HIV Talks 7: What every doctor should know about TDF and TAF
Background on TAF and TDF
To understand the relationship between TDF and TAF, we need to go back in time, says Dr Moyle. “When tenofovir was originally synthesised, its oral bioavailability was poor. The first successful attempt to overcome this obstacle was TDF.1 Shortly after, TAF was synthesized.2 However, as TDF was doing well in clinical trials, TAF was not developed any further at that time as some concerns were raised about TAF achieving very high levels of tenofovir diphosphate (the active form of tenofovir) inside lymphocytes.”
After administration of TDF by oral ingestion, the disoproxil fumarate part of the molecule is processed in the gut wall resulting in tenofovir entering the circulation. It then goes to the cells, where it is diphosphorylated to tenofovir diphosphate.3 TAF on the other hand, is absorbed and circulates as tenofovir alafenamide. It is selectively taken up in certain cell lines, especially those of lymphoid cell lineage – those that are affected by HIV – but also by hepatocytes. Alafenamide is then processed off using a cathepsin inside the cells, resulting in tenofovir being converted into the active diphosphate form.4 “As TAF accumulates in the lymphoid tissue and in the hepatocytes, a lower total amount of tenofovir can be administered to achieve the same or higher concentrations inside the cells with TAF”, says Dr Moyle.
Efficacy of TAF and TDF in clinical practice
During the preclinical and clinical development of TDF, some potential adverse events (AEs) were identified, firstly in animal models and subsequently in human studies. “This included concerns whether TDF may affect the renal tubule and bone mineral density (BMD)”, Dr Moyle explains. “These were carefully investigated in a Phase 3 study with TDF administered with efavirenz, 3TC and FTC. Some changes were observed, relative to comparator groups, regarding some decline in BMD and very modest changes in calculated renal function by estimated glomerular filtration rate (eGFR).5 Although these findings were not alarming, it meant that TDF was avoided in certain circumstances, such as in people who already had low BMD or challenges regarding renal function. When TDF was developed in comparison with TAF, the latter was supposed not to have renal and bone complications. However, there were some differences between TDF and TAF in terms of weight gain and an effect on lipids, with TAF leading to weight gain and TDF reducing low density lipid cholesterol (LDL-C) with approx. 8% over 2 weeks in healthy volunteers.6
Regarding efficacy, comparative studies of TDF versus TAF were performed on the background of elvitegravir with cobicistat and emtricitabine in which no differences were observed between the TDF and TAF regarding efficacy.7 Similar results were seen in a comparative study of TDF and TAF in people with hepatitis B (HBV).8 Dr Moyle adds that in a small number of circumstances, there may be some differences between TDF and TAF: “The DISCOVER PrEP study showed slightly fewer acquisitions of HIV in people who were treated with TAF/FTC versus TDF/FTC as PrEP.9 A study conducted in predominantly Asian people with HIV/HBV coinfection showed no difference in anti-HIV efficacy between TDF and TAF, but a greater suppression and seroconversion of HBV with TAF when combined with bictegravir/FTC versus TDF/FTC and dolutegravir.8 Nevertheless, for the average person taking the drug as part of initial therapy or as switch therapy, the efficacy of TDF and TAF is similar.”
TAF and TDF with regards to bone and renal side effect
When TDF was co-developed with non-nucleoside side drugs such as efavirenz, rilpivirine and raltegravir, no difference was observed between comparators in randomised clinical trials (RCTs) regarding renal and bone safety.5 However, when TDF was used in combination with a booster drug, either ritonavir or cobicistat (which increases the exposure of tenofovir in the plasma), a higher impact on renal and bone parameters was noted.5 According to Dr Moyle, renal parameters are predominantly related to microproteinuria of which the clinical meaning is unclear (“It is not related to a specific outcome”). He continues: “The bone outcomes relate to lower BMD over time in an exposure-dependent manner. When using TDF with a non-nucleoside side drug, safety renal data over the 3-5 years that those RCTs ran are generally similar to comparative regimens. If TDF is used with a booster – which we are increasingly trying to eliminate in clinical practice due to problems with drug-drug interactions (DDI) – then we need to be more careful about the renal and bone complications over long term use of TDF.”
Reversibility of renal side effects
In people who experience a change in eGFR while on TDF – which is typically associated with some microproteinuria, increased loss of beta-2 microglobulin and other microproteins of which the clinical significance is uncertain – removing TDF from the regimen is usually associated with recovery of renal function over time and loss of microproteinuria. Dr Moyle emphasises that when large cohorts of individuals with renal disfunction are evaluated, there will be multiple other risk factors for renal function, such as female sex, African origin and other renal ‘trauma’ such as medication or the use of recreational drugs that may be relevant to the deterioration of renal function over time. “Furthermore, diabetes or hypertension are also relevant to albuminuria and microproteinuria”, he adds.
Weight gain in patients on a TDF or TAF containing regimens
In multiple circumstances where TDF has been investigated, it appears to be associated with a weight loss effect. This was seen in the iPrEx PrEP study where the TDF group saw a weight loss over the year of treatment of about 0.5 to 1.0% and the placebo group showed a weight gain of 0.5 to 1.0%.10 The same phenomenon was observed in the DISCOVER trial comparing TDF with TAF. The TAF group was associated with weight gain similar to that in the placebo group in the iPrEx study.9,10 In the HPTN-083 study, TDF was associated with less weight gain compared to cabotegravir which was associated with a similar weight gain to other PREP comparators.11 “Clinical trial data show that individuals who take TDF tend to gain less weight than with comparative regimens in the light of relatively similar safety and efficacy comparisons”, Dr Moyle explains. “Regarding AZT, we see relatively more weight loss due to nausea and gastrointestinal (GI) issues, whereas TAF is very well tolerated by the GI system and more weight gain in the TAF group is seen.”
In switch circumstances, removal of TDF results in a transient period of increased weight gain. This was first described in cohort studies such as the OPERA cohort and recognised in a recent meta-analysis.12,13 “This weight gain takes place, regardless of whether someone switches to TAF or a two-drug regimen with dolutegravir/lamivudine or an injectable regimen such as cabotegravir plus rilpivirine.”
Dr Moyle mentions that most recently, data from an extension study of the ADVANCE study have become available. “The ADVANCE study originally randomised people to TDF/FTC with either efavirenz or dolutegravir or TAF/FTC with dolutegravir. There were differences observed regarding weight changes. The group receiving TDF/ efavirenz experienced the least amount of weight gain, those on TDF/dolutegravir had an intermediate amount of weight gain, and individuals on TAF/dolutegravir had the greatest amount of weight gain. It is known that some of that effect of efavirenz is related to efavirenz exposure as it inhibits weight gain in people who get a high exposure to the drug.14-15 At the end of the study, all 3 groups went over to the World Health Organisation (WHO) standard of care (SOC) which was TDF/3TC and dolutegravir. This meant that in some cases, TAF was removed and replaced with TDF. Those people experienced some decline in their weight. Those who remained on TDF but removed efavirenz and replaced it with dolutegravir saw some weight gain which one would expect after the removal of efavirenz. Adding TDF back into the regimen will lead to some period of weight loss for that individual.”16 Although a weight gain of 0.5-1 kilogram may seem modest and is in line with what is observed in the general population, Dr Moyle points out that there will be some variation in weight. “In general, small weight changes are usually not of clinical concern although it may distress the individual. However, those outliers who gain large amounts of weight after modifying treatment are of concern. The meta-analysis by Erlandson et al. demonstrated that most of those weight changes are influenced by what is removed such as TDF or efavirenz rather than what it is changed to.”13
Risk factors for weight gain
There are specific risk factors for weight gain. “Possibly, people of African-American origin and women experience more weight gain, and it is certainly the case in those underweight at baseline and in people removing TDF or efavirenz from their treatment regimen.”13-16 On the contrary, people who are overweight or obese at baseline are less likely to experience substantial weight gain when they start or switch their ART regimen.17 The ADVANCE study – with 60% (black) women – had greater weight gain in the dolutegravir and TAF group because it contained no drugs that contain weight gain such as TDF or efavirenz. Greater weight gain was observed amongst women versus men.14-16 There are little (in vitro) data with dolutegravir suggesting that women may be at an increased risk due to an interaction between dolutegravir and the estrogen receptor.18 However, in the ADVANCE study, rapid metabolisers of efavirenz (thus having low levels of efavirenz) gained very similar amounts of weight compared to those on dolutegravir with both TDF/FTC.14
Effects of TAF and TDF on lipid profile
A study in healthy volunteers showed that people who received TDF had a decline in LDL-C and total cholesterol (TC) of around 8-10%.6 When comparing TDF and TAF, lipids rose in people who received TAF based regimens whilst less lipid increase was observed with TDF.7 Replacing TDF with TAF in switch studies demonstrated an increase in LDL and TC.19 Several cohorts looked at risk factors for cardiovascular (CV) events in PLWH and the small lipid lowering effect of TDF has not been associated with the prevention of myocardial infarction (MI).20 “This is partly because we compare against the background of drugs associated with an increased risk of MI”, Dr Moyle states. “Any drug that reduces LDL-C will be associated with improved CV outcomes over time. However, we do not have large enough studies to prove it. For both primary and secondary prevention of CV disease, LDL-C is a key risk factor. The lower you go, the lower the risk of an event.”21
Recently, a press release of the American REPRIEVE study – assessing the use of statins versus placebo in approximately 7500 PLWH with moderate to high CV risk – showed that the best way to prevent a CV event in PLWH is by using a statin.22 This relies on the same recommendation as applied to the general population. It has been suggested that statins may have a bigger effect than expected in PLWH on reducing multiple vascular endpoints. “No mechanistic studies have been conducted into why TDF reduces lipids. It appears that as TAF has a 90% lower exposure in plasma, no effect is seen, it must be an exposure-dependent phenomenon as is the inhibitory effect on weight with TAF. It is a useful phenomenon to get people closer to the target values one may want to achieve in LDL-C and TC”, Dr Moyle adds.
TAF and TDF and cardiovascular risk management
Most of what clinicians do in the setting of HIV is conventional CV risk management. This means encouraging PLWH to stop smoking, prescribing a statin in case of a moderate or high CV risk, managing hypertension, promoting a healthy balanced diet with sufficient fruit and vegetables as well as regular CV exercise and maintaining an appropriate weight. “TDF is useful for weight control and controlling LDL-C. Other than avoiding abacavir and some protease inhibitors that are associated with MI, we should not be thinking to prescribe a particular antiviral for CV risk prevention”, Dr Moyle thinks. “The aim is to optimally manage HIV and approaching CV risk management in a more conventional way. However, TDF sometimes helps in getting closer to the targets that lipid specialists would like us to achieve in CV prevention.”
TAF or TDF in certain patients
TDF is preferred globally, as recommended by current WHO guidelines.23 People in whom TDF may be avoided include young patients < 25 years that have not reached their peak BMD. TDF may not be prescribed to avoid the risk of failing to fully reach their peak BMD and its consequences in later life. Other reasons to avoid TDF are significant renal disease (eGFR < 60) or declining eGFR particularly associated with proteinuria; this would be a criterium to switch to TAF. “It might also include people who are diabetic or hypertensive whose proteinuria is monitored regularly.” For those with very low BMD, a DEXA scan may be scheduled around the age of 50 to assess if they have developed osteopenia or osteoporosis. If so, then TDF can be changed. Dr Moyle emphasises that vitamin D supplementation at the time of TDF initiation may offer an additional benefit. “This could prevent bone density loss which is typically associated with the start of TDF. This is especially important for people in the northern hemisphere who may not get enough sunshine and/or may not consume a sufficient amount of wild oily fish (the main dietary source of vitamin D). Topping individuals up with vitamin D – which is stored in fat – can often be an important strategy to prevent any bone effects to be observed with starting TDF. The dose is 20,000-40,000 units each week for 6-12 weeks; a daily pill is also possible.24 In effect, this is a very practical and easy, widely available and costeffective strategy.”25
Switching to TAF
Dr Moyle explains that when counseling people who are on a TDF based regimen considering a switch to TAF based regimen, lipid and weight changes are discussed as risk factors. “Mostly though, we switch a small number of people to TAF for a reason such as renal and bone issues as a result of TDF use. The only circumstance that one is compelled to use TAF, is in some cases when bictegravir is preferred to be part of the regimen.” He mentions that it has been suggested that perhaps TAF with a 2nd generation integrase strand transfer inhibitor (INSTI) regimen works slightly better than TDF in case of extended nucleotide side/resistance.It is also known that TDF and a dolutegravir regimen works well in second line failure circumstances.26 Dr Moyle concluded by saying that TDF will remain the preferred regimen in large areas. In certain niches, TAF will be a preferred agent due to bone and renal issues. “This is based on the WHO guidelines as well as European and UK guidelines based on the advantages of TDF regarding costs, but also because of its safety in the majority of situations, thus TDF remains a suitable option in a wide range of treatment circumstances.”
Short biography Dr Graeme Moyle
Dr Graeme Moyle, MD, MB BS, Dip. GUM, has been caring for PLWH since 1988 after receiving his medical degree (MB, BS) from the University of Adelaide in Adelaide, South Australia in 1986 and subsequently doctorate (MD) in 1994. Over the years, Dr Moyle has worked on HIV research since the late 1980s in the field of HIV therapy, drug resistance and pharmacology and has published over 220 original scientific articles as well as reviews and editorials. He is a consultant physician and HIV specialist at the Chelsea & Westminster Hospital in London, U.K., and personally cares for a large cohort of PLWH. He is a member of the IAS core faculty, having also served on the British HIV Association Treatment Guidelines Writing Committee and works with several HIV advocacy and education groups.
Benieuwd hoe het verdraagzaamheidsprofiel van doravirine eruit ziet?
- Watkins ME, et al. Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate. J Pharm Sci. 2017;106(3):906-919.
- Fischer, J, et al. Analogue-based Drug Discovery. John Wiley & Sons.2006, page 505.
- Summary of Product Characteristics Viread. Available at https://www.ema.europa.eu/en/documents/product-information/ ireadepar-product-information_en.pdf.
- Markowitz M, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother. 2014;69(5):1362-9.
- Hill A, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018;4(2):72-79.
- Randell PA, et al. The effect of tenofovir disoproxil fumarate on wholebody insulin sensitivity, lipids and adipokines in healthy volunteers. Antivir Ther. 2010;15(2):227-33.
- Sax PE, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615.
- Avihingsanon A, et al. Week 48 results of a phase 3-randomized controlled trial of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+F/TDF) as initial treatment in HIV/HBV-coinfected adults (ALLIANCE). AIDS 2022. Abstract OALBX0105.
- Mayer KH, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV preexposure prophylaxis (DISCOVER): primary results from a randomised, doubleblind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396(10246):239-254.
- Glidden DV, et al. Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. Clin Inf Dis. 2018;67(3):411-419.
- Landovitz RJ, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021;385:595- 6082021.
- Mallon PWG, et al. Weight gain before and after switch from TDF to TAF in a U.S. cohort study. J Int AIDS Soc. 2021 ;24(4): e25702.
- Erlandson KM, et al. Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials. Clin Infect Dis. 2021;73(8):1440-1451.
- Venter WD, et al. Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV. 2020;7:e666-76.
- Venter WF, et al. Final week 192 results from the ADVANCE trial: first-line TAF/FTC/DTG, TDF/FTC/DTG vs TDF/FTC/EFV. AIDS 2022. Poster abstract PELBB01.
- Bosch B, et al. Weight and Metabolic Changes After Switching From Tenofovir Alafenamide/Emtricitabine (FTC) +Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC + DTG, and TDF/FTC/ Efavirenz to TDF/Lamivudine/DTG. Clin Inf Dis. 2023;76(8):1492–5.
- Silverberg M, et al. Changes in body mass index over time in persons with and without HIV. AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAB0603.
- Kim SF, et al. A loss of ERA attenuates DTG-mediated disruption of thermogenesis in brown adipocytes. CROI 2023. Abstract 147.
- Milinkovic A, et al. Reversible effect on lipids by switching from tenofovir disoproxil fumarate to tenofovir alafenamide and back. AIDS. 2019;33(15):2387-2391.
- D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417-1426.
- Packard C, et al. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart. 2021;107:1369-1375.
- NIH. Daily statin reduces the risk of cardiovascular disease in people living with HIV, large NIH study finds. Tuesday, April 11, 2023. Available at https://www.nih.gov/news-events/news-releases.
- WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendation for a public health approach. July 2021.
- Overton ET, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial. Ann Intern Med.2015; 162:815-24.
- Weaver CM, et al. Cost-benefit analysis of calcium and vitamin D supplements. Arch Osteoporos. 2019;14(1):50.
- Paton NI, et al. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. N Engl J Med. 2021;385:330- 341
NL-NON-02331 | juni 2023