Tenofovir Disoproxil Fumarate (TDF): What to consider?

Tenofovir Disoproxil Fumarate (TDF): What to consider?

DELSTRIGO®▼ (doravirine/3TC/TDF)
Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland) [External links]
PIFELTRO®▼ (doravirine)
Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland) [External links]

Tenofovir disoproxil fumarate (TDF) has widely been used for treatment of human immunodeficiency virus (HIV) infection for almost two decades, and it remains among the recommended agents in BHIVA¹ and EACS² guidelines³.

Why should you consider a TDF containing treatment regimen?

Doravirine/3TC/TDF = DELSTRIGO (doravirine/lamivudine/tenofovir disoproxil fumarate).

PIFELTRO®▼ (doravirine) 100 mg film-coated tablet is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults, and adolescents aged 12 years and older, weighing at least 35 kg, infected with HIV-1, without past or present evidence of resistance to the NNRTI class.

DELSTRIGO®▼ (100 mg doravirine/300 mg lamivudine/300 mg tenofovir disoproxil fumarate, equivalent to 245 mg tenofovir disoproxil) is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine or tenofovir.

DELSTRIGO®▼ is also indicated for the treatment of adolescents aged 12 years and older weighing at least 35 kg, who are infected with HIV-1, without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil.

Please consult the SmPC for further information before making any prescribing decisions.

Data on renal/bone

Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14,894 patients across 14 trials⁴

Objective:

To undertake an updated summary of existing comparisons of the efficacy and safety of tenofovir alafenamide fumarate (TAF) vs. tenofovir disoproxil fumarate (TDF) with and without booster coformulation.⁴

Study design:

This is an update of a previous systematic review⁵ conducted comparing TAF and TDF in treatment of HIV-1 and chronic Hepatitis B in randomised head-to-head clinical trials.

• 14 clinical trials comparing TDF and TAF regimens were identified​⁴
• Efficacy was measured by viral suppression (VL <50 copies/ml)
• Safety endpoints included all AE’s, serious AE’s, Grades 3–4 AE’s and AE’s leading to discontinuation
• Specific bone and renal markers were also assessed

Findings:

Efficacy outcomes⁴

• A significant difference (P=0.0004) in efficacy was shown in the boosted subgroup in favour of TAF, but no difference was seen in the unboosted subgroup

Safety outcomes⁴ ​

• No statistically significant differences between TAF and TDF for any of the key safety endpoints​
• No differences seen for the bone markers analysed and fractures​
• No difference in the occurrence of actual renal tubular events
• Difference in risk for discontinuation due to renal adverse events when boosted (P = 0.03), but none when unboosted

Key AEs boosted

Key AEs unboosted

Adapted from Pilkington V, et al. AIDS 2020⁴

This data suggests that TDF can be considered when you are using unboosted regimens, which are more commonly used in modern HIV treatment.⁴

Data on lipids

TDF: Evidence for changes in lipid parameters. Reversible effect on lipids by switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) and back​⁶

Study design

This is a retrospective data collection on effectively suppressed people living with HIV initially switched from TDF to TAF based antiretroviral treatment (ART) as a result of optimization of therapy, in a single site. After the introduction of generic versions of TDF, 168 of 385 patients from the cohort were switched back from TAF to TDF, again keeping all other components of ART and concomitant medication unchanged. Lipid profile was measured at 12-week intervals after switch to TDF as part of the clinical routine.

Key results:⁶

• Participants with higher increases in TC after switching from TDF to TAF also showed more pronounced decreases after switching back
• Demonstrated a reversible effect on lipids by switching from TDF to TAF and back

Time course of total cholesterol after switch from tenofovir disoproxil fumarate to tenofovir alafenamide and back according to change in total cholesterol

Adapted from Milinkovic A et al., AIDS 2019⁶

TDF appears to have a long-lasting beneficial lipid-lowering effect, since its withdrawal even after years of exposure led to worsening of lipid profile³.

Data on weight

TDF: Evidence for changes in weight – CHARACTERISE TRIAL

CHARACTERISE: single centre, follow-up, observational, cross-sectional study⁸

Background:⁸

CHARACTERISE enrolled participants previously part of ADVANCE and evaluated 1-year outcomes after a switch to TDF/3TC/DTG

• 1053 patients who were randomized to ADVANCE, 172 participated in CHARACTERISE
• ​70 originally on TAF/FTC+DTG, 71 on TDF/FTC+DTG, and 31 on TDF/FTC/EFV​
• Participants were 62% female and 100% Black ethnicity
• At follow up, participants were assessed for weight, lipids, fasting glucose, HbA1c and HIV RNA​
• Changes in weight and laboratory parameters during the first 192 weeks of randomised treatment and then after switch to TDF/3TC/DTG were evaluated in each treatment arm using paired non-parametric tests 

ADVANCE and CHARACTERISE trials

Change in weight after switch to TDF/3TC/DTG – females and males

Adapted from Bosch et al. Oral Presentation at CROI 2023⁷

Results:⁸

• For women switching from TAF/FTC + DTG to TDF/3TC/ DTG after Week 192, there was a statistically significant reduction in weight (median: −1.6 kg). This change in weight was not significant in men (median: −0.2 kg)
• Participants switching from TAF/FTC + DTG to TDF/3TC/DTG after Week 192 showed significant reductions in total cholesterol, LDL, triglycerides, glucose, and HbA1c. The reduction in HDL and increase in systolic and diastolic blood pressure was not significant

In summary on what to consider about TDF:

• Data suggests that TDF can be considered when you are using unboosted regimens, which are more commonly used in modern HIV treatment⁴
• Demonstrated a reversible effect on lipids by switching from TDF to TAF and back⁶
• Study findings suggests that TDF may have a restrictive effect on weight, particularly in women^7,8
• TDF recommended in clinical guidelines BHIVA¹, EACS² as well as in band 2 of the National Procurement Framework⁹

Abbreviations

3TC = Lamivudine; AE = Adverse Event; DOR = Doravirine; DRV/r = Ritonavir-boosted Darunavir; DTG = Dolutegravir; EFV = Efavirenz; FTC = Emtricitabine; HbA1c = Haemoglobin a1c; HDL= High-Density Lipoprotein; LDL = Low-Density Lipoprotein; NRTI = Nucleoside Reverse Transcriptase Inhibitor; NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor; n.s = not significant; SmPC = Summary of Product Characteristics; TAF = Tenofovir Alafemide; TC = Total Cholesterol; TDF = Tenofovir Disoproxil Fumarate; TLD = Tenofovir Disoproxil Fumarate/lamiduvine/dolutegravir.

References

1. BHIVA guidelines on antiretroviral treatment for adults living with HIV-1 2022.
2. EACS, European AIDS Clinical Society Guidelines, Version 11.1, October 2022.
3. Kauppinen KJ et al., Switching from tenofovir alafenamide to tenofovir disoproxil fumarate improves lipid profile and protects from weight gain, AIDS 2022, 36:1337–1344.
4. Pilkington V. et al., Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14 894 patients across 14 trials .​ AIDS. 2020;34:2259–2268.​
5. Hill A. et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? Journal of Virus Eradication 2018; 4: 73-80.
6. Milinkovic A et al., Reversible effect on lipids by switching from tenofovir disoproxil fumarate to tenofovir alafenamide and back, AIDS 2019, 33:2387–2391​.
7. Bosch  B et al., Weight and Metabolic Changes After Switching From Tenofovir Alafenamide (TAF)/Emtricitabine (FTC) +Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC+ DTG, ​and TDF/FTC/Efavirenz (EFV) to TDF/Lamivudine (3TC)/DTG, Characterize trial. Oral presentation at Conference on Retroviruses and Opportunistic Infections, CROI 2023.
8. Bosch B. et al., Weight and Metabolic Changes After Switching From Tenofovir Alafenamide (TAF)/Emtricitabine (FTC)+Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC+DTG, and TDF/FTC/Efavirenz (EFV) to TDF/Lamivudine (3TC)/DTG, Clinical Infectious Diseases, December 2022, Brief Report.
9. National antiretroviral treatment prescribing toolkit, HIV CRG Drugs Subgroup February 2022.

Supporting documentation

DELSTRIGO®▼ Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland)
PIFELTRO®▼ Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland)
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