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IAS 2017: Acute Kidney Injury Uncommon on Tenofovir, No Link Seen to Bone Breaks


Doctors need to monitor patients regularly for kidney function if they are taking tenofovir disoproxil fumarate (TDF), especially if combined with ritonavir, according to a report at the 9th International AIDS Society Conference on HIV Science (IAS 2017) last month in Paris.

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Fanconi syndrome is an acute type of kidney failure caused by leakage out of the blood into the urine of substances that should normally be reabsorbed by the kidney: phosphates (which help build bone), amino acids, and bicarbonate, which can raise the acidity of the blood to dangerous levels (acidosis).

Nicholas Medland of Monash University in Melbourne told conference delegates that Fanconi syndrome was "uncommon, but not rare" among people taking tenofovir, with 1.25% (1 in 80) of his patient cohort developing the condition within a 10-year period. Importantly, it could appear unexpectedly in people with no characteristics linked to kidney disease.

In another presentation, Dominique Costagliola of the French national medical research agency INSERM told delegates she had found no association between tenofovir DF, or any other HIV drug, and the risk of bone fractures of the type associated with low bone mineral density.

Fanconi Syndrome, Tenofovir and Ritonavir

Medland studied a cohort of 1044 patients who started and continued taking tenofovir DF between 2002 and 2016, 398 of whom were also taking ritonavir as a booster for protease inhibitor drugs.

Their average age was 38 (41 for ritonavir takers), 89% were male, and 75% gay men. The average time taking tenofovir was 3.5 years, or 4 years for those also taking ritonavir.

On average, patients had normal kidney function when they started tenofovir DF (eGFR 106) and only 2.5% had kidney malfunction as defined by an eGFR below 50 (1.6% of those also taking ritonavir).

There were 13 cases of Fanconi syndrome among 1044 patients (1.25%), and the annual incidence was 1 case per 920 patients per year (0.11%). The average time patients spent on tenofovir before Fanconi syndrome developed was 5.5 years.

Importantly, Fanconi syndrome was not associated with any predisposing factor for kidney dysfunction including age, sex, high blood pressure or lipids, diabetes, viral hepatitis, low CD4 count or lowest-ever count, or baseline low eGFR.

"These were well patients in whom Fanconi syndrome developed suddenly," said Medland.

Out of the 13 cases, 9 were in patients who were also taking ritonavir, and the annual incidence in this group was 1 in 182 patients per year (0.55%). Ritonavir co-administration raised the risk of Fanconi syndrome nearly 5-fold (adjusted hazard ratio 4.71).

"All these cases could have been spotted with a cheap urine dipstick test at every HIV checkup," said Medland, urging continued monitoring even for patients with perfectly normal kidney function.

Tenofovir, Protease Inhibitors, and Fractures

Tenofovir disoproxil fumarate has been associated with low bone mineral density and osteoporosis, as have protease inhibitors -- but does this translate into a higher risk of bone fractures?

To answer this question, Costagliola's group looked at the French HIV Hospital Database, which includes the majority of people with HIV attending clinics in the country.

Between 2000 and 2010, she found 1026 fractures in 62,776 patients. However, only 261 of these had evidence of "low energy" fractures, i.e., fractures associated with impacts that should not normally break bones, such as falls from standing height, and at skeletal sites where osteoporosis most often occurrs.

The researchers matched 254 of these patients with 376 control patients who had the same age, sex, length of HIV diagnosis, and if possible attendance at the same clinic. The average age of these 630 patients was 49, and two-thirds were men. About two-thirds were diagnosed before 1997, about 40% started antiretroviral therapy (ART) before 1997, and 70% started ART before 2001.

There were 38 control patients and 8 with fractures who were never on ART between 2000 and 2010.

Patients with fractures were more likely to be men who have sex with men (34% vs 20%) and less likely to be sub-Saharan Africans (4% vs 11%). They were also more likely to be underweight (13% vs 6%) -- low body weight is a well-known risk factor for fracture -- to have had a prior AIDS diagnosis (31% vs 20%), to have used medical steroids (10% vs 4%), and to drink more than 2 alcoholic drinks a day (24% vs 13%). Other factors, apart from existing osteoporosis (10% vs 2%), were not significant.

Costagliola's team then looked at the relationship between specific HIV drugs and the risk of fractures. In terms of whether drugs had been used at all, protease inhibitors were associated with a 67% increased risk of fracture, and the individual protease inhibitors atazanavir (Reyataz) and lopinavir (in Kaletra) had a similar raised risk. In terms of duration of cumulative use, the only drug with a significant association with fracture was atazanavir.

However, in a model that adjusted for all other risk factors, no HIV drug was associated with the risk of fracture. Tenofovir DF was, in this model, associated with a 24% raised risk, but this was a trend rather than being statistically significant.

Efavirenz (Sustiva) was associated with a 40% reduced risk of fracture in this model, but this again was only a trend rather than being statistically significant.

Costagliola said she had found no definite association between any antiretroviral drug and fracture, but also noted that because this was a patient group who had started ART early, only 9% had tenofovir DF in their first ART regime. Similar studies of cohorts starting treatment later should therefore be done in the future to see if newer antiretrovirals are associated with fracture, especially as patients age.



NA Medland et al. Incidence of renal Fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxyl fumarate. 9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Abstract MOPDB0102.

D Costagliola et al. Impact of exposure to each antiretroviral treatment (ARV) on the risk of fracture in HIV-1-infected individuals: an analysis from FHDH ANRS CO4.9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Abstract WEAB0103.