A single-tablet regimen containing the new tenofovir alafenamide (TAF) – to be marketed as Genvoya – suppressed HIV as well as a coformulation containing the older tenofovir disoproxil fumarate (TDF), according to a poster presented at the 15th European AIDS Conference in Barcelona. A related study found that people who switched from an atazanavir (Reyataz) regimen to the new combination had superior virological outcomes, and in both trials participants saw improvements in kidney and bone biomarkers.
Gilead Sciences’ TAF is a new pro-drug formulation that delivers the active agent to HIV-infected cells more efficiently than the current TDF formulation (Viread, also in Truvada, Atripla, Eviplera and Stribild). TDF is generally safe and well-tolerated but it can cause a small amount of bone loss soon after starting therapy and can lead to kidney problems in susceptible people.
Presenter Bart Rijnders from Erasmus Medical Centre in Rotterdam explained that TAF has a longer half-life, allowing more time for active tenofovir to enter CD4 T-cells. TAF therefore produces sufficient intracellular drug levels with a smaller dose, which means a lower concentration in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.
As described in a late-breaking poster, David Wohl of the University of North Carolina at Chapel Hill and colleagues did a head-to-head comparison of first-line therapy using single-tablet regimens containing the integrase inhibitor elvitegravir (150mg), the booster cobicistat (150mg), emtricitabine (200mg) and either TAF (10mg) or TDF (300mg). The existing TDF coformulation is marketed as Stribild and the TAF coformulation will be called Genvoya.
These two international randomised phase 3 studies together enrolled 1,733 treatment-naive participants with near-normal kidney function. About 85% were men, about 40% were white and the median age was 34 years. The median baseline CD4 cell count was approximately 400 cells/mm3 and nearly a quarter had high viral load (>100,000 copies/ml). Both coformulations demonstrated similar high efficacy at 48 week: 92% for Genvoya and 90% for Stribild. The EACS poster reported that viral suppression rates remained high at 96 weeks: 87% and 85%, respectively.
By 96 weeks 1.2% of TAF recipients and 0.9% taking TDF had virological failure with drug resistance. Virological outcomes did not differ by age, sex, race/ethnicity, geographic region, baseline viral load or CD4 count. Treatment was generally safe and well-tolerated, with similar rates of overall and serious adverse events, but TAF had less detrimental effects on the kidneys and bones than TDF. Rates of discontinuation due to adverse events were low in both treatment arms (1.2% for Genvoya and 2.3% for Stribild). The most common side effects were headache, diarrhoea and nausea.
Multiple laboratory tests of kidney function and specific tubular function favoured the TAF regimen. No cases of renal tubulopathy (including Fanconi Syndrome) occurred in the TAF-containing arm, compared with two cases in the TDF-containing arm (one of which led to treatment discontinuation).
People taking the TAF-containing coformulation had a significantly smaller mean decrease in bone mineral density (BMD) at the lumbar spine (-0.96 vs -2.79) and the hip (-0.67 vs -3.28) at 96 weeks. Total, LDL and HDL cholesterol increases were significantly larger in the TAF arm – a known side effect of tenofovir – but the total-to-HDL cholesterol ratio remained stable. The number of people who needed to start lipid-modifying medications was similar in both arms: 3.8% for Genvoya vs 4.4% for Stribild.
“After two years, TAF combined with (elvitegravir/cobicistat/emtricitabine) produced a high rate of virologic suppression (87%) and remained non-inferior to Stribild in treatment-naive patients,” the researchers concluded. “(Genvoya) continued to have a statistically superior bone and renal safety profile compared with Stribild.”
Rijnders presented findings from a sub-analysis of another TAF study in which people with stable viral suppression.
The overall study population included 1,436 participants. They had near-normal kidney function (median estimated glomerular filtration rate (eGFR) 106 ml/min) and 9% had proteinuria (protein in the urine) at baseline. Results from the full study were presented at the International AIDS Society Conference this summer in Vancouver.
This sub-analysis focused on 601 participants who switched to Genvoya from a regimen of TDF, emtricitabine and atazanavir boosted with either ritonavir or cobicistat. In this analysis 86% were men, about 65% were white, the median age was 41 years and the median CD4 count was approximately 650 cells/mm3.
At 48 weeks, 97% of participants who switched to Genvoya and 92% of those who stayed on their atazanavir regimen maintained HIV RNA 50 copies/ml). Rijnders noted that the difference in response rates was driven by missing data, mostly due to withdrawal of consent.
Again, treatment was generally safe and well-tolerated. Rates of most adverse events were similar in the two treatment arms, but as expected elevated bilirubin was more common with atazanavir (55% vs <1% with Genvoya).
Measures of proteinuria and specific tubular proteinuria improved significantly. However, Rijnders explained that cobicistat inhibits excretion of serum creatinine, which can result in elevated levels that do not actually reflect impaired kidney function.
Both hip and spine bone density improved significantly in the Genvoya arm according to DXA scans – a difference that was apparent by week 24. At week 48 spine BMD rose by +2.18% in the Genvoya arm while falling by -0.54% in the atazanavir arm. Changes in hip BMD were +11.74% vs -0/54%, respectively. The proportion of people who met the criteria for osteopenia or osteoporosis at the spine or hip decreased in the Genvoya arm, while rising or remaining stable in the atazanavir arm.
Blood lipid levels rose more with the TAF-containing regimen, but the total cholesterol-to-HDL ratio again did not change significantly. More people taking Genvoya started lipid-modifying medications (8.7% vs 5.0%).
“In both the overall population and in prior boosted atazanavir and (emtricitabine)/TDF users, those switching to (Genvoya) had significantly more virological success,” the researchers concluded, as well as significant improvements in spine and hip BMD, less osteoporosis, and improvements in proteinuria, tubular proteinuria and albuminuria, but higher creatinine and blood lipids.
Based on favourable study findings to date, Gilead has requested US and European regulatory approval of the elvitegravir/cobicistat/emtricitabine/TAF single-tablet regimen. The US Food and Drug Administration is scheduled to make a decision in November.
In addition, the company has also requested approval of other TAF single-tablet regimen containing rilpivirine or darunavir and a dual coformulation of TAF and emtricitabine that would be a successor to Truvada. Stand-alone TAF is also being developed as a treatment for hepatitis B.
Background: Tenofovir disoproxil fumarate can cause renal and bone toxic eff ects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens.
Methods: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratifi ed by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff , and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defi ned by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specifi ed renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445.
Findings: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted diff erence 2•0%, 95% CI –0•7 to 4•7). Patients given E/C/F/tenofovir alafenamide had signifi cantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0•08 vs 0•12 mg/dL; p<0•0001), signifi cantly less proteinuria (median % change –3 vs 20; p<0•0001), and a significantly smaller decrease in bone mineral density at spine (mean % change –1•30 vs–2•86; p<0•0001) and hip (–0•66 vs–2•95; p<0•0001) at 48 weeks.
Interpretation: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile