As mentioned previously in this issue of TreatmentUpdate, clinical trials assessing the new formulation of tenofovir (tenofovir alafenamide, or TAF) and sometimes comparing it to the original formulation (tenofovir disoproxil fumarate, or TDF) are ongoing. Studies have found that TAF is as effective as TDF and is very likely safer, particularly for the kidneys and bones. Participants enrolled in these studies had relatively good kidney health.
But will TAF be safe in people with pre-existing kidney dysfunction? To try to answer this question, researchers conducted study 292-0112. In this study, researchers sought participants who had mild-to-moderate kidney dysfunction graded with the use of eGFR (estimated glomerular filtration rate). After screening, researchers recruited 242 HIV-positive participants who had an eGFR between 30 and 69 mL/minute, who were on stable combination anti-HIV therapy (commonly called ART) and who had a viral load less than 50 copies/ml. All participants were switched to a TAF-containing regimen and monitored for 48 weeks. In general, TAF was safe and when this formulation of tenofovir was substituted for TDF, improvements in bone density and kidney health were seen. However, not every participant who switched from TDF to TAF had improvement in kidney injury, particularly in cases of severe injury to these organs.
All 242 participants were switched from their current regimen to the following regimen:
- TAF + FTC + elvitegravir + cobicistat (this fixed-dose combination pill is called Genvoya)
The average profile of participants when they entered the study was as follows:
- age -- 58 years (note that 28% of participants were at least 65 years old)
- 79% men, 21% women
- CD4+ count -- 632 cells/mm3
- HIV viral load -- less than 50 copies/ml
- 40% had hypertension
- 14% had type 2 diabetes
- eGFR -- 56 mL/minute (note that 34% of participants had an eGFR of at least 60 mL/min)
- 33% had mild-to-moderate levels of protein in their urine, suggestive of kidney injury
Overall, 158 participants were taking TDF as part of their regimen and 84 participants were taking other nukes.
In the everyday world outside a clinical trial, when assessing kidney health, doctors usually request lab analyses of blood, and in particular the amount of the waste product creatinine. They can then put the amount of creatinine detected into a formula and get an estimate of the functioning of the kidneys. This is called the estimated glomerular filtration rate (eGFR). Doctors routinely use eGFR because assessing the actual GFR (written as aGFR) would be cumbersome for patients. Note that the eGFR is an estimate and it is useful for routine laboratory analyses requested by doctors.
However, in the present research setting, it was important to find out about the aGFR because eGFR is a calculated value (not a measured one). In the present study, researchers were able to assess the actual GFR. They found that there were no significant changes in the aGFR and only minor ones with eGFR after participants switched to a TAF-based regimen. Overall, this suggests that TAF does not have a major impact on the kidneys' ability to filter blood.
The researchers also had laboratories analyse participants' urine and they assessed certain proteins in the urine, as follows:
- protein to creatinine ratio
- albumin to creatinine ratio
- retinol-binding protein to creatinine ratio
- beta2-microglobulin to creatinine ratio
They found significant reductions in these proteins among TAF users but not TDF users. Overall, this suggests that TAF helped to reduce kidney injury compared to TDF.
A Moderate-to-Severe Degree of Kidney Injury
Researchers focused on people with high levels of total protein in their urine samples (more than 200 mg/gram,) as this sub-group would likely have a higher level of kidney injury than other participants.
Switching From TDF to TAF
In conducting their analyses, researchers found that among participants who had been on a TDF-containing regimen at the start of the study, 47% had high levels of protein in their urine, suggestive of kidney injury. After switching from TDF to TAF, 48 weeks later the proportion with a high level of protein in their urine was 13%. This difference was statistically significant. It shows that switching from TDF to TAF is associated with significant improvements in kidney health. However, note that this switch does not help everyone who used TDF. Perhaps not everyone's kidneys recovered after the switch because of the severity of kidney injury, or there may have been other factors that could have affected kidney health that were unrelated to TAF, such as the presence of higher-than-normal blood pressure, type 2 diabetes and so on.
No Initial Use of TDF but Using TAF
Among participants who had not been taking TDF but were instead taking other nukes at the start of the study, 29% had high levels of protein in their urine. After these participants switched their regimens to TAF, 48 weeks later the proportion with a high level of protein in their urine was 22%. This difference was not statistically significant.
These changes confirm that TDF can play a major role in kidney injury and that switching to TAF may greatly reduce the severity of kidney injury in some patients.
A Focus on Albumin
Another way to assess kidney injury is to measure the levels of a specific protein -- albumin -- in the urine.
The distribution of elevated albumin levels among participants who entered the study using TDF was as follows:
- at the start of the study -- 55% had elevated albumin levels in their urine
- after being on TAF for 48 weeks -- 22% had elevated levels of albumin in their urine
This difference in albumin levels was statistically significant. Thus, there may be a role for replacing TDF with TAF in people with kidney injury.
In contrast, among participants who used nukes other than TDF at the start of the study and then exchanged these nukes for TAF, there was little change in elevated albumin levels. Among these participants, the distribution of elevated albumin levels was as follows:
- at the start of the study -- 37% had elevated albumin levels in their urine
- after being on TAF for 48 weeks -- 34% had elevated levels of albumin in their urine
Changes in Bone Mineral Density
The following changes in bone mineral density occurred during the study:
- participants who switched from TDF to TAF -- an increase of 2.3%
- participants who switched from another nuke to TAF -- an increase of 1%
- participants who switched from TDF to TAF -- an increase of 1.5%
- participants who switched from another nuke to TAF -- an increase of 0.7%
Changes in Lipids
As with other studies, participants who switched from TDF to TAF generally had an increase in their fasting lipid levels, including the following:
- total cholesterol
- bad cholesterol (LDL-C)
- good cholesterol (HDL-C)
Participants who switched to TAF from a nuke other than TDF had modest decreases in their lipid levels.
Switching from a regimen based on TDF to TAF resulted in improvements in assessments of kidney and bone health.
Participants who were not using a TDF-based regimen who switched to TAF did not have significant changes in assessments of kidney or bone health. However, their lipid levels decreased somewhat.
Overall, the data from the present study suggest that people who are encountering kidney dysfunction while taking a TDF-based regimen can generally expect improvement when they switch to a TAF-based regimen. Note that not every participant who switched to a TAF-based regimen had such an improvement.
Gupta S, Pozniak A, Arribas J, et al. Subjects with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 48 weeks. In: Program and abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2015, Vancouver, Canada. Abstract TUAB0103.