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 published in the Journal of Virus Eradication. 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. “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.


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.


Relating to the kidneys.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.


When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

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.

A 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 3347 people received TDF and 4763 were treated with TAF. In all, 4574 people (7190 person-years of follow-up) were allocated to a regimen containing a boosting agent, and 3537 individuals (3594 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.”


Hill A et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety. Journal of Virus Eradication, 4: 73-80, 2018.