a fixed-dose combination containing the newer tenofovir alafenamide (TAF). After 48 weeks of treatment, bone mineral density at the spine and hip increased in the TAF group but declined among individuals who remained on TDF.

Bone loss is a well-recognised disease of older age, and thanks to improvements in treatment and care, an ever-increasing proportion of people with HIV in older age groups. The findings of this study are especially important because infection with HIV and the side effects of some older antiretrovirals have been associated with bone loss, increasing the risk of fractures.  

“The increases in bone mineral density observed in these people with HIV after switching from TDF to TAF have potentially important clinical consequences in terms of morbidity and mortality,” comment the authors. “The bone mineral density increases were greater than expected in the general population.”

Glossary

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 

lipid

Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

renal

Relating to the kidneys.

cholesterol

A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

fixed-dose combination (FDC)

Two or more drugs contained in a single dosage form, such as a capsule or tablet. By reducing the number of pills a person must take each day, fixed-dose combination drugs may help improve adherence.

The authors of an accompanying editorial also believe that the findings have important implications for the care of older people with HIV. They comment: “This study shows for the first time that bone loss is reversible in people living with HIV aged 60 years or older – i.e. people with physiologically reduced bone mineral density.”

But the findings were not universally in favour of TAF, with increases in blood lipids observed in the group that switched to this therapy.

TDF has been a mainstay of antiretroviral therapy for almost 20 years. The drug is potent, durable, has few interactions and is generally well tolerated. However, it has been associated with reductions in bone mineral density as well as renal toxicities. TAF has the same potent anti-HIV effect but has lower concentrations in the blood. It has been shown to be safer in terms of bone and kidney toxicities.

Older people with HIV can be especially vulnerable to diseases associated with older age, including osteoporosis, reduced renal function and cardiovascular disease. Many are taking multiple medications to control or prevent these conditions, in addition to their anti-HIV drugs.

There is little information on the potential benefits of switching from TDF to TAF specifically for older people with HIV.

A group of researchers led by Professor Franco Maggiolo of the Sacco Hospital, Milan, therefore designed a study involving 167 people with HIV aged 60 years and older who were randomised to remain on a TDF-containing regimen or switch to a fixed-dose combination consisting of elvitegravir, cobicistat, emtricitabine and TAF (Genvoya).

The primary end-point was changes in bone mineral density in the spine and hip. This was assessed using DEXA scans at screening for the study, at its 24-week midpoint and the 48-week conclusion.

Secondary endpoints were maintenance of viral suppression, changes in CD4 cell count, assessment of renal function and analysis of blood lipids.

Recruitment and follow-up took place between late 2015 and early 2017. Treatment was open-label and data were prospectively obtained. Participants were cared for at 36 clinics across Europe.

Key recruitment criteria were current therapy with TDF, an undetectable viral load and age of at least 60 years.

Participants were randomised on a 2:1 basis to switch to the TAF-containing regimen or remain on their TDF-based therapy.

The participants had an average age of 66 years, 89% were men and 92% were white. The median CD4 cell count was 634.

The key finding of the study was that after 48 weeks of treatment, switching to TAF was associated with increases in bone mineral density at both the spine (2.24%) and hip (1.33%). However, declines in bone mineral density at both the spine (-0.10%) and hip (-0.73%) were observed among individuals who remained on TDF.

At baseline, approximately 50% of individuals in both the TAF and TDF groups had normal bone mineral density at both the spine and hip. By the end of follow-up, this had increased to 56% in the TAF group but had fallen to 46% in the TDF group. Moreover, those assigned to TAF were more likely to have improvements in pre-existing osteopenia.

"The findings were not universally in favour of TAF, with increases in blood lipids also seen."

Both groups maintained high rates of viral suppression. CD4 cell counts remained stable among people remaining on TDF but increased slightly among those assigned to TAF. As CD4 cell counts were already normal, this difference is unlikely to have had any real impact on long-term outcomes.

Analysis of kidney function favoured TAF. Blood lipids remained stable in the TDF group but increased among individuals taking TAF. Total cholesterol increased by a median of 24 mg/dL, LDL cholesterol by 19 mg/dL and triglycerides by 31 mg/dL.

“The importance of any small increases in lipids on cardiovascular health and outcomes might be outweighed by the other major concerns noted with TDF, such as potential renal effects and decreased bone mineral density,” comment the authors.

There were no serious treatment-related adverse events. Four people (4%) in the TAF group and two individuals (2%) remaining on TDF stopped treatment because of side effects.

The authors of the editorial comment, Dr Nicola Gianotti and Dr Antonella Castagna, were generally enthusiastic about the study’s focus on the safety of antiretrovirals in older people. They call for more research involving women and other racial groups, but conclude: “We now know that switching from TDF allows a partial recovery of bone mass in men living with HIV aged 60 years and older, which will probably reduce the risk of fractures in this population and improve quality of life in older people living with HIV.”