As mentioned previously in this issue of TreatmentUpdate, TAF is being tested as a replacement for TDF -- the original formulation of tenofovir. In this report we provide details about two pivotal trials of TAF-based regimens. Note that since the trials are identical in design, the data are pooled, or combined.
In two double-blind clinical trials, researchers randomly assigned 1,733 HIV-positive participants to receive one of the following regimens, taken once daily:
Prior to the study none of the participants had taken potent combination anti-HIV therapy (commonly called ART).
Analysis after 48 weeks found that the virological effectiveness of the TAF-based regimen was no worse (the technical term for this is non-inferior) than the TDF-based regimen. Increases in CD4+ cell counts were broadly similar between regimens. Furthermore, TAF users had, on average, fewer signals of kidney injury compared to TDF users and decreases in bone mineral density were generally milder. Long-term studies are needed to assess if these favourable changes with TAF persist.
Researchers recruited participants from the following regions and countries:
The average profile of participants upon entering the study was as follows (note that percentages are rounded so the total may not equal 100%):
HIV disease status:
HIV risk factor:
All study regimens were taken with food.
After 48 weeks the proportion of participants whose viral load was less than 50 copies/ml was as follows:
Using a viral load assay with a lower limit of quantification (that could accurately count down to as low as 20 copies/ml), the proportion of participants in each regimen with an undetectable viral load was as follows:
This suggests that both formulations of tenofovir are roughly equivalent.
Among participants who entered the study with a viral load in the blood greater than 100,000 copies/ml, the proportion with a viral load less than 50 copies/ml at week 48 was as follows:
The TAF-based regimen was modestly more effective in women and in people with a baseline viral load of less than 100,000 copies/ml. However, the number of women in this study was relatively small (260 women out of 1,733 participants, making up 15% of all participants) and this clinical trial is not the definitive study of TAF in HIV-positive women.
Most clinical trials of modern ART calculate a median change in CD4+ count to smooth large changes that might occur when participants begin a study with very high or very low CD4+ counts. However, in the two studies reported here, Gilead scientists appeared to have done something unusual -- they reported the average change in CD4+ counts. Furthermore, they assert that the change in average CD4+ cell counts favours the TAF-based regimen. This is particularly odd since many other important changes in nearly all other major lab tests were reported as median values. This suggests the possibility that the median changes in CD4+ counts were not statistically different between the two study regimens. We cannot be certain about this, as Gilead has not reported the median changes in CD4+ cell counts. However, we urge our readers to treat any claims of a TAF-based regimen somehow resulting in a superior CD4+ count in these studies with caution. At any rate, it is likely that the increases in CD4+ cell counts between the regimens were broadly similar -- in the range of about 200 more CD4+ cells/mm3 at week 48.
Researchers defined virological failure in one of the following ways:
Participants who fulfilled one of these criteria underwent further viral load testing.
Cases of virological failure were distributed as follows:
Analysis of their HIV found that all participants had developed resistance to FTC (and 3TC).
Eight participants developed HIV that was resistant to the integrase inhibitor elvitegravir, distributed as follows:
In all eight of the above cases, lab tests found that HIV was still susceptible to another integrase inhibitor, dolutegravir (Tivicay and in Triumeq). This meant that should these people and their doctors choose to do so, they could use dolutegravir in a future treatment regimen.
According to the researchers, the study drugs were "well tolerated" and most side effects were graded as having mild or moderate intensity. There were no new side effects associated with use of TAF. Common side effects reported with both regimens were similarly distributed and included the following:
Deaths in the study were distributed as follows:
Investigation revealed that these deaths were not caused by the study medicines.
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