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Switching to new tenofovir alafenamide keeps virus in check and improves kidney and bone health
Liz Highleyman, 2015-07-28 11:30:00
People who switch from the current version of tenofovir to tenofovir alafenamide (TAF) – a new formulation that reaches higher levels in HIV-infected cells – maintained undetectable viral load and saw improvements in liver function biomarkers and bone density, according to a pair of studies presented at the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) last week in Vancouver, Canada.
Gilead Sciences' tenofovir disoproxil fumarate(Viread) is one of the most widely used antiretroviral drugs. It is a component of the Truvada coformulation – used for both HIV treatment and pre-exposure prophylaxis (PrEP) – and of the single-tablet regimens Atripla, Eviplera and Stribild. Tenofovir disoproxil fumarate(TDF) is generally considered safe and well-tolerated but it may cause a small amount of bone loss soon after starting treatment and lead to kidney problems in susceptible people.
TAF is a new pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. TAF produces adequate intracellular drug levels with lower doses, which means much lower concentrations in the blood plasma and less drug exposure for the kidneys, bones and other organs and tissues.
Two phase 3 clinical trials, presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI), showed that TAF is as effective as TDF for previously untreated people, but has fewer detrimental effects on the kidneys and bones compared with the current version.
At the IAS conference, Tony Mills of the Southern California Men’s Medical Group in Los Angeles presented findings from another phase 3 study, this one looking at treatment-experienced people who switched from the old to the new tenofovir formulation.
This analysis included 1436 people living with HIV who had normal kidney function and who at study entry had suppressed viral load (<50 copies/ml) on one of the following combination regimens for at least 96 weeks:
- TDF/emtricitabine/elvitegravir/cobicistat (Stribild).
- TDF/ emtricitabine/efavirenz (Atripla).
- Atazanavir (Reyataz), boosted with either ritonavir (Norvir) or cobicistat (Tybost), plus TDF/emtricitabine (Truvada).
Participants in this open-label study were randomly assigned to either remain on their current TDF-containing regimen or switch to a new single-tablet regimen consisting of TAF (10mg), emtricitabine (200mg), elvitegravir (150mg) and cobicistat (150mg) – essentially a new version of Stribild that substitutes TAF for TDF.
Most study participants (about 90%) were men, two-thirds were white, 19% were black (a group at higher risk for kidney problems) and the median age was 41 years. The median baseline CD4 cell count was approximately 670 cells/mm3. At study entry, they were required to have an estimated glomerular filtration rate (eGFR) – a measure of kidney function – above 50 ml/min using the common Cockcroft-Gault method, with a median of 107 ml/min (>90 ml/min is generally considered normal). About 9% had grade 1 or mild dipstick proteinuria (protein in the urine) but less than 1% had grade 2 or moderate proteinuria.
Both treatment regimens were highly effective, showing that switching to the TAF regimen was non-inferior to staying on a TDF regimen, Dr Mills said.
After 48 weeks of treatment, virological response rates were high in both groups: 97% of people who switched to the TAF coformulation had undetectable viral load (<50 copies/ml), compared with 93% of those who stayed on their existing regimen – a significant difference in favour of TAF. Virological failure was likewise low in both groups (about 1%). People who switched from Atripla or atazanavir/Truvada to the TAF coformulation saw significantly better responses, while those who switched from Stribild did about the same.
Overall safety and tolerability were good in both treatment groups, with few discontinuations in either arm due to adverse events (0.9% in the TAF group vs 2.5% in the TDF group).
Most types of side-effects and laboratory abnormalities were similar in the two groups, although bilirubin levels were higher in the pre-existing regimen arm (likely attributable to some participants using atazanavir).
However, there were some notable differences related to kidney function and bone health.
Looking first at kidney function, two participants who switched to the TAF regimen and five people staying on their TDF regimen discontinued therapy due to kidney-related adverse events. There were no cases of Fanconi syndrome, a type of serious kidney disease, in the TAF study arm and one case in the TDF-containing arm.
People who switched to TAF experienced improvements in kidney function markers while those who stayed on TDF regimens worsened. Dr Mills noted that these changes began by week 2 and persisted through week 48.
Statistically significant improvements were seen in urine protein-to-creatinine ratio (-21% vs +10% change), urine albumin-to-creatinine ratio (-18% vs +9%), retinol binding protein-to-creatinine ratio (-33% vs +18%) and beta-2-microglobulin-to-creatinine ratio (-52% vs +19%). Cobicistat is known to raise serum creatinine levels, which lowers eGFR, without actually impairing kidney function, so ratios showing these markers in relation to creatinine may be more useful.
Turning to bone health, spine bone mineral density (BMD) rose by an average +1.79% in the TAF arm while falling by a mean of -0.28% among those who stayed on existing TDF regimens. The corresponding mean changes in hip BMD were +1.37% and -0.26%, respectively. Both differences were statistically significant. People who switched to TAF saw significant improvements in osteopenia or osteoporosis of the spine and hip, which remained the same in the non-switch arm. Dr Mills noted that all fractures seen in the study were due to trauma, not fragility.
Fasting lipids increased by a small amount among people switching to TAF, although the total-to-HDL cholesterol ratio stayed about the same.
"Participants who switched to [the TAF coformulation] were significantly more likely to maintain virologic success," the researchers concluded, and they "had significant improvements in spine and hip BMD, had significant reductions in osteopenia/osteoporosis, and had significant improvements in proteinuria and other markers of renal function."
Particularly for women and others at risk for bone loss, or for people at risk for kidney function problems, TAF "provides a great new option," Dr Mills suggested.
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