A 2020 meta-analysis assessed the impact of oral tenofovir disoproxil fumarate plus emtricitabine (TDF plus FTC; Truvada) on bone mineral density (BMD) and risk of osteoporosis, low bone mass, and fractures among people taking it as pre-exposure prophylaxis (PrEP) and human immunodeficiency virus (HIV) treatment. Of the 25 included studies, ten investigated PrEP users, while 15 investigated HIV, with a minimum duration of 48 ± 4 weeks. Compared to non-TDF users, those taking TDF had a significantly greater BMD decline when taken for PrEP (lumbar spine: mean difference [MD] -0.82%, 95% confidence interval [CI] -1.28 to -0.37%, I^2= 38%; total hip: MD -0.81%, 95% CI -1.22 to -0.40%, I^2= 48%) and HIV treatment (lumbar spine: MD -1.62%, 95% CI -2.30 to -0.95%, I^2=93%; total hip: MD -1.75%, 95% CI -2.08 to -1.42%, I^2=83%; femoral neck: MD -1.26%, 95% CI -2.15 to -0.38%, I^2= 43%). Results on the incidence of osteoporosis or low bone mass varied among examined studies. Pooled data from 5 studies revealed no significantly increased risk of fractures associated with TDF compared with no PrEP (rate ratio 1.12, 95% CI 0.752 to 1.74, I^2= 26%). Though not directly compared to tenofovir alafenamide fumarate (TAF; Descovy), study findings illustrate the clinically significant BMD decline caused by TDF, suggesting its use should be closely considered in those with existing risk factors of bone loss. [1]
A 2020 systematic review and meta-analysis compared the safety and efficacy of TDF and TAF, incorporating 14 clinical trials (N= 14,894 patients). The key efficacy outcome, a number of patients achieving viral suppression (HIV RNA <50 copies/mL), was evaluated based on 9 studies. In patients boosted with a third agent, either a nonnucleoside reverse transcriptase inhibitor (NRTI) or integrase or protease inhibitor, 94% of patients receiving TAF/emtricitabine became or remained virally suppressed at 48 weeks, compared to 92% of TDF/emtricitabine patients (difference 2%, 95% CI 1-4%, p= 0.0004). For unboosted patients, 89% vs. 90% were virally suppressed at 48 weeks, respectively, with no significant difference between groups. No significant difference was reported between TAF and TDF for bone parameters and also for the occurrence of adverse events of any grade or death from any cause. For renal parameters, a greater number of discontinuations due to renal adverse events occurred in the boosted regimen subgroup (p= 0.03). [2]
A 2020 meta-analysis provided another general comparison of the efficacy and safety of regimens containing TAF vs. TDF. A total of 7 randomized controlled trials (RCTs) were included (N= 6,269 participants). General results again concluded similar efficacy; adult patients who were antiretroviral-naive with HIV-1 on both the TAF-containing and the TDF-containing regimens were observed to express similar combined virologic suppression effects (RR, 1.02; 95% CI, 1.00–1.04; p> 0.05) at week 24 (93.99% vs. 94.20%), week 48 (90.71% vs. 89.54%), and week 96 (86.16% vs. 84.80%). Neither group demonstrated significant improvements in CD4 cell count for the naive patients during 48 weeks of therapy (standardized mean difference [SMD], 0.09; 95% CI, 0.01 to 0.16; p<0.05). While most adverse events were similar between groups, there was a divergence between TAF and TDF for bone-related outcomes. Based on data from 5 RCTs, median percentage change in BMD decreases of > 3% were 15.82% (TAF-containing regimens) vs. 47.42% (TDF-containing regimens) at the hip, and 26.93% (TAF-containing regimens) vs. 46.20% (TDF-containing regimens) at the spine, respectively. TDF-containing regimens were associated with more significant declines in BMD vs. TAF-containing regimens in both the hip (RR, 0.33; 95% CI, 0.29–0.39; p<0.05) and spine (RR, 0.58; 95% CI, 0.51–0.65; p<0.05) over 48 weeks. BMD changes in the hip with TAF regimens were significantly smaller at both the hip (−0.51 vs. −2.95, p<0.05) and the spine (−1.17 vs. −3.01, p<0.05) compared to TDF-containing regimens from baseline to week 48. Additionally, over 48 weeks, a biomarker of bone turnover, procollagen Type 1 N-terminal propeptide (P1NP), was significantly decreased in TAF-containing regimens (4.63 vs. 48.70, p<0.05). Additionally, data from 6 RCTs again demonstrated significantly lower renal events with TAF-containing regimens than with TDF-containing regimens after 48 weeks (RR, 0.31; 95% CI, 0.18–0.55; p<0.05). [3]
A 2019 study performed a pooled analysis of 26 clinical studies observing renal safety data between TAF and TDF (either as treatment-naive or antiretroviral switch studies). Data were collected based on A total of 9,322 adult and children patients which equated to 12,519 person-years exposure to TAF and 5,947 person-years exposure to TDF. Proximal renal tubulopathy events were the primary renal safety outcomes along with discontinuation due to renal events. Ten episodes of proximal renal tubulopathy occurred in the TDF group versus none in the TAF group (p<0.001), and there were 14 discontinuations due to renal events in the TDF group versus 3 in the TAF group (p<0.001). Two studies of treatment-naive patients observed fewer renal adverse events in the TAF group versus the TDF group (5.4% vs. 8.5%; p= 0.042). Five studies of virologically suppressed people with HIV saw no difference in renal adverse events when switching from TDF to TAF or continuing baseline TDF regimens (5% vs. 5%; p= 1.00). Concomitant medications that may have influenced the reported outcomes as boosting agents like ritonavir and cobicistat are also known to contain renal risk. [4]
A 2021 study explored the estimated effects of treatment-related (e.g., dolutegravir) maternal weight gain on adverse pregnancy outcomes. Using a meta-analysis, the relative risk (RR) of adverse pregnancy outcomes was established for women with pre-pregnancy body mass index (BMI) ≥ 30 vs. normal BMIs of 18.5 to 24.9 kg/m^2. A hypothetical scenario was created, based on a sample of 3,000 nonpregnant women with normal baseline BMIs who were evenly divided to receive tenofovir alafenamide/emtricitabine/dolutegravir (TAF/FTC+DTG), tenofovir disoproxil fumarate/emtricitabine/dolutegravir (TDF/FTC+DTG), or tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV). The treatment-associated obesity rates from the ADVANCE trial were used to calculate the number of women with obese and normal BMIs expected at Week 96 in this hypothetical sample of 3,000 nonpregnant women. Based on the ADVANCE trial, the treatment-associated obesity rates at Week 96 in women with a normal baseline BMI were 14.1% for TAF/FTC+DTG, 7.9% for TDF/FTC+DTG, and 1.5% for TDF/FTC/EFV. Subsequently, incorporating established RR of adverse pregnancy outcomes based on previous meta-analysis, the percentage increase in the number of women predicted to experience adverse pregnancy outcomes at their Week 0 BMI versus Week 96 BMI was 10% with TAF/FTC+DTG and 5% with TDF/FTC+DTG compared to only 1% with TDF/FTC/EV, likely reflecting an increased risk of adverse pregnancy outcomes with TAF in these hypothetical samples of patients with treatment-associated obesity. [5]
A 2020 cost-effective study was performed to assess the non-inferiority of Descovy versus generic TDF as PrEP among U.S. men who have sex with men (MSM) based on a potentially improved safety profile. Previous studies were collected for analysis. A five-year time horizon was established, and the highest predictive price of branded Descovy was compared to generic TDF. To reflect the extreme input values, the efficacy and safety of Descovy were intentionally favored over TDF while attempting to avoid overstating the consequences on bone and renal effects. Hip fracture rates have attributed a cost of $70,400, while costs from renal complications were estimated to be around $92,100 to $95,500 based on age-dependent hemodialysis costs. The estimated price of Descovy was $16,600/year, while the assumed generic price for TDF was $8,300/year (price reduction of 50%). Age was a significant factor in determining cost efficacy. [6]
Based on these parameters, all patients switching to Descovy would increase total expenditures over five years by $5.0 billion U.S. dollars. An incremental cost-effectiveness ratio (ICER) of $7,201,200/quality-adjusted life year (QALY) was identified based on Descovy potentially averting 2,101 excess hip fractures and 25 excess end-stage renal disease cases. The additional cost per person was estimated to increase by $370 per person. While there may be a benefit to using the newer brand-name product, the authors do not presume an urgency to switch from generic TDF to Descovy which would increase the payer's cost. [6]
A 2021 pharmacokinetic study compared concentrations of tenofovir-diphosphate (TFV-DP), the active metabolite of tenofovir, in peripheral blood mononuclear cells (PBMCs) from less than daily dosing between TAF and TDF. To evaluate TFV-DP concentrations in patients with low, medium, and high adherence, two separate, randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted. HIV-negative adults were randomized to a 12-week regimen of either emtricitabine/TAF 200 mg/25 mg (TAF-DBS) or emtricitabine/ TDF 200 mg/300 mg (DOT-DBS), each with 33%, 67% or 100% of daily dosing compliance, separated by a 12-week washout period. Specific dosing regimens were defined as follows: 33% was dosing on day 1, followed by no dosing on days 2-3, repeated for a total of 12 weeks; 67% was dosing on days 1 and 2, followed by no dosing on day 3, repeated for 12 weeks; 100% was daily dosing for 12 weeks. Steady-state concentrations (Css) in PBMCs were quantified and compared periodically. At different daily dose adherence levels (100%, 67%, and 33%), PBMC TFV-DP Css for emtricitabine/TAF were 7.3- (95% CI 6.4 to 8.2), 7.1- (95% CI 5.9 to 8.2), and 6.7- (95% CI 4.4 to 8.9) fold higher (p<0.0001) vs. emtricitabine/TDF. Additionally, TFV-DP was 2.6-fold higher with 33% emtricitabine/TAF vs. 100% emtricitabine/TDF. Emtricitabine/TAF regimen also exhibited a longer estimated half-life of TFV-DP in PBMC compared to emtricitabine/TDF (2.9 vs. 2.1 days). Overall, results support increased potency and pharmacologic forgiveness with emtricitabine/TAF in the PBMC compartment; however, TFV-DP concentrations in the mucosa or lymph node tissue were not evaluated in this study. [7]