Assessing Virologic Success and Metabolic Changes in Patients Switching From a TDF to TAF Containing Antiretroviral Therapy Regimen

• ClinicalTrials.gov Identifier: NCT03646370
• Recruitment Status: Completed
• First Posted: August 24, 2018
• Last Update Posted: September 23, 2019
• Sponsor: Thomas Jefferson University
• Information provided by (Responsible Party): Thomas Jefferson University

Study Description

Brief Summary:

Switching patients with HIV infection from tenofovir disoproxil fumarate (TDF) to a tenofovir alafenamide (TAF) based drug regimen can provide many safety benefits including preserving bone mineral density and kidney function. This study will examine metabolic changes that patients may encounter due to the switch in medication regimens and the maintenance of viral suppression.

Condition or disease	Intervention/treatment
HIV-1-infection; Metabolic Syndrome; Cardiovascular Diseases; Weight Gain; Renal Function Abnormal; Hyperglycemia	Drug: Tenofovir Alafenamide

Detailed Description:

Many providers of HIV medicine are switching patients from TDF to TAF containing ART regimens for safety reasons including significant improvements in bone health and kidney function that have been demonstrated in clinical trials.1-3 Multiple studies have evaluated the efficacy and safety of switching from TDF to TAF based regimens, but most allowed other components of the ART regimen to change in addition to TDF which may confound study results. For example, a recent meta-analysis demonstrated that TDF accompanied by ritonavir or cobicistat boosting was associated with higher risks of bone and renal adverse events and lower rates of virologic suppression in comparison to TAF. In contrast, when ritonavir and cobicistat were not used, there were not efficacy differences and only marginal safety differences between tenofovir agents.4 Additionally, measures of treatment success aside from maintaining virologic suppression including requirements for additional regimen changes due to tolerability, cost and access have not been formally evaluated. Furthermore, aside from renal function and bone health, comprehensive evaluations of metabolic changes following TDF to TAF switches have not been performed. Specifically, alterations in weight, body mass index, and glycemic control have not been studied in patients switching from TDF to TAF in clinical trials and changes in cholesterol and cardiovascular disease risk have had only minimal assessment.5 Weight gain most commonly occurs following the initiation of ART in treatment naïve patients, but has been noted in virologically suppressed patients making certain ART changes. Weight gain following TDF to TAF switches was not measured in clinical trials, but has been noted anecdotally within our clinic population and is believed to warrant additional investigation.

In terms of cholesterol and cardiovascular disease risk, previous clinical trials have identified differences in serum cholesterol measurements in patients receiving TDF and TAF, but formal assessments of the resulting potential differences in cardiovascular disease risk have not occurred:

• The first trial was a phase II, randomized, double-blind, double-dummy, multi-center study that compared the safety and efficacy of TAF and TDF.6 The active-controlled arm received elvitegravir 150mg, cobicistat 150mg, emtricitabine 200mg, and TDF 200mg (E/C/F/TDF). The study arm received elvitegravir, cobicistat, emtricitabine, and TAF (E/C/F/TAF). Subjects receiving E/C/F/TAF experienced more Grade 3 or 4 increases in low-density lipoprotein cholesterol (LDL) (9% vs. 3%). However, the median increase in fasting LDL was similar between groups (+17 vs. +11 mg/dL, p=0.11). Significant differences were observed for total cholesterol (+30 vs +17 mg/dL, p=0.007) and high-density lipoprotein (HDL) (+7 vs +3 mg/dL, p=0.023), but the total cholesterol:HDL ratio remained similar for both treatment arms.
• A second phase II, randomized, double-blind, double-dummy multicenter trial compared darunavir 800mg/cobicistat 150mg/emtricitabine 200mg/TAF 10mg (D/C/F/TAF) to darunavir 800mg, cobicistat 150mg, and co-formulated emtricitabine 200mg/TDF 300mg (D+C+F/TDF).7 More than 230 subjects were screened, and 153 were randomized 2:1 to receive either D/C/F/TAF (n=103) or D+C+F/TDF (n=50). The primary efficacy outcome was virologic suppression at weeks 24 and 48. Safety and tolerability were assessed through renal, bone, and metabolic measurements. At the end of the trial, fasting lipid changes from baseline were greater in the TAF group at week 48 for total cholesterol (+40 vs. +5 mg/dL, p<0.001), LDL (+26 vs. +4 mg/dL, p<0.001), HDL (+7 vs. +3 mg/dL, p=0.009), and triglycerides (+29 vs. -5 mg/dL, p=0.007). The total change in total cholesterol:HDL ratio was again comparable between groups (0 vs. -0.2, p=0.15).
• A randomized, active-controlled, open-label study assessed the safety and efficacy of switching virologically suppressed HIV-infected patients from their TDF-based regimen to E/C/F/TAF.8 The study assessed 601 patients who were randomized 2:1 to receiving E/C/F/TAF (n=402) or maintain their current regimen of FTC/TDF plus atazanavir boosted with cobicistat or ritonavir (n=199). Again, patients receiving E/C/F/TAF had statistically significant median increases in total cholesterol (+23 vs. + 5 mg/dL, p<0.001) and in LDL (+9 vs -1 mg/dL, p<0.001). Additionally, the proportion of patients who initiated lipid-modifying agents was greater in the E/C/F/TAF group but was not statistically significant (8.5% vs. 5%, p=0.14).

In each trial, it is evident that patients receiving TAF have greater elevations in serum cholesterol levels in comparison to TDF. However, the majority of trials also note that the total cholesterol:HDL ratio appears to be similar among TDF and TAF recipients. This value has been used by investigators to suggest that differences in cardiovascular disease risk are unlikely to be present among TDF and TAF recipients despite considerable increases in total cholesterol, LDL and triglycerides levels in TAF recipients. The current ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults, do not recommend the use of the total cholesterol:HDL ratio to determine risk for cardiovascular disease.9 Rather, they recommend using the atherosclerotic cardiovascular disease (ASCVD) scoring system, which incorporates cholesterol values in additional to other factors that influence cardiovascular disease risk. This level of cardiovascular disease risk assessment has not been performed and assessed for TAF and TDF in clinical trials.

The current study is significant because it will add to the current clinical knowledge of TAF in terms of efficacy, safety and tolerability. It will evaluate treatment success when patients have isolated TDF to TAF switches by analyzing virologic and immunologic responses in addition to the need for subsequent regimen changes due to poor tolerability, cost restriction or access limitations. This study will also provide a comprehensive assessment of potential metabolic changes following isolated TDF to TAF changes. This includes changes in the incidence of metabolic syndrome, alterations in cholesterol and cardiovascular disease risk, changes in weight and body mass index (BMI), and changes in glycemic control and renal function.

Study Design

• Study Type: Observational
• Actual Enrollment: 110 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Assessing Virologic Success and Metabolic Changes in Patients Switching From a TDF to TAF Containing Antiretroviral Therapy Regimen
• Actual Study Start Date: July 25, 2018
• Actual Primary Completion Date: July 24, 2019
• Actual Study Completion Date: July 24, 2019

Groups and Cohorts

Intervention Details:

• Drug: Tenofovir Alafenamide
  Patients with HIV infection who are virally suppressed receiving a tenofovir disoproxil fumarate-based antiretroviral therapy regimen that switched to tenofovir alafenamide without switching any other components of their treatment regimen.

Outcome Measures

Primary Outcome Measures :

1. Changes in weight [ Time Frame: 1 year ]
   Changes in weight will be determined through comparisons of average baseline and endpoint weights
2. Changes in metabolic syndrome [ Time Frame: 1 year ]
   Changes in the presence of metabolic syndrome will be determined through comparisons of baseline and endpoint modified metabolic syndrome diagnostic criteria defined by the American Heart Association.
3. Changes in glycemic control [ Time Frame: 1 year ]
   Changes in glycemic control will be determined through comparisons of baseline and endpoint fasting blood glucose and hemoglobin A1C levels
4. Changes in kidney function [ Time Frame: 1 year ]
   Changes in kidney function will be determined through comparisons of baseline and endpoint creatinine clearance estimations.
5. Changes in cholesterol [ Time Frame: 1 year ]
   Changes in cholesterol will be determined through comparisons of baseline and endpoint total cholesterol levels.
6. Changes in 10-year cardiovascular disease risk [ Time Frame: 1 year ]
   Each patient's estimated 10-year cardiovascular disease risk will be calculated at baseline and endpoint after the ART regimen switch using the ASCVD scoring system.

Secondary Outcome Measures :

1. Treatment success [ Time Frame: 1 year ]
   • Patients will meet criteria for treatment success after their ART regimen switch if they maintain viral suppression and adherence to their TAF regimen for 12 months without having to incur additional ART switches due to toxicity, poor tolerability, cost restriction or access limitations.
   • Subgroup analyses will be performed to investigate factors associated with a lack of treatment success, if present, including the presence of a boosting agent within the ART regimen.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Adults living with HIV infection who are on antiretroviral therapy and virally suppressed who have switched one medication within their treatment regimen for safety reasons.

Criteria

Inclusion Criteria:

• Patients with HIV who are virally suppressed receiving a tenofovir disoproxil fumarate-based antiretroviral therapy regimen that switched to tenofovir alafenamide without switching any other components of their medications.

Exclusion Criteria:

• Patients are excluded if their switch was prior to 2015

Contacts and Locations

Locations

United States, Pennsylvania

Thomas Jeffeson University

Philadelphia, Pennsylvania, United States, 19107

Sponsors and Collaborators

Thomas Jefferson University

More Information

Publications:

Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, Elion R, Cavassini M, Madruga JV, Brunetta J, Shamblaw D, DeJesus E, Orkin C, Wohl DA, Brar I, Stephens JL, Girard PM, Huhn G, Plummer A, Liu YP, Cheng AK, McCallister S; GS-US-292-0109 team. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016 Jan;16(1):43-52. doi: 10.1016/S1473-3099(15)00348-5. Epub 2015 Nov 2.

Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, Avihingsanon A, Crofoot G, Benson P, Lichtenstein K, Ramgopal M, Chetchotisakd P, Custodio JM, Abram ME, Wei X, Cheng A, McCallister S, SenGupta D, Fordyce MW; GS-US-292-0112 Study Team. Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr. 2016 Apr 15;71(5):530-7. doi: 10.1097/QAI.0000000000000908.

Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018 Apr 1;4(2):72-79.

Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, Wang H, Callebaut C, Martin H, Fordyce MW, McCallister S. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014 Sep 1;67(1):52-8. doi: 10.1097/QAI.0000000000000225.

Mills A, Crofoot G Jr, McDonald C, Shalit P, Flamm JA, Gathe J Jr, Scribner A, Shamblaw D, Saag M, Cao H, Martin H, Das M, Thomas A, Liu HC, Yan M, Callebaut C, Custodio J, Cheng A, McCallister S. Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor-Based Single-Tablet Regimen for Initial HIV-1 Therapy: A Randomized Phase 2 Study. J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):439-45. doi: 10.1097/QAI.0000000000000618.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a. Epub 2013 Nov 12. Erratum in: Circulation. 2014 Jun 24;129(25 Suppl 2):S46-8. Erratum in: Circulation. 2015 Dec 22;132(25):e396.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT03646370
• Other Study ID Numbers: 18G.433
• First Posted: August 24, 2018
• Last Update Posted: September 23, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Cardiovascular Diseases; Metabolic Syndrome; Hyperglycemia; Weight Gain; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Body Weight Changes; Body Weight; Tenofovir; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents