Friday, 29 March, 2024
HomeHIV/AIDSTAF only superior to TDF when used with a boosting agent

TAF only superior to TDF when used with a boosting agent

The benefits of tenofovir alafenamide (TAF) over tenofovir disoproxil fumarate (TDF) may have been overstated, according to the results of a meta-analysis. It was only when used in an antiretroviral therapy regimen containing a boosting agent that TAF was superior to TDF in terms of viral suppression and bone and renal side-effects. There was no difference between the safety and efficacy of TAF and TDF in the context of unboosted antiretroviral therapy.

“In randomised clinical trials where TAF and TDF were used without pharmacokinetic enhances – ritonavir and cobicistat – there was no benefit of TAF versus TDF for HIV RNA suppression, clinical adverse events, discontinuation for renal adverse events, bone fractures or discontinuation for bone-related adverse events,” comment the authors led by Andrew Hill at the University of Liverpool. “By contrast, in randomised clinical trials where TAF and TDF were boosted by ritonavir or cobicistat, TAF showed significantly higher rates of HIV RNA suppression that TDF, and there were lower risks of renal and bone-related adverse events.”

Tenofovir belongs to the nucleoside reverse transcriptase inhibitor (NRTI) class of antiretrovirals and is widely used in the treatment of HIV, for HIV pre-exposure prophylaxis (PrEP) and also in hepatitis B virus (HBV) therapy.

The original TDF formula was developed as a daily 300mg dose. Potent and generally very safe, this tenofovir formula has, however, been associated with bone and renal abnormalities.

A tenofovir pro-drug formulation, TAF, has been developed. It achieves high intracellular concentrations. But serum concentrations are typically 90% lower than TDF, therefore reducing the risk of bone and kidney changes.

TAF is licensed in the US and Europe but at a cost premium over TDF.

The team of UK investigators wanted to see if virological and safety outcomes between the two tenofovir formulations differed according to the use of a boosting agent. The boosting agents ritonavir or cobicistat are used with protease inhibitors and the integrase inhibitor elvitegravir to boost levels of those drugs but have also been observed to increase plasma levels of TAF and TDF. Dosing of TAF is reduced from 25mg a day to 10mg if used in regimens containing ritonavir or cobicistat to take into account this boosting effect.

They conducted a meta-analysis of eleven studies directly comparing HIV suppression and safety between TDF and TAF. Nine of the studies involved people with HIV; the two other recruited people living with HBV.

Participants had a mean age of 41 years, 59% were white and 83% were male. Average baseline CD4 cell count was 300 cells/mm3. A total of 3,347 people received TDF and 4763 were treated with TAF. In all, 4,574 people (7,190 person-years of follow-up) were allocated to a regimen containing a boosting agent, and 3537 individuals (3,594 person-years of follow-up) were randomised to an unboosted regimen.

Analysis of people taking a boosting agent showed that TAF was associated with 2% higher rates of viral suppression (p = 0.05). However, rates of viral suppression were comparable between TDF and TAF when the drug was taken as part of an unboosted regimen.

In terms of safety, there were no significant differences in Grade 1-4 adverse events, serious adverse events, or Grade 3-4 laboratory abnormalities and deaths between TDF and TAF in both the boosted and unboosted subgroups.

Rates of treatment discontinuations for renal events were 1% (p = 0.002) lower for TAF than TDF when taken with a booster. Discontinuation rates due to renal side-effects were comparable between the two formulations when therapy was unboosted.

The risk of bone fracture was 1% lower for boosted TAF compared to boosted TDF (p = 0.04). However, there was no difference in fracture risk between TDF and TAF when unboosted. People treated with boosted TAF were 1% less likely than those taking boosted TDF to stop treatment because of bone-related side-effects. There was no difference between TDF and TAF in the risk of discontinuation for bone-related events when therapy was unboosted. Regardless of the use of a boosting agent, reductions in bone mineral density (BMD) in the hip and spine were more pronounced among individuals taking TDF than TAF (all comparisons, p < 0.001). However, the investigators note that the clinical significance of these changes in BDM is uncertain.

With these findings in mind, can it be justified paying more for TAF? “The only known economic analyses comparing TAF and TDF used input parameters derived from studies administering boosted TDF, which may not be appropriate,” comment the authors.

“Economic analyses should instead consider TAF against unboosted TDF to inform national policies. In the UK, the cheapest TAF regimen (TAF/emtricitabine/rilpivirine) costs $8246 PPPY [per patient per year], while the TDF patent is set to expire from 2018 across Europe. In the generic-inaccessible context, money may be saved by using generic TDF-based regimens costing $107 PPPY.”

They conclude, “the purported safety benefits of TAF over TDF may be overstated.”

Abstract
Background: Higher plasma tenofovir concentrations are associated with higher risks of renal and bone adverse events. The pharmacokinetic boosters ritonavir (RTV) and cobicistat (COBI) significantly increase plasma area under the curve (AUC) concentrations of tenofovir disoproxil fumarate (TDF), by 25–37%. When combined with RTV or COBI, the dose of tenofovir alafenamide (TAF) is lowered from 25 mg to 10 mg daily, but the TDF dose is maintained at 300 mg daily.
Objective: To assess the differences in safety and efficacy between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) in regimens with and without the pharmacokinetic boosters RTV and COBI.
Methods: A PubMed/Embase search inclusive of dates up to 17 July 2017 identified 11 randomised head-to-head trials (8111 patients) of TDF versus TAF. The Mantel–Haenszel method was used to calculate pooled risk differences and 95% confidence intervals using random-effects models. A pre-defined sub-group analysis compared TAF with TDF, either when boosted with RTV or COBI, or when unboosted.
Results: Nine clinical trials compared TAF and TDF for treatment of HIV-1 and two were for hepatitis B treatment. The eleven clinical trials documented 4574 patients with boosting RTV or COBI in both arms, covering 7198 patient-years of follow-up. Some 3537 patients received unboosted regimens, totalling 3595 patient-years of follow-up. Boosted TDF-treated patients showed borderline lower HIV RNA suppression <50 copies/mL (P=0.05), more bone fractures (P=0.04), larger decreases in bone mineral density (P<0.001), and more discontinuations for bone (P=0.03) or renal (P=0.002) adverse events. By contrast, there were no significant differences in HIV RNA suppression rates or clinical safety endpoints between unboosted TAF and unboosted TDF.
Conclusions: TDF boosted with RTV or COBI was associated with higher risks of bone and renal adverse events, and lower HIV RNA suppression rates, compared with TAF. By contrast, when ritonavir and cobicistat were not used, there were no efficacy differences between TAF and TDF, and marginal differences in safety. The health economic value of TAF versus low-cost generic TDF may be limited when these drugs are used without cobicistat or ritonavir.

Authors
Andrew Hill, Sophie L Hughes, Dzintars Gotham, Anton L Pozniak

[link url="http://www.aidsmap.com/TAF-only-superior-to-TDF-when-used-with-a-boosting-agent/page/3255399/"]Aidsmap material[/link]
[link url="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892670/"]Journal of Virus Eradication abstract[/link]

MedicalBrief — our free weekly e-newsletter

We'd appreciate as much information as possible, however only an email address is required.