Tenofovir alafenamide single-tablet regimen shows good efficacy with improved kidney and bone safety

Bart Rijnders, presenting at EACS 2015. Photo by Liz Highleyman, hivandhepatitis.com

A single-tablet regimen containing the new tenofovir alafenamide (TAF) – to be marketed as Genvoya – suppressed HIV as well as a co-formulation containing the older tenofovir disoproxil fumarate (TDF), according to a poster presented this week 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.

TAF vs TDF with elvitegravir

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 co-formulation is marketed as Stribild and the TAF co-formulation will be called Genvoya.

Glossary

formulation

The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 

lipid

Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

cholesterol

A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

These two international randomized 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).

As described at this year's Conference on Retroviruses and Opportunistic Infections, both co-formulations demonstrated similar high efficacy at 48 weeks: 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."

Switching from atazanavir/ritonavir & TDF to Genvoya

Rijnders presented findings from a sub-analysis of another TAF study in which people with stable viral suppression (< 50 copies/ml for at least a year) on TDF-containing regimens were randomised to either stay on the same treatment or switch to Genvoya.

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. No patients in this sub-analysis experienced virological failure (viral load > 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 co-formulation of TAF and emtricitabine that would be a successor to Truvada. Stand-alone TAF is also being developed as a treatment for hepatitis B.

References

Wohl D et al. A randomized, double-blind comparison of tenofovir alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat and emtricitabine (E/C/F) for initial HIV-1 treatment: week 96 results. 15th European AIDS Conference, abstract LBBPD1/1, 2015.

Rijnders B et al. Switching from ritonavir or cobicistat boosted atazanavir (ATV) plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) to a tenofovir alafenamide (TAF)-based single tablet regimen (STR): week 48 data in virologically suppressed adults. 15th European AIDS Conference, abstract PS10/3, 2015.