Tenofovir Toxicity. Caribbean HIV ECHO. Presenter: Dr. Chris Behrens. Date: 22-August-2018
I thought uh today i would talk about the um toxicities associated with uh uh tenofovir uh at least the the formulation of tanafir that’s most widely used in the region tdf this came up during last week’s case presentation and given how many individuals in the region are on this medication i thought it would be useful to review some of this i have no relevant
Disclosures hopefully by the end of this you will able be able to describe uh incidents and pathophysiology of tenofovir induced renal toxicity describe the association between tenofovir and bone mineralization disorders and discuss the implications of these toxicities for the clinical management of hiv infected persons so tenofovir has its impact on the kidney
At the area of the proximal tubule this is a diagram of the nephron the key working unit of the kidney and what tenofovir can do in certain individuals is cause the proximal tubular cells to malfunction and the proximal tubular cells are important for resorbing quite a few compounds from the urine back into the bloodstream specifically certain small proteins
Uh glucose phosphate uric acid uh vitamin d and so uh any disruption of the function of those cells can result in spilling of those compounds into the urine at inappropriate levels uh severe dysfunction can actually lead to death of these cells in the proximal tubule acute tubular necrosis even interstitial scarring um we’ve actually been able to work out the
The very likely pathophysiology of what’s going on here this is a schematic of cells in the proximal tubule at top panel a shows a normal physiology tenofovir shown as the little blue tf circles is imported into the the cell and then ideally should be promptly cleared by proteins called mrp2 and mrp4 unfortunately as shown in panel b in some individuals for
Various reasons that tenofovir doesn’t get cleared efficiently and it builds up and unfortunately tenofovir like many other drugs in its class has a cross affinity for a key enzyme in the mitochondria called dna polymerase gamma and so when you get enough tenofovir in these cells it starts to bind to that key enzyme in the mitochondria and the mitochondria
Stop working and the mitochondria of course are the key energy producing unit for the cell without functioning mitochondria the cell starts to develop some very severe problems and performing its essential function and you can even see with electron microscopy the the distortions in the mitochondria within these cells when they get poisoned in this manner on
The left you see a normal mitochondria um and on the right you see one that’s been uh essentially poisoned by this process the cristae are disorganized or these bizarre inclusion bodies so you can actually see this on a kidney biopsy in patients who have this toxicity how big a problem is it well the uh you know we didn’t see this very often in initial clinical
Trials but you have to remember that uh clinical trials typically enroll pretty healthy patients i think better information comes from these longer term longitudinal observational studies this comes from one such study involving over 10 000 patients in the veterans administration service in the united states and um what they found was that uh every year of using
Tenofovir was associated with about a one-third increase in the risk of developing proteinuria about a one-third increase in the risk of developing chronic kidney disease and about an 11 increase in the risk of developing sort of rapid kidney renal dysfunction other risk factors for this kidney toxicity include the usual sort of risk factors for kidney disease
Hypertension diabetes older age lower body mass establish kidney disease also interestingly retonavir probably because it inhibits one of those transport proteins as well as certain there’s a certain genetic predisposition one of the genes that codes for one of these transport proteins in the kidney if that gene has a mutation in it then the transporter will
Not function as efficiently and that can lead to an intracellular accumulation of the tenofovir um so in terms of the you know sort of epidemiology and how widespread this is again it kind of depends on whether you look at the initial randomized trials versus the observational studies observational studies typically showing this to be a bit more serious problem
In a large cross-sectional study of about 3 000 patients found that nearly 6 of patients developed a drop in their creatinine clearance below 60 mils per minute um after four years of exposure to a regimen that included tenofovir and a uh retinovir boosted protease inhibitor and then again that that larger study in the va involved over 10 000 patients um and
Notably in that study the the kidney function typically did not recover after the tenofovir was stopped and we’ve seen conflicting reports about whether uh stopping the tanoff here will lead to resolution of the problem or not um it it probably can if it’s caught early enough but uh if you get tubular necrosis and interstitial scarring then the impact may be
Permanent now tenofovir has also been associated with bone toxicity the pathophysiology of that has not been worked out as clearly but the the kidney is intimately involved in bone metabolism and there are certain hormones and compounds that are involved in bone metabolism such as calcitriol vitamin d phosphate parathyroid hormone so anytime you start to cause
Kidney dysfunction you run the risk of disrupting normal bone metabolism and it’s probably through one of those mechanisms that we’re seeing the impact on bones this is these are data from a randomized controlled study that was really looking at the efficacy of two different nucleotide backbones either tenofovir combined with ftc versus a bachelor combined with
3tc but helpfully they performed a sub study to look at bone mineral density in these patients and what you see in the left hand box patients randomized to receive tenofovir are shown in the sort of light purple um had a significantly more drop in their bone mineral density as compared with patients who received a bacavir instead so there’s definitely an impact
On bone mineral density this has been seen in other studies as well um just how clinically significant is it well um most studies have not identified increased risk of fracture but but this one did and this was a pretty large study also coming out of the va involving over 50 000 patients that were tracked during the heart era and they found that any use of
Tenofovir uh was associated with a significantly increased risk of developing an osteoporotic fracture so the bone mineral density effects are are probably real and deserve to be thought about so implicational management i would say you need to avoid tinafir if at all possible in patients who already have significant pre-existing renal or bone disease patients
Who are on tenofovir should be monitored for renal dysfunction ideally like a renal panel every three to six months and also urinalysis every six months because again often the problem starts with spilling of glucose phosphate and protein it’s important to minimize the other potential risk factors for renal dysfunction or bone demineralization and actually
Consider screening for osteoporosis in patients who have other risk factors and are on tenofovir if a patient on tanakovir develops a decline in renal function or develops osteopenia or osteoporosis it’s worth looking at stopping the tenofovir if at all possible and again if god early enough this this may have a significant beneficial impact for the patient
Because switch studies have shown improvement for many patients either in renal function or in bone mineral density after the tenofovir is discontinued now last week i alluded to a newer version of tenofovir that’s come out tenofovir alephenamide we abbreviate that as taf or taf this compound appears to lack the the renal and bone toxicities that tenofovir has
And that’s primarily because uh it re administration of taft results in much much lower about 90 percent less circulating levels of tenofovir in the plasma as compared with uh tenofovir disoproxyl fumarate or tdf and that’s going to the fact that it’s much more efficiently carried in the plasma and into the target cells so you just you simply have much much
Less of it around much less of it getting into the kidneys and therefore we’ve seen far less toxicity with that so just to wrap up with conclusions tenofovir has been clearly associated with a renal proximal tubule pathology that results in elevated risk of proteinuria acute kidney injury and chronic kidney disease it’s also been associated with decreases
In bone mineralization and even an increased risk of osteoporotic fractures in one study so implications for clinical management include avoiding tonoff of your where possible in patients with pre-existing renal or bone disease minimizing additional risk factors for renal or bone disease regular monitoring of renal function in persons on tunofevir and consider
Osteoporosis or bone mineral density screening in these individuals as well and discontinue to nofavir uh wherever possible in patients who develop renal or or bone toxicity that is either severe enough or that could be uh attributable to the tenant officer here so i’ll go ahead and stop there and open it up to questions and comments
Transcribed from video
Tenofovir Toxicity. Caribbean HIV ECHO. Presenter: Dr. Chris Behrens. Date: 22-August-2018 By CARIBBEAN HIV ECHO