Dolutegravir + Tenofovir Alefenamide Metabolic Effects in Healthy Volunteers

Overseen By Janaki C Kuruppu, 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

Trial Summary

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.

What data supports the effectiveness of the drug Dolutegravir + Tenofovir Alefenamide?

The research suggests that switching to a dolutegravir-based regimen may have different metabolic effects compared to tenofovir alafenamide-based regimens, such as changes in cholesterol and body weight. However, specific effectiveness data for the combination of Dolutegravir and Tenofovir Alefenamide in healthy volunteers is not directly provided. ^{1 2 3 4 5}

What makes the drug Dolutegravir + Tenofovir Alefenamide unique compared to other treatments?

Dolutegravir + Tenofovir Alefenamide is unique because it combines two drugs that work together to treat HIV by blocking the virus from multiplying, which is different from other treatments that might use different combinations or single drugs. This combination is known for its effectiveness and lower side effects compared to older HIV treatments. ^{6 7 8 9 10}

What is the purpose of this trial?

Background: People with HIV take drugs to keep the amount of virus in their body low. One type of these drugs, called integrase strand transfer inhibitors (INSTIs), can cause weight gain over time. Weight gain can cause diabetes, heart disease, and other serious issues. Researchers want to understand how INSTIs cause weight changes. Objective: 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). Eligibility: Healthy people aged 18 to 55. Design: Participants will be screened. They will have a physical exam and blood tests. They will have a nutritional assessment and tests of their heart function. Participants will have 2 inpatient stays at the clinic. Each stay will be for 11 nights, with a 3-week break between. Both DTG and TAF are gel caps swallowed once per day by mouth. Participants will take 1 drug for 8 days during each stay. Participants will have tests to see how their body uses energy: They will spend 23 continuous hours in a special room that measures how much oxygen they breathe in and how much carbon dioxide they breathe out. They will do this a total of 6 times. They will have a DEXA (dual-energy X-ray absorptiometry). DEXA is a kind of X-ray that measures body fat and bone density. They will lie on a table. Electrodes will be placed on their hands and feet to measure body fat and lean body mass. They will stand still on a platform for about 30 seconds. High-resolution laser cameras will scan their bodies.

Research Team

Janaki C Kuruppu, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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 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 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]

References

1. England 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Switching from tenofovir alafenamide to tenofovir disoproxil fumarate improves lipid profile and protects from weight gain. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Cardiometabolic Parameters 3 Years After Switch to Dolutegravir/Lamivudine vs Maintenance of Tenofovir Alafenamide-Based Regimens. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Investigating the effect of antiretroviral switch to tenofovir alafenamide on lipid profiles in people living with HIV. [2021]

5. England 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. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Effect of dexfenfluramine on energy expenditure in obese patients on a very-low-calorie-diet. [2014]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of dexfenfluramine on free fatty acid turnover and oxidation in obese patients with type 2 diabetes mellitus. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Correlation between metabolic and behavioral effects of dexfenfluramine treatment. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Dexfenfluramine reduces cardiovascular risk factors. [2014]

10. Australia pubmed.ncbi.nlm.nih.gov

Dexfenfluramine in type II diabetes: effect on weight and diabetes control. [2022]