Introduction
Tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is a well tolerated, and widely used combination used for preexposure prophylaxis (PrEP), hepatitis B virus (HBV) and as the nucleoside reverse transcriptase inhibitor (NRTI) backbone in HIV-1 antiretroviral therapy, as well as for treating hepatitis B. Lamivudine (3TC) is regarded as equivalent in terms of potency to FTC, and both are extremely well tolerated with no effect on weight changes.
The major downside to the TDF component is its effect on bone mineral density and renal toxicity, which has been observed in HIV-positive and HIV-negative individuals [1,2]. Its use has, therefore, been replaced by tenofovir alafenamide (TAF), in guidelines for HIV-1 [3]. The TAF/FTC combination has more recently been approved for PrEP [4], after being shown to be noninferior to TDF and because of less impact on bone density and renal tubular effects.
Despite this, a meta-analysis showed no safety differences in renal and bone markers when TDF was used in ‘unboosted’ regimens, when compared with TAF [5]. Generic TDF/FTC is now available and may be a more cost-effective option for treatment and prevention of HIV. TDF has more favourable metabolic effects compared with TAF, with TDF demonstrating lipid-suppressive effects in previous studies [6,7]. In HBV studies, treatment with TAF led to greater grade 3 and above hyperglycaemia and fasting low-density lipoproteins greater than 190 mg/dl vs. TDF [8,9]. In HIV-1 studies, switching from TDF to TAF has also been associated with weight and lipid changes [10–14]. It is unclear whether this is because of the removal of TDF suppressing weight gain or TAF directly contributing to weight. In the DISCOVER PrEP trial, TDF/FTC was associated with weight loss and declines in lipids compared with TAF/FTC [2]. Initiating TAF has also shown to increase weight to a greater extent than TDF, especially when combined with integrase inhibitors in HIV studies, and particularly in black women [15–17].
Obesity and weight gain is a growing public health concern for persons with HIV (PWH), particularly as they are predisposed to CVD [18]. Recent analyses show that weight changes could lead to an increased risk of myocardial infarction, diabetes and adverse birth outcomes [19,20]. Risk factors for weight gain include a baseline low CD4+ count, high viral load, Black race and female sex [21,22]. Choice of ART also contributes, with integrase inhibitors increasing weight, and evidence of efavirenz lowering weight [21].
The objective of this analysis is to establish how TDF plays a role in weight changes, and if it contributes to weight loss. In this analysis, we will be analysing the data from PrEP studies. This will enable us to focus on the independent effect of TDF on weight compared with placebo, or to other control treatments, eliminating the return-to-health effect seen in HIV trials and the effect of other antiretrovirals on weight.
Methods
We performed a systematic search of MedLine, Embase, Global health database, conference proceedings and clinical trial registry clinicaltrials.gov, to identify all randomized trials comparing oral TDF/FTC or TDF as intervention to placebo for PrEP for HIV. The methodology of this search has been previously described [23]. We also conducted a separate search to identify randomized trials comparing TDF/FTC to TAF/FTC or Cabotegravir. We included studies, which reported adverse event data on 5% or grade 2/moderate severity weight loss or grade 1–4 gastrointestinal adverse events in this analysis.
We extracted the data on the safety outcomes from 10 included studies, VOICE, TDF-2, FEM-PrEP, BKK, PARTNERS, iPReX, IPERGAY, US Safety Study, HPTN 084 and HPTN 083 [24–33], comparing endpoints in the TDF arm versus the control arm. Where the data was not available publicly, authors were contacted to attempt to obtain some of the data. The primary safety outcome was weight loss. This was reported as ‘>5% weight loss’ or ‘grade 2 abnormal loss of weight.’ Grade 2 weight loss is classified as more than 5% weight loss in the Division of AIDS grading of severity of adverse events [34]. Two studies had two arms containing TDF (TDF/FTC or TDF). For the meta-analysis, the adverse events in these two arms were added up.
We also conducted a separate analysis on the gastrointestinal safety data and extracted the safety data on the number of Grade 1–4 adverse events of nausea, vomiting, diarrhoea and loss of appetite.
The meta-analyses were performed on Review Manager Software Version 5.4 (Cochrane Collaboration, London, UK). The Mantel–Haenszel test with random-effects modelling was applied to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Statistical heterogeneity was assessed with the I2 statistic. An I2 value less than 30% was considered low; 30 to 50%, moderate and more than 50% substantial.
Results
We identified eight randomized trials comparing TDF/FTC or TDF to placebo [24–31] and two studies comparing TDF/FTC to cabotegravir [32,33], which reported the safety endpoints for this analysis: 5% weight loss and gastrointestinal adverse events, nausea, vomiting, diarrhoea and loss of appetite. Table 1 contains a summary of the studies included in this analysis.
Table 1 -
Summary of studies included in the analysis and safety data extracted.
|
|
|
|
5% Weight loss |
Nausea |
Vomiting |
Diarrhoea |
Loss of appetite |
| Study |
Arms |
Population |
Location |
TDF |
Control |
TDF |
Control |
TDF |
Control |
TDF |
Control |
TDF |
Control |
| VOICE [24] |
(TDF or TDF/FTC versus PBO) |
Women |
SA, Uganda, Zimbabwe |
49/2010 |
17/1009 |
21/2010 |
15/1009 |
12/2010 |
9/1009 |
33/2010 |
21/1009 |
3/2010 |
2/1009 |
| TDF-2 [25] |
TDF/FTC versus PBO |
MSM + women |
Botswana |
133/611 |
72/608 |
132/611 |
48/608 |
87/611 |
47/608 |
93/611 |
76/608 |
– |
– |
| FEM-PrEP [26] |
TDF/FTC versus PBO |
Women |
Kenya, SA, Tanzania |
1/1025 |
0/1033 |
52/1025 |
33/1033 |
38/1025 |
12/1033 |
18/1025 |
21/1033 |
10/1025 |
4/1033 |
| BKK [27] |
TDF versus PBO |
IVDU |
Thailand |
140/1204 |
135/1209 |
113/1204 |
71/1209 |
113/1204 |
71/1209 |
302/1204 |
312/1209 |
– |
– |
| PARTNERS [28] |
TDF or TDF/FTC versus PBO |
SC |
Kenya/Uganda |
13/3163 |
6/1584 |
1/3163 |
0/1584 |
– |
– |
86/3163 |
39/1584 |
– |
– |
| iPReX (39) |
TDF/FTC versus PBO |
MSM + TW |
Thailand, Brazil, Ecaudor, Peru, SA, USA |
34/1251 |
19/1248 |
22/1251 |
10/1248 |
– |
– |
49/1251 |
61/1248 |
– |
– |
| IPERGAY [30] |
TDF/FTC versus Placebo |
MSM |
France and Canada |
– |
– |
16/199 |
48/201 |
3/199 |
0/201 |
8/199 |
6/201 |
– |
– |
| US Safety Study [31] |
TDF versus Placebo |
MSM |
USA |
– |
– |
27/201 |
13/199 |
– |
– |
42/201 |
57/199 |
|
|
| HPTN 084 [32] |
TDF/FTC versus CAB |
Women |
SSA |
101/1610 |
78/1614 |
– |
– |
– |
– |
– |
|
|
|
| HPTN 083 [33] |
TDF/FTC versus CAB |
MSM/TGW |
Argentina, Brazil, Peru, US, SA, Thailand, Vietnam |
|
|
– |
– |
– |
– |
158/2284 |
148/2282 |
|
|
| Total |
|
|
|
471/11054 (4.3%) |
327/8305 (3.9%) |
384/9964 (3.9%) |
238/7498 (3.2%) |
253/5049 (5%) |
139/4060 (3.4%) |
631/9664 (6.5%) |
593/7091 (8.4%) |
13/3035 (0.4%) |
6/2042 (0.3%) |
TDF, tenofovir disoproxil fumarate.
Weight loss
Of these, seven studies (n = 19 359) reported grade 2+ loss of weight or at least 5% weight loss as an endpoint. Taking oral TDF was associated with 44% greater odds of 5% weight loss, compared with placebo or cabotegravir (Fig. 1). This was statistically significant (P = 0.005). However, there was substantial heterogeneity in the results (I2 = 52%).
;)
Fig. 1: Display of forest plot of preexposure prophylaxis versus control for weight loss.
Gastrointestinal adverse effects
Nausea
Nausea was reported as an adverse events in eight of the studies comparing TDF to placebo. Meta-analysis found no significant association with exposure to TDF versus placebo (P = 0.25), with substantial heterogeneity (I2 = 87%) (Fig. 2.1).
Fig. 2: Display of forest plot of preexposure prophylaxis versus control for gastrointestinal adverse events.
Vomiting
Five studies assessing TDF to placebo reported vomiting as an adverse event. The odds of vomiting on exposure to TDF greater than on exposure to placebo (OR 1.81; 95% CI 1.20 – 2.73; P < 0.005) (Figure 2.2). There was substantial heterogeneity (I2 = 58%).
Diarrhoea
The difference in number of events of reported diarrhoea was not statistically significant between TDF and placebo or cabotegravir (P = 0.75) (Fig. 2.3).
Loss of appetite
Two studies, VOICE and FEM-PrEP, reported loss of appetite as an adverse events. TDF/FTC was not statistically associated with a loss of appetite (P = 0.36) (Fig. 2.4).
When including only grade 2 and above adverse events, there was no difference between TDF/FTC and placebo (OR 1.29 95% CI 0.32–5.24 P = 0.73)
Discussion
This analysis shows that TDF may be associated with unintentional weight loss. Weight changes have been reported in some of the PrEP studies. In the DISCOVER (TAF/FTC versus TDF/FTC) [2] iPReX study (TDF/FTC versus placebo [29,35] and HPTN 083 (TDF/FTC versus cabotegravir [33] studies, transient weight loss was observed in the first 24 weeks in participants on the TDF/FTC arm. However, in all three studies, participants returned to their baseline weight and continued to gain weight at the same rate as the control arm. At week 48, the difference between TAF/FTC (+1.1 kg) and TDF/FTC (−0.1 kg) was statistically significant (P < 0.001). In both the HPTN 083 and HPTN 084 trials, weight changes in the cabotegravir arm compared with the TDF/FTC arm were statistically significant [32,33].
In the phase 2a study, HPTN 077, no weight difference was observed between cabotegravir and placebo (1.48 versus 1.57 kg/year, respectively) [36]. This suggests that cabotegravir may be weight neutral in HIV-negative individuals, and that the weight differences observed between cabotegravir and TDF/FTC in HPTN 083 and 084, could in fact be because of a weight-suppressive effect of TDF.
Our analysis also highlights that TDF may be associated with an increased risk of gastrointestinal adverse events, in particular, vomiting, compared with placebo, and may be a contributing factor to weight loss. In the ADVANCE HIV study, there was a difference in GI adverse events between the TAF/FTC+dolutegravir (DTG) and TDF/FTC+DTG arm (24.8 versus 28.2%, respectively). However, when participants reporting these side effects were excluded from the analysis, TAF/FTC+DTG group had significantly greater weight gain compared with those taking TDF/FTC+DTG [15]. By contrast, in the DISCOVER study, there was no difference in gastrointestinal adverse events between the groups taking TDF/FTC and those taking TAF/FTC [2].
The effect of TDF on lipid suppression may also be a contributing factor to weight loss. This effect has been observed in the PrEP DISCOVER (TAF versus TDF) and iPrEX (TDF placebo) studies [2,35].
Future studies should report grade 1 events, as well as grade 2–4. To assist in understanding the contribution to this weight difference. One of the limitations of this study, was the lack of consistency in the reporting of gastrointestinal adverse events. Some studies reported a breakdown of the adverse events by grade, other stated that the adverse events were grade 2+. However, some studies did not state, which grade the adverse events were, and so we were unable to stratify by grade in our analysis. Substantial clinical heterogeneity was also present in our analysis.
Furthermore, a lack of representation of all ethnic groups or the female gender in these trials could provide an external limitation to this analysis. In HIV studies, identified risk factors for weight gain include being black, female and having a high baseline BMI [21]. Differences in weight changes could be greater if all groups were equally represented in this analysis, or if these factors were controlled for in this analysis.
More research is required to understand the mechanism of TDF and weight loss, and whether this may have clinical implications. It is also unclear whether these observed changes are transient or persist long-term. Longer term data is required to ascertain stronger evidence. However, considering the results of this analysis, the use of TDF should be preferred in patients who are at a risk of weight gain as it could have unintended benefits for certain groups who may go on to develop metabolic syndrome and obesity-linked noncommunicable disease secondary to weight gain. Clinically, patients taking TDF as part of their therapy for PrEP, HIV or HBV should have their weight closely monitored. Future clinical trials should report gastrointestinal and metabolic adverse events, and weight data.
In conclusion, TDF is associated with a higher risk of 5% weight loss in HIV-negative individuals taking pre-exposure prophylaxis therapy. This could be attributed to some gastrointestinal side effects associated with TDF therapy. More research and reporting of weight data is required to widen the evidence base and to establish clinical significance.
Acknowledgements
S.S. and V.P. performed the meta-analysis. All authors have reviewed and approved of the submitted manuscript.
Conflicts of interest
There are no conflicts of interest.
References
1. Gupta SK, Post FA, Arribas JR, Eron JJ, Wohl DA, Clarke AE, et al.
Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials.
AIDS Lond Engl 2019; 33:1455–1465.
2. Mayer KH, Molina J-M, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ, et al.
Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV preexposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, noninferiority trial.
Lancet 2020; 396:239–254.
3. European AIDS Clinical Society. Initial regimens: ART-naïve adult. EACS Guidelines. 2020 [cited 17 November 2020]. Available at:
https://eacs.sanfordguide.com/art/initial-regimens-arv-naive-adults. [Accessed 7 October 2021]
4. FDA. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic [Internet]. FDA. FDA; 2019 [cited 28 May 2021]. Available at:
https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic. [Accessed 7 October 2021]
5. Pilkington V, Hughes SL, Pepperrell T, McCann K, Gotham D, Pozniak AL, et al.
Tenofovir alafenamide vs tenofovir disoproxil fumarate: an updated meta-analysis of 14894 patients across 14 trials.
AIDS 2020; 34:2259–2268.
6. Tungsiripat M, Kitch D, Glesby MJ, Gupta SK, Mellors JW, Moran L, et al.
A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206.
AIDS Lond Engl 2010; 24:1781–1784.
7. Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, et al.
Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials.
JAIDS J Acquir Immune Defic Syndr 2020; 83:310–318.
8. Agarwal K, Brunetto M, Seto WK, Lim Y-S, Fung S, Marcellin P, et al.
96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection.
J Hepatol 2018; 68:672–681.
9. Lampertico P, Buti M, Fung S, Ahn SH, Chuang W-L, Tak WY, et al.
Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre noninferiority study.
Lancet Gastroenterol Hepatol 2020; 5:441–453.
10. Lacey A, Savinelli S, Barco EA, Macken A, Cotter AG, Sheehan G, et al.
Investigating the effect of antiretroviral switch to tenofovir alafenamide on lipid profiles in people living with HIV within the UCDID Cohort.
AIDS Lond Engl 2020; 34:1161–1170.
11. Hagins D, Kumar P, Saag M, Wurapa A, Brar I, Berger DS. Week 48 outcomes from the BRAAVE 2020 Study: A randomized switch to B/F/TAF in African American adults with HIV [Internet]. ID Week; 2020. Available at:
https://doi.org/10.1093/ofid/ofaa439.1232. [Accessed 7 October 2021]
12. Taramasso L, Biagio AD, Riccardi N, Briano F, Filippo ED, Comi L, et al.
Lipid profile changings after switching from rilpivirine/tenofovir disoproxil fumarate/emtricitabine to rilpivirine/tenofovir alafenamide/emtricitabine: different effects in patients with or without baseline hypercholesterolemia.
PLoS One 2019; 14:e0223181.
13. Surial B, Mugglin C, Calmy A, Cavassini M, Günthard HF, Stöckle M, et al. Swiss HIV Cohort Study.
Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV: a cohort study.
Ann Intern Med 2021; 74:758–767.
14. Erlandson KM, Carter CC, Melbourne K, Brown TT, Cohen C, Das M, et al.
Weight change following antiretroviral therapy switch in people with viral suppression: pooled data from randomized clinical trials.
Clin Infect Dis 2021; ciab444.
15. Venter WDF, Sokhela S, Simmons B, Moorhouse M, Fairlie L, Mashabane N, 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, noninferiority trial.
Lancet HIV 2020; 7:E666–E676.
16. Orkin C, Eron JJ, Rockstroh J, Podzamczer D, Esser S, Vandekerckhove L, et al. AMBER study group.
Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
AIDS Lond Engl 2020; 34:707–718.
17. Hill A, McCann K, Chirwa L, Qavi A, Mulenga L. A randomized prospective study evaluating virologic outcomes among patients switching with detectable and undetectable viral loads from efavirenz and nevirapine-based first line ART regimens to DTG regimens in Zambia. In:
23rd International AIDS Conference. 2020.
18. Shah ASV, Stelzle D, Lee KK, Beck EJ, Alam S, Clifford S, et al.
Global burden of atherosclerotic cardiovascular disease in people living with HIV.
Circulation 2018; 138:1100–1112.
19. McCann K, Shah S, Hindley L, Hill A, Qavi A, Simmons B, et al.
Implications of weight gain with newer antiretrovirals: 10-year predictions of cardiovascular disease and diabetes.
AIDS Lond Engl 2021; 35:1657–1665.
20. Asif S, Baxevanidi E, Hill A, Chandiwana N, Fairlie L, Masenya M,
et al. The predicted risk of adverse pregnancy outcomes from treatment-induced obesity in the ADVANCE trial. In:
23rd International AIDS Conference. 2020.
21. Sax PE, Erlandson KM, Lake JE, McComsey GA, Orkin C, Esser S, et al.
Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials.
Clin Infect Dis 2020; 71:1379–1389.
22. Lake JE, Wu K, Bares SH, Debroy P, Godfrey C, Koethe JR, et al.
Risk factors for weight gain following switch to integrase inhibitor-based antiretroviral therapy.
Clin Infect Dis 2020; 71:e471–e477.
23. Pilkington V, Hill A, Hughes S, Nwokolo N, Pozniak A.
How safe is TDF/FTC as PrEP? A systematic review and meta-analysis of the risk of adverse events in 13 randomised trials of PrEP.
J Virus Erad 2018; 4:215–224.
24. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. VOICE Study Team.
Tenofovir-based preexposure prophylaxis for HIV infection among African women.
N Engl J Med 2015; 372:509–518.
25. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. TDF2 Study Group.
Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana.
N Engl J Med 2012; 367:423–434.
26. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. FEM-PrEP Study Group.
Preexposure prophylaxis for HIV infection among African women.
N Engl J Med 2012; 367:411–422.
27. Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. Bangkok Tenofovir Study Group.
Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial.
Lancet Lond Engl 2013; 381:2083–2090.
28. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Partners PrEP Study Team.
Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.
N Engl J Med 2012; 367:399–410.
29. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. iPrEx Study Team.
Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.
N Engl J Med 2010; 363:2587–2599.
30. Molina J-M, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. ANRS IPERGAY Study Group.
On-demand preexposure prophylaxis in men at high risk for HIV-1 infection.
N Engl J Med 2015; 373:2237–2246.
31. Grohskopf LA, Chillag KL, Gvetadze R, Liu AY, Thompson M, Mayer KH, et al.
Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States.
JAIDS J Acquir Immune Defic Syndr 2013; 64:79–86.
32. Delany-Moretlwe S, Hughes J, Bock P, Gurrion S, Hunidzarira P. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: results from HPTN 084. 2019 Jan [cited 27 May 2021].
HIV R4P virtual conference. Available at:
https://www.084life.org/wp-content/uploads/2021/02/210123-HPTN-084-HIV-R4P-final-final.pdf. [Accessed 7 October 2021]
33. Raphael J. Landovitz. HPTN 083 FINAL RESULTS: preexposure prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men. AIDS 2020; 2020; Virtual. Available at:
https://www.hptn.org/sites/default/files/inline-files/HPTN083_PrimaryAIDS2020_Landovitz-Final_web.pdf. [Accessed 7 October 2021]
34. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. 35. 2017 July (Accessed 7 Oct 2021). Available at:
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables
35. Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, et al.
Metabolic effects of preexposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine.
Clin Infect Dis 2018; 67:411–419.
36. Landovitz RJ, Zangeneh SZ, Chau G, Grinsztejn B, Eron JJ, Dawood H, et al.
Cabotegravir is not associated with weight gain in human immunodeficiency virus-uninfected individuals in HPTN 077.
Clin Infect Dis 2020; 70:319–322.
