The influence of having bariatric surgery on the pharmacokinetics, safety and efficacy of the novel non-nucleoside reverse transcriptase inhibitor doravirine (LABRADOR)

People living with HIV (PLWH) report high obesity trends similar to those to
the general population [1]. Especially in PLWH, obesity is associated with a
greater risk of morbidity and mortality compared to the general population,
i.e. a higher incidence of cardiovascular diseases, diabetes and malignancies
[2-4].
Bariatric surgery (BS), commonly sleeve gastrectomy (SG) and gastric bypass
(GBP), is the most persistent and effective intervention when diet and
lifestyle changes fail to achieve weight goals. BS improves obesity-related
comorbidities and overall quality of life despite high remission rates seen in
the general population [5].
When patients undergo BS to prevent significant morbidity and mortality
associated with overweight, this may have a profound impact on the
pharmacokinetics (PK) of drugs that they are taking. Because of the
manipulation of the gastrointestinal (GI) tract after BS, most likely
absorption of drugs can be impaired, including absorption of antiretroviral
agents (ARVs). In case inadequate absorption of ARVs occurs development of
resistance may lead to treatment failure, which needs to be prevented [6-8].

Currently, there is either scarce or conflicting data regarding PK changes
post-BS making it difficult to make any clinical recommendations. Also, HIV
treating Guidelines such as HIV/AIDS Treatment and Prevention Guidelines (DHHS)
and European AIDS Clinical Society (EACS) do not mention data on selection (and
dosing) of ARVs in HIV-infected patients who have undergone BS.
Among several ARVs, the novel agent doravirine (DOR) might be an attractive
candidate - on a theoretical basis - for patients to be used after BS. It meets
a number of preferred PK properties [6], such as a good absorption profile that
is independent from (fat) food and low gastric pH as well as a favourable
interaction profile with post-surgery standard medications [9]. DOR has been
demonstrated to be an effective switch regimen in the DRIVE-SHIFT trial where
patients were virologically suppressed on various regimens [10]. Most likely,
patients who are candidates for BS are also virologically suppressed, but most
likely were not represented in the DRIVE-SHIFT trial.

We propose a multicentre phase IV study to collect evidence that a DOR-based
regimen can be safely and effectively administered to virologically suppressed
HIV-infected patients undergoing BS.

Primary objective:
• To assess the pharmacokinetics of DOR in patients prior to and after BS

Secondary objectives:
• To assess the safety of DOR in patients prior to and after undergoing BS
• To assess the viral response to DOR in patients prior to and after undergoing
BS

The study will include two full PK days before and after surgery in addition
to two single PK samples on two other occasions. For full PK curves, 9 blood
samples will be taken per PK day.
1st PK day: Between week -4 and week 0 before the surgery, a 24h PK curve will
be recorded.
2nd PK day: After BS, a 2nd PK curve will be recorded at approximately week 12
post-BS.
To assist early and late effect on DOR PK levels, additional two trough PK
samples at the end of the dosing interval (24h ± 4h) will be taken from each
patient at week 4 and week 24 post BS.
Data on VL, HIV associated immune response (CD4 count), and safety data will be
monitored and reported at each PK visit until week 24 post BS.

Patients who participate in the study will receive standard treatment.
Therefore the risk for participation in this study is regarded negligible.
The use of DOR is not mentioned to be contradicted with having bariatric
surgery in the drug label.
Patients will not directly benefit from participating in this study. However,
participants may benefit from the regular and optimized monitoring of their HIV
response to medication (using HIV VL and CD4 count) after the surgery by their
treating physicians, and thus, maybe protected from any small progression of
their HIV status.