Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05477407 |
| Other study ID # |
CREPATS 14 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 15, 2022 |
| Est. completion date |
September 15, 2025 |
Study information
| Verified date |
November 2023 |
| Source |
Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Integrase-strand-transfer-inhibitors (INSTIs) based regimens have been associated with body
weight gain and increase in total body adipose tissue (AT). Whereas there is by now no clear
understanding of the mechanisms that induce these changes, we have observed modifications of
AT in vitro, in animals models or in vivo in obese patients with raltegravir (RAL) and
dolutegravir (DTG) with the presence of increased peri-adipocyte fibrosis and high levels of
collagen VI that have been associated with poor metabolic prognoses together with cellular
insulin resistance and decreased adiponectin secretion.
One major clinical question is whether such AT abnormalities are reversible.
Doravirine (DOR), the most recent available Non-Nucleosidic Reverse Transcriptase Inhibitor
(NNRTI) drug, has an excellent metabolic profile and as a NNRTI is expected to induce neither
changes in fat tissue distribution nor changes in body weight. Tenofovir disoproxil fumarate
(TDF) is associated with a protective lipid profile and, unlike tenofovir alafenamide (TAF)
which seems to potentiate weight gain in combination with INSTI, has not been associated with
weight gain.
One major clinical question is whether such AT abnormalities are reversible.
Doravirine, the most recent available NNRTI drug, has an excellent metabolic profile and as a
NNRTI is expected to induce neither changes in fat tissue distribution nor changes in body
weight. Tenofovir DF is associated with a protective lipid profile and, unlike TAF which
seems to potentiate weight gain in combination with INSTI, has not been associated with
weight gain.
We hypothesized that modifications in morphology and function of the adipose tissue in
patients with significant weight gain under an INSTI-based regimen could be improved after
switching to the triple drug TDF/Emtricitabine/DOR and that fat increase and body weight will
be stopped or reversed.
This pathogenesis study aimed to evaluate potential changes in adipose tissue after switching
from an INSTI-based regimen (Raltegravir or Dolutegravir or Bictegravir) to
TDF/Emtricitabine/DOR. Each patient will be evaluated with an adipose tissue biopsy performed
before (D0) and after a 48 week switch (W48) from an INSTI-based regimen to the non
INSTI-based regimen combining TDF/3TC/Doravirine.
With a number of 22 patients at D0, a total of 20 patients with paired adipose tissue
biopsies are expected at W48.
The antiretroviral therapy with TDF/emtricitabine/Doravirine will be used as routine practice
recommends.
Description:
Integrase-strand-transfer-inhibitors (INSTIs) represent the most largely prescribed
antiretroviral therapy as recommended either as first-line antiretroviral treatment or as
switch strategy due to their high efficacy, good tolerability and high genetic barrier to
resistance for the latest compounds.
Recently, weight/fat gain has been reported in INSTIs-exposed patients, raising concerns on
possible deleterious clinical outcome. Several studies performed in naïve or in
Antiretroviral Therapy-suppressed individuals, revealed that dolutegravir (DTG), raltegravir
(RAL) or bictegravir (BIC) based therapy resulted in weight gain.
In the large ADVANCE trial, which has compared in Africa three Antiretroviral Therapy
initiation strategies, changes in weight, obesity and trunk/limb were greater with
dolutegravir/tenofovir alafenamide/Emtricitabine (+6 kg), than with dolutegravir/tenofovir
disoproxil fumarate/emtricitabine (+3 kg) and even more than with tenofovir disoproxil
fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) (+1 kg) at W48.
Women, blacks and persons over 60 years experienced greater weight gain in the two years
after versus before switch in the follow-up from 1997-2017 of AIDS-Clinical-Trials-Group
(A5001 and A5322) participants who were switched to DTG, RAL or elvitegravir (EVG).
In the Women's Interagency HIV study (WIHS) from 2006-2017, women who switched to or added an
INSTI (DTG/RAL/EVG) to Antiretroviral Therapy, experienced mean greater increase in body
weight compared to women who did not. The increases in weight gain were limited or not
reported in other retrospective studies that included mainly men and Caucasian individuals.
However, most of these studies were retrospective and evaluated weight but not fat mass.
Reasons for this weight gain are still unknown.
Adipose tissue (AT) plays a major role in the regulation of energy metabolism given its
metabolic and secretory functions. In the general population, trunk fat accumulation is
associated with alterations in metabolic functions and low-grade inflammation with
cardio-metabolic consequences. Adipose tissue inflation disorders such as obesity leads to
emergence of fibrosis and low-grade inflammation related to production of pro-inflammatory
factors. AT fibrosis is characterized by an impaired remodeling effect on extracellular
matrix (ECM) that will limit the " storage capacities" of AT and will favor infiltration by
immune cells leading, overall, to a fibro-inflammatory state responsible of several
comorbidities such as insulin resistance.
The pathophysiological mechanisms involved in AT dysfunction in the context of HIV infection
and INSTI-based treatments are still poorly understood and most likely multifactorial. We
recently reported that dolutegravir and raltegravir can directly impact adipocytes and AT and
result in higher levels of fibrosis with adipocyte hypertrophy and insulin resistance. Thus,
some INSTIs can be responsible for fat gain and associated AT insulin resistance. The
possibility that treatment with INSTI could play a role in the onset of diabetes, as
suggested by some studies, needs to be further assessed.
Furthermore, recently it has been shown that the "beiging" of AT (presence of beige
adipocytes within white AT) exerts a beneficial effect on AT homeostasis. Indeed, these beige
adipocytes are characterized by a thermogenic capacity (through the expression of the
uncoupling protein UCP1) that favors the increase in energy expenditure and results in a
reduction in adipocyte hypertrophy. Interestingly, recent data from the literature suggest
that patients receiving INSTIs exhibit a decrease in the expression of "beiging" markers
within their subcutaneous AT.
Doravirine (DOR) is a new second generation Non-Nucleosidic Reverse Transcriptase Inhibitor
(NNRTI) highly effective both in naïve and experienced patients in combination with tenofovir
and lamivudine. It has been shown to be highly effective with no difference in terms of
efficacy when compared to the protease inhibitor darunavir or the first generation NNRTI
efavirenz. Doravirine is well tolerated with nausea, headache, diarrhea, fatigue, dizziness,
abdominal pain, vomiting reported as main doravirine-related adverse event (≥2% incidence).
In terms of metabolic impact, as expected from a NNRTI, doravirine induced significantly less
lipid changes compared to boosted darunavir over 96 weeks. In terms of LDL and
non-HDL-cholesterol, there was a mean decrease of 4.5 mg/dL in the DOR group compared to a
mean increase of 14.0 mg/dL in LDL cholesterol and 17.7 mg/dL in non-HDL cholesterol in the
ritonavir-boosted darunavir.
The second large phase III study has compared doravirine 100 mg once daily to efavirenz, a
first generation NNRTI, with tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) in the
DRIVE-AHEAD study. The rate of suppression with plasma viral load less than 50 copies /ml at
week 48, was 84.3% in the DOR/3TC/TDF recipients and 80.8% in the EFV/FTC/TDF group
(difference 3.5%, 95% Confidence Interval (CI), -2.0, 9.0). Neurosensorial tolerability, a
frequent issue in the NNRTI class, was better with doravirine, with lower rates of dizziness
(8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4%
vs 8.2%) than EFV/FTC/TDF.
There was a benefit for doravirine in terms of changes in LDL-cholesterol (-1.6 vs +8.7
mg/dL) and non-HDL-cholesterol (-3.8 vs +13.3 mg/dL) with DOR/3TC/TDF as compared to
EFV/FTC/TDF respectively.
In terms of body weight changes, fat tissue and dual energy x-ray absorptiometry evolution
with doravirine, only few data are available. Body weight and Body Mass Index (BMI) have been
evaluated in a post-hoc analysis of a phase II 2 and the 2 phase III studies DRIVE Forward
and DRIVE Ahead with a total of 855 patients in the DOR groups, 383 in the darunavir group,
and 472 in the EFV group. Patients were mostly male (85%), of Caucasian origin (60%) with a
median BMI of 25 kg/m2 and body weight of 75 kg. Over 96 weeks, a median body weight increase
of 1.5 kg in the DOR groups, 0.7 kg in the darunavir group and 1.0 kg in the EFV group was
observed. The rate of patients with >10% weight gain was 14% in the DOR and EFV groups.
In a phase 2 study comparing the combination islatravir/doravirine to TDF/3TC/DOR, no major
changes in body weight and body mass index were observed.
Finally, in contrast with all other NNRTIs, One major clinical question is whether such AT
abnormalities are reversible; doravirine has no drug-drug interactions, which is a real
advantage in patients with metabolic comorbidities.
