No significant
differences in viral suppression between groups on daily dosing versus alternate-day
dosing of combination fixed-dose tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV,
better known with the brand name of Atripla) were
found in a randomised clinical trial published in AIDS by Dr Rita Bellagamba and colleagues at the Italian National
Institute of Infectious Diseases.
While levels of
efavirenz in plasma concentrations showed a significant decrease in the
alternate-day dosing group, this did not significantly affect viral
suppression.
Researchers are looking
at the possibility of reduced doses of antiretrovirals with long half-lives,
such as TDF/FTC/EFV. While efavirenz-based treatment is not as widely used in
high-resource settings – due to concerns over neuropsychological symptoms and
possible suicidal ideation/suicide – it is still widely used in developing
countries, and with pregnant women.
Previous
research included two randomised studies investigating treatment interruption
using the FOTO strategy (five days on, two days off) in virally suppressed adults
and young
people on efavirenz-based treatment. When compared with standard schedules,
there were no virological failures at 48 weeks. A
proof of concept study looking at reduced dosing of TDF/FTC/EFV to three
days a week showed no virological failure at 24 weeks. A recent double-blind,
placebo-controlled randomised trial reported that a reduced dose of 400mg
EFV was as successful at maintaining an undetectable viral load as the standard
dose of 600mg at 48 and 96 weeks.
The study
The current
randomised clinical trial aimed to investigate the effects of reducing combined
TDF/FTC/EFV dosing to alternate days versus the standard of care regimen
(taking one pill daily) after 48 weeks. Some inclusion criteria comprised: being on fixed-dose TDF/FTC/EFV, with persistent virological
suppression (less than 40 copies of HIV per ml) for 6 months or more. People were excluded if they had previous virological failure, resistance to any of
the medications, or if they were pregnant.
A total of
197 people from an Italian treatment centre were randomised, with 98
allocated to the daily treatment group and 99 allocated to the reduced dosing
group. Of the entire sample, a large percentage of people were male (90%),
with a median age of 43.2. Most of these had acquired HIV through homosexual
contact (68%). The median CD4 cell count was 677 (IQR: 525-814), with the
median time being on Atripla 38.3
months (IQR: 23.3-55). Individuals had been living with HIV for a median of 6.8
years. The two groups were not significantly different, except that there was a
higher proportion of males on the TDF/FTC/EFV regimen for a longer duration in the
daily treatment group. Baseline efavirenz plasma concentrations in both groups
were similar with a median of 2421ng/ml.
The study
included therapeutic drug monitoring to measure efavirenz concentrations in
plasma at baseline and at 48 weeks. Participants were sent text messages with
reminders to take their doses. The main outcome was virological failure at week
48 (defined by a viral load of more than 40 copies/ml) or treatment
interruption.
Results
A high
percentage in both groups showed successful viral suppression at 48 weeks (97%
in the daily group and 94% in the alternate-day dosing group), with a -3%
overall risk difference (95% CI: -8.86-2.86%). This was not a statistically
significant difference.
Virological
failure was reported in one person from the daily dosing group (1%) and three
people from the alternate day dosing group (3%). In addition, five people had withdrawn from the study.
Of those
who experienced treatment failure, all four cases had a low level viral load
rebound (less than 250 copies/ml); all reported more than 95% adherence. The three
people in the alternate-day group were switched to daily TDF/FTC/EFV with
adherence recommendations. The person in the daily dosing group had experienced
low efavirenz plasma levels (less than 1000ng/ml) at failure and was prescribed
a new drug regimen of TDF/FTC/elvitegravir/cobicistat (despite not being
resistant to efavirenz). At 12 month follow-up, all these four people were virally suppressed.
Secondary outcome
differences were noted in terms of CD4 levels and efavirenz plasma
concentrations: median CD4 cell increase from baseline to week 48 was 29.4
cells/mm3
(95% CI: 2.5-56.4) in the daily dosing
group and 61 cells/mm3
(95% CI: 32.1-89.9) in the alternate-day
dosing group. More research is required to understand the larger increase of
CD4 cells in the alternate-day group, but it could be linked to reduced EFV
toxicity.
Median change of efavirenz concentration at week 48
from baseline was -6.5 ng/ml (95% CI: -103--55) in the daily dosing group and -1124
ng/ml (95% CI: -1375--928) in the alternate-day group.
There were no significant differences between the
groups in terms of cholesterol or triglyceride changes and neuropsychological
symptoms (such as sleep
quality, anxiety and dizziness).
Self-reported adherence was higher for the
alternate-day group (86% vs 73% for the daily dosing group), with significant
differences at 12, 24 and 36 weeks.
Conclusion
Despite a significant decrease in efavirenz levels in
the alternate-day dosing group, both groups were able to maintain high levels
of viral suppression. Of the people who experienced virological failure, only
one required a complete change of regimen and all were virally suppressed at
12 month follow-up. Adherence was significantly better in the alternate-day
dosing group.
As many people living with HIV, especially in
low-resource settings, continue to take medications with long half-lives such
as TDF/FTC/EFV, these findings are encouraging as they suggest that
alternate-day dosing may be a realistic option for many individuals who fit the
profile of participants in this study. Benefits include reduced costs and
potentially better adherence.
Participants will be followed up to 96 weeks for
further results. It is important to note that researchers excluded pregnant
women from this study, and thus further research needs to be done on this
group.
