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IAS 2015: Switching to Tenofovir Alafenamide Keeps HIV Suppressed, Helps Kidneys and Bones

People who switch from the current version of tenofovir (TDF) to tenofovir alafenamide (TAF) -- a new formulation that reaches higher levels in HIV-infected cells -- maintained undetectable viral load and saw improvements in kidney function biomarkers and bone density, according to a pair of studies presented at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention last week in Vancouver.

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, Complera, and Stribild. TDF is generally considered safe and well-tolerated, but it can cause 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.

A pair of 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 less detrimental effects on the kidneys and bones compared with the current version.

At the IAS conference, Tony Mills from the Southern California Men’s Medical Group in Los Angeles presented findings from another Phase 3 study (GS-US-292-0109), this one looking at treatment-experienced people who switched from the old to the new tenofovir formulation.

This analysis included 1436 HV-positive people with normal kidney function 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 (2:1) to either remain on their current TDF-containing regimen or switch to a new single-tablet regimen consisting of TAF (10 mg), emtricitabine (200 mg), elvitegravir (150 mg), and cobicistat (150 mg) -- 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 T-cell count was approximately 670 cells/mm³. At study entry they were required to havean 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.

Results

• Both treatment regimens were highly effective, showing that switching to the TAF regimen was non-inferior to staying on a TDF regimen.
• At48 weeks virological response rates were high in both groups: 97% of people who switched to the TAF coformulationhad undetectable viral load (<50 copies/mL) compared with 93% of those who stayed on their existing regimen -- a significant difference in favor of TAF.
• Virological failure was likewise low in both groups (about 1%).
• People who switched from Atripla or atazanavir/TDF/emtricitabineto 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 2 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.
• 2 participants who switched to the TAF regimen and 5 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 arm and 1 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, with these changes beginning by week 2 and persisting 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 blinding protein-to-creatinine ratio (-33% vs +18%), and beta-2-microglobulin-to-creatinine ratio (-52% vs +19%).
• 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, and 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.
• All fractures seen in the study were due to trauma, not fragility.
• Fasting lipids increased by a small amount among people switching to TAF, though 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," Mills suggested.

Impaired Kidney Function

Samir Gupta from Indiana University followed with findings from an ongoing Phase 3 study (GS-US-292-0112) evaluating TAF in people with mild or moderate kidney function impairment.

Many experts advise against using TDF in people with impaired kidney function unless the expected benefits outweigh the risks. Current prescribing directions call for dose reductions for people with pre-existing kidney impairment.

This analysis included 242 participants with stable viral suppression. A majority (about 80%) were men, about 18% were black, the median age was 58 years, and the median CD4 count was approximately 630 cells/mm³. Many had kidney disease risk factors including about 40% with hypertension and 14% with diabetes.

At study entry participants had mild to moderate kidney impairment with eGFR ranging from 30 to 69 mL/min using the Cockcroft-Gault method(median 56 mL/min). About a quarter had grade 1 and 10% had grade 2 dipstick proteinuria, but none had grade 3-4.

In this open-label study participants switched from existing regimens -- which could contain TDF or not  -- to the same TAF-containing single-tablet regimen used in the study described above. Pre-switch, 65% were taking TDF, 22% were taking abacavir (Ziagen), 7% were on other nucleoside reverse transcriptase inhibitors, and 5% were taking no drugs in this class. In addition, 44% were taking HIV protease inhibitors, 42% were on NNRTIs, and 24% were on integrase inhibitors.

Gupta noted that baseline characteristics were not matched between the groups taking TDF-containing and non-TDF regimens at baseline, with more women and blacks taking TDF, and more hypertension and proteinuria in the TDF group.

At week 24 there were no significant changes in actual GFR (using the iohexol clearance test), regardless of whether people switched from TDF-containing or non-TDF regimens to the TAF coformulation.

At week 48, among participants switching from TDF to TAF, estimated GFR rose by a median of +0.2 mL/min using the Cockcroft-Gault method and by +2.7 mL/min/1.73m² using the cystatin C method, the latter of which was statistically significant. Among people who switched from non-TDF regimens to TAF, eGFR fell by -1.8 mL/min and -1.4 mL/min/1.73m², respectively, neither of which were significant.

Looking at the various measures of proteinuria, significant -- and in some cases large -- improvements were seen urine protein-to-creatinine ratio, urine albumin-to-creatinine ratio, retinol blinding protein-to-creatinine ratio, and beta-2-microglobulin-to-creatinine ratio among people switching from TDF to TAF. However, changes were small and not significant among those switching from non-TDF regimens to TAF.

At week 48 kidney markers in people who switched from TDF to TAF "seemed to approximate" those of people who did not take tenofovir at all, Gupta said.

The proportion of participants with clinically meaningful proteinuria (UPCR >200 mg/g) decreased from 47% to 13%, while those with clinically meaningful albuminuria (UACR >30 mg/g) decreased from 55% to 22% when switching from TDF-containing regimens to TAFT -- both significant differences. Here too, changes were not significant for those switching from non-TDF regimens.

Again, significant increases in mean spine BMD (+2.95%) and hip BMD (+1.85%) were observed at 48 weeks among participants switching from TDF to TAF, with no significant changes among those switching from non-TDF combinations.

Finally, total cholesterol, LDL, HDL, and triglyceride levels rose -- and the total-to-HDL cholesterol ration worsened -- after switching from TDF to TAF, while falling among those who switched from non-TDF regimens. The researchers said this was "consistent with [an] independent effect of circulating tenofovir on reducing cholesterol levels."

"Participants on TDF at time of switch had no change in actual GFR, significant improvements in urinary markers of renal function, significant improvements in BMD, [and] significant increases in lipids," the researchers summarized.  "Participants not on TDF at time of switch had no changes in actual GFR, stable urinary markers of renal function, and BMD [and] significant decreases in cholesterol fractions."

"These 48 week data support the renal and bone safety of once-daily, single-tablet [TAF coformulation] for adults with HIV and renal impairment," they concluded.

Asked about the mechanism of the improvements after switching from TDF to TAF, Gupta suggested we could be "taking the gas off mitochondrial dysfunction," but emphasized that this was "only speculation at this point."

Based on favorable study findings to date, Gilead has submitted the TAF/emtricitabine/elvitegravir/cobicistat coformulation for regulatory review in the U.S. and Europe. The Food and Drug Administration is expected to make a decision by November.

In addition, Gilead has requested approval of a dual coformulation of TAF and emtricitabine -- which would be a successor to Truvada -- and is developing 2 other single-tablet TAF regimens, one containing the NNRTI rilpivirine (Edurant) and the other the HIV protease inhibitor darunavir (Prezista). Stand-alone TAF is also being developed as a treatment for hepatitis B. Gilead has indicated that it is collaborating with the Centers for Disease Control and Prevention (CDC) on a monkey study of TAF/emtricitabine for PrEP.

7/27/15

References

T Mills, J Andrade, G DiPerri, et al. Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen: data in virologically suppressed adults through 48 weeks of treatment. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0102.

S Gupta, A Pozniak, J Arribas, et al. Subjects with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 48 weeks. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0103.