Dolutegravir + Tenofovir Alefenamide Metabolic Effects in Healthy Volunteers

Overseen By Brian P Epling, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Anticonvulsants, Rifamycins, St. John's wort, others

Disqualifiers: HIV, Hepatitis, Diabetes, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the HIV medication dolutegravir (DTG) affects energy use in the body, particularly regarding weight changes. Researchers will compare DTG with another drug, tenofovir alafenamide (TAF), to determine any differences in their impact on weight and metabolism. Participants must be healthy and willing to stay at the clinic for two 11-night visits. The study focuses on healthy volunteers to isolate the drugs' effects, not involving individuals currently living with HIV. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications and supplements that can affect energy metabolism, such as carbamazepine, metformin, and thyroid medications, among others. If you are taking any of these, you would need to stop them to participate in the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that dolutegravir (DTG) can cause some changes in the body. Some individuals might gain weight, and rare cases of high blood sugar have been reported. These changes could lead to health issues such as obesity or insulin resistance, where the body doesn't use insulin properly to control blood sugar.

For tenofovir alafenamide (TAF), studies indicate it might cause slight weight gain and increases in cholesterol and triglycerides, which are types of fat in the blood. There is also a small increase in the risk of heart problems.

Both medications are usually well-tolerated, but awareness of these possible side effects is important. Participants in clinical trials like this one help researchers learn more about these effects in healthy people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Dolutegravir and Tenofovir alafenamide because these treatments offer potential advancements in managing HIV. Dolutegravir is known for its high barrier to resistance, which means the virus is less likely to become resistant to it over time compared to older HIV medications. Tenofovir alafenamide, on the other hand, is celebrated for its ability to deliver effective doses of the drug with lower toxicity, reducing the risk of kidney and bone side effects. Together, these treatments might provide more effective and safer options for people living with HIV.

What evidence suggests that this trial's treatments could be effective for weight changes in healthy volunteers?

This trial will compare the metabolic effects of Dolutegravir (DTG) and Tenofovir alafenamide (TAF) in healthy volunteers. Research shows that DTG, a common HIV medication, can alter fat cells, potentially leading to weight gain and issues like insulin resistance, where the body struggles to control blood sugar levels. Studies have linked DTG with metabolic issues, including weight gain and rare cases of high blood sugar. Meanwhile, TAF has been found to cause more weight gain compared to other treatments that don't include Tenofovir. However, switching from TAF to a different medication has been associated with weight loss and improved cholesterol levels. Both DTG and TAF can affect body weight and metabolism, but they do so in different ways. Participants in this trial will receive either DTG or TAF to assess these effects. ^{1 2 3 4 6}

Who Is on the Research Team?

Brian P Epling, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Healthy individuals aged 18 to 55 who can consent and stay in a clinic for two periods of 11 days. They shouldn't have asthma, COPD, HIV, hepatitis A/B/C, extreme weight changes recently or be athletes. No cancer (except certain skin cancers), diabetes, thyroid issues, glaucoma, psychological conditions like claustrophobia or depression that affect participation safety. Not for pregnant/post-partum women or those with high blood pressure, anemia, drug/alcohol abuse history within five years.

Inclusion Criteria

Able to provide informed consent

Willing to allow samples and data to be stored and shared for future research

I am willing to stay in the hospital for two 11-day periods over 5 weeks.

Exclusion Criteria

Fasting serum glucose >126 mg/dL

Anemia, defined as hemoglobin <13 g/dL (males) or <12 g/dL (females)

I have had weight loss surgery in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Evaluation

Participants undergo an initial baseline evaluation over 3 days

3 days

Inpatient stay

Treatment Period 1

Participants take either DTG or TAF once daily for 8 days during the first inpatient stay

8 days

Inpatient stay

Washout Period

Participants have an 18-day washout period at home between treatment periods

18 days

Treatment Period 2

Participants take the alternate drug (DTG or TAF) once daily for 8 days during the second inpatient stay

8 days

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dolutegravir
• Tenofovir alafenamide

Trial Overview

The trial is testing how the HIV medication dolutegravir affects body energy use compared to tenofovir alafenamide. Participants will take one drug for eight days during each clinic stay and undergo tests including room calorimetry measuring oxygen intake and carbon dioxide output six times; DEXA scans for body fat and bone density; plus other assessments of body composition.

How Is the Trial Designed?

Group I: Tenofovir alafenamide Active Control 1 Intervention

25mg one tablet orally once a day for 8 days.

Group II: Dolutegravir Active Control 1 Intervention

50mg one tablet orally once daily for 8 days.

Dolutegravir is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Tivicay for:

• HIV-1 infection

Approved in United States as Tivicay for:

• HIV-1 infection

Approved in Canada as Tivicay for:

• HIV-1 infection

Approved in Japan as Tivicay for:

• HIV-1 infection

Approved in Switzerland as Tivicay for:

• HIV-1 infection

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Switching from a TAF-based triple regimen to a DTG-based two-drug regimen significantly improved lipid profiles, with reductions in total cholesterol by 10.7 mg/dL and LDL cholesterol by 8.3 mg/dL after 6 months, indicating a potential decrease in cardiovascular risk.

The study, involving 118 patients with a high virological suppression rate (98% VL < 50 copies/mL), demonstrated that the two-drug regimen was effective and well-tolerated, with an overall virological effectiveness of 85.6% at 6 months and no cases of virological failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Change in metabolic parameters after switching from triple regimens with tenofovir alafenamide to dolutegravir-based dual therapy. Bi-lipid study. Bendala-Estrada, AD., Diaz-Almiron, M., Busca, C., et al.[2023]

Switching from tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) resulted in significant improvements in plasma lipid profiles, with total cholesterol and LDL cholesterol decreasing by approximately 12% after one year.

The switch also led to a reduction in the atherosclerotic cardiovascular disease (ASCVD) risk score from 6.3% to 6.0%, while those who continued TAF therapy experienced an increase in their ASCVD risk score.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching from tenofovir alafenamide to tenofovir disoproxil fumarate improves lipid profile and protects from weight gain. Kauppinen, KJ., Aho, I., Sutinen, J.[2022]

In a study involving 741 adults with virologically suppressed HIV-1, switching to the 2-drug regimen of dolutegravir/lamivudine (DTG/3TC) showed comparable cardiometabolic health outcomes to those continuing with a 3-/4-drug tenofovir alafenamide (TAF)-based regimen after 3 years.

Both treatment groups had similar rates of significant weight gain and other cardiometabolic parameters, indicating that DTG/3TC is a safe and effective option for patients looking to switch regimens without negatively impacting their metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiometabolic Parameters 3 Years After Switch to Dolutegravir/Lamivudine vs Maintenance of Tenofovir Alafenamide-Based Regimens. Batterham, RL., Espinosa, N., Katlama, C., et al.[2023]

In a study involving 11 obese female patients with non-insulin-dependent diabetes mellitus, dexfenfluramine (dF) significantly increased free fatty acid (FFA) oxidation and turnover rates, suggesting its potential to enhance fat metabolism.

dF administration also led to a notable decrease in serum glucose levels without affecting insulin secretion, indicating a weight-independent effect on glucose metabolism that could be beneficial for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dexfenfluramine on free fatty acid turnover and oxidation in obese patients with type 2 diabetes mellitus. Greco, AV., Mingrone, G., Capristo, E., et al.[2019]

In a 12-week study involving 29 overweight, hyperlipidaemic individuals, dexfenfluramine led to a significant reduction in energy intake compared to placebo, suggesting its potential to aid weight management.

Despite the reduction in energy intake, the study found no significant changes in biochemical risk factors for cardiovascular disease, indicating that while dexfenfluramine may help with weight loss, it may not directly improve cardiovascular health markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexfenfluramine reduces cardiovascular risk factors. Bremer, JM., Scott, RS., Lintott, CJ.[2014]

In a study of 238 people living with HIV who switched to tenofovir alafenamide (TAF)-containing antiretroviral therapy, significant increases in lipid levels were observed, including total cholesterol and low-density lipoprotein (LDL), after a median of 24 weeks.

The proportion of individuals experiencing severe dyslipidaemia also increased significantly after switching to TAF, raising concerns about potential cardiovascular risks and the need for lipid-lowering therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the effect of antiretroviral switch to tenofovir alafenamide on lipid profiles in people living with HIV. Lacey, A., Savinelli, S., Barco, EA., et al.[2021]

In a three-month study involving 40 overweight type II diabetic patients, dexfenfluramine led to a significant weight loss of 3.8 kg compared to a slight weight gain of 0.3 kg in the placebo group.

Dexfenfluramine also improved diabetic control, as evidenced by a reduction in fasting plasma glucose levels by 1.0 mmol/L and a decrease in glycosylated hemoglobin levels by 1.4%, indicating better blood sugar management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexfenfluramine in type II diabetes: effect on weight and diabetes control. Stewart, GO., Stein, GR., Davis, TM., et al.[2022]

In a study involving 12 female Wistar rats, dexfenfluramine (dFF) treatment significantly reduced food intake, which was linked to a decrease in the respiratory quotient (RQ), indicating increased fat storage (lipogenesis).

The increase in energy expenditure observed with dFF was primarily related to locomotor activity rather than an increase in the thermic effect of feeding, suggesting that dFF affects metabolism through mechanisms related to glucose and lipid metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation between metabolic and behavioral effects of dexfenfluramine treatment. Even, P., Coulaud, H., Aucouturier, JL., et al.[2013]

In a study of 1260 people living with HIV, switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) resulted in a significant weight gain of approximately 1 kg after 6 months and 1.4 kg after 12 months, compared to no significant weight change in a matched control group.

The switch to TAF also led to a notable increase in body mass index (BMI) in the Switch group, indicating that this change in medication may have implications for weight management in certain populations at risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight gain following the single substitution of tenofovir disoproxil fumarate by tenofovir alafenamide in HIV-infected people from the French Dat'AIDS cohort: A propensity score-matched analysis. Hocqueloux, L., Menard, A., Arvieux, C., et al.[2023]

In a study of 20 obese females, dexfenfluramine (dF) did not lead to significant differences in weight loss or resting metabolic rate (RMR) compared to a placebo during a very low-calorie diet (VLCD).

However, dF was found to decrease the thermic effect of food (TEF) during the VLCD, indicating that it may alter energy expenditure related to food processing, even though overall energy expenditure remained similar between the dF and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dexfenfluramine on energy expenditure in obese patients on a very-low-calorie-diet. Recasens, MA., Barenys, M., Sola, R., et al.[2014]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11179510/

A review of dolutegravir-associated weight gain and ...

Dolutegravir causes changes in the structure of fat cells that may promote obesity and insulin resistance, according to studies of cells taken ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05652478

NCT05652478 | Early Metabolic Effects of Dolutegravir or ...

They are usually conducted with healthy volunteers, and the goal is to determine the drug's most frequent and serious adverse events and, often, how the drug is ...

3.

trialx.com

trialx.com/clinical-trials/listings/243582/early-metabolic-effects-of-dolutegravir-or-tenofovir-alefenamide-in-healthy-volunteers/

Early Metabolic Effects of Dolutegravir or Tenofovir ...

To see how a common INSTI, dolutegravir (DTG), affects how the body uses energy. DTG will be compared with a non-INSTI drug, tenofovir alafenamide (TAF).

4.

thelancet.com

thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00141-8/abstract

Metabolic implications and safety of dolutegravir use in ...

Dolutegravir has been associated with metabolic complications, including weight gain and rare events of hyperglycaemia, that could affect maternal, fetal, and ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11635881/

Metabolic Syndrome Among People Living With HIV on ...

This study aimed to assess the burden of metabolic syndrome among people living with HIV (PLWH) on dolutegravir (DTG)- and efavirenz (EFV)-based regimens.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04771754

The Effect of Dolutegravir on Whole-body Insulin Sensitivity ...

This study will investigate changes in insulin resistance, lipid metabolism and endocrine profile in HIV-negative subjects exposed to dolutegravir (an ...