Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial

doi:10.1016/S2352-3018(16)30121-7

The Lancet HIV

Volume 3, Issue 12, December 2016, Pages e561-e568

https://doi.org/10.1016/S2352-3018(16)30121-7 Get rights and content

Summary

Background

The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents.

Methods

We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12–18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per μL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m² by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUC_tau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUC_last) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775.

Findings

Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUC_tau for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUC_last for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults.

Interpretation

The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children.

Funding

Gilead Sciences.

Introduction

In the USA in 2014, 22% of all new HIV infections occurred in people aged 13–24 years.¹ Additionally, the cohort of children getting older who are infected by vertical transmission adds to the pool of HIV-infected youth. Adherence to antiretroviral therapy (ART) can be challenging for adolescents;2, 3 because poor adherence can increase their risk of drug resistance and virological failure,⁴ single-tablet, once-daily HIV-treatment regimens⁵ might address some of their adherence challenges. Before the approval of the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen for adolescents in the USA and Europe, the regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate was the only available one-pill, once-daily option for adolescents in the USA, and no such options were available in Europe.6, 7

Research in context

Evidence before this study

The novel prodrug tenofovir alafenamide achieves high intracellular concentrations while maintaining 91% lower concentrations of plasma tenofovir than tenofovir disoproxil fumarate, and is associated with better renal and bone safety. We searched PubMed for randomised clinical trials of tenofovir alafenamide in HIV-1 infected individuals, with search terms including “tenofovir alafenamide”, “HIV”, and “randomised” or “randomized”. We limited searches to articles published in English between Jan 1, 1997, and May 31, 2016. The search yielded eight articles, but we excluded two because they described short-term, proof-of-concept, monotherapy studies. Four articles summarised week 48 or 96 data from clinical trials in treatment-naive adults (phase 2 and 3 trials comparing single-tablet regimens of elvitegravir, cobicistat, emtricitabine, and either tenofovir alafenamide or tenofovir disoproxil fumarate; and a phase 2 trial comparing darunavir, cobicistat, emtricitabine, and either tenofovir alafenamide or tenofovir disoproxil fumarate); one summarised a trial with virologically suppressed adults (phase 3 comparing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide vs tenofovir disoproxil fumarate-containing regimens); and one summarised a trial in adults with renal impairments (a phase 3, single-arm assessment of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide). The results from these studies showed that tenofovir alafenamide is as effective as tenofovir disoproxil fumarate, but is safer from the standpoint of renal and bone toxicity, as assessed by estimated glomerular filtration rate, quantitative urinary protein, and bone mineral density. The PubMed search did not generate any reports of trials of tenofovir alafenamide in adolescent patients.

Added value of this study

Our 48 week, phase 2/3, single-arm, open-label trial investigated the safety, efficacy, and pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive adolescents aged 12 to younger than 18 years, and is the first clinical trial to assess a single-tablet regimen containing tenofovir alafenamide in a paediatric cohort. The results were consistent with findings in adults, showing greater than 90% efficacy (as measured by virological suppression to <50 copies of HIV-1 RNA/mL) at week 48, no study drug discontinuations because of adverse events, improvement in total and tubular proteinuria compared to baseline, and positive gains in bone mineral density in spine and total body less head at week 48. Although ours was a small, non-comparative study of 50 adolescents, it provided the important evidence that led to the recent approval of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for this age group. This regulatory pathway is similar to that of dolutegravir, also approved in adolescents based on a small, non-comparative study (n=23). Such study designs are consistent with, and responsive, to HIV paediatric regulatory guidance from the European Union and USA, which allow extrapolation of adult efficacy data.

Implications of all the available evidence

Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a promising single-tablet regimen for HIV with proven efficacy and safety in several populations, now including treatment-naive, HIV-infected adolescents who might especially benefit from an improved bone safety profile during a period of peak bone growth and development. Results from this trial have led to the approval of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected children aged 12 years and older in several countries, and its selection by the US Department of Health and Human Services paediatric HIV treatment guidelines panel as a preferred first-line regimen for adolescents. The study results also support further assessment of regimens containing tenofovir alafenamide in clinical trials of HIV-infected children younger than 12 years.

Tenofovir disoproxil fumarate, one of the most commonly used nucleotide reverse transcriptase inhibitors (NRTI), is associated with nephrotoxicity and reduced bone mineral density.8, 9, 10 Because of concerns about associated bone toxicity, this drug is generally not considered for first-line NRTI treatment for prepubertal adolescents.⁴ Tenofovir alafenamide is also an oral prodrug of tenofovir, but compared with tenofovir disoproxil fumarate it is more stable in plasma and is associated with a higher intracellular concentration of the active phosphorylated metabolite tenofovir diphosphate and approximately 90% lower circulating tenofovir,¹¹ favourable pharmacokinetic characteristics that offer the potential for a better safety profile than tenofovir disoproxil fumarate.12, 13

Findings from phase 3 clinical trials2, 14 in HIV-infected adults randomly assigned to either elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide or a regimen based on tenofovir disoproxil fumarate showed that tenofovir alafenamide was associated with less bone and renal toxicity than was tenofovir disoproxil fumarate, but otherwise, general safety profiles and efficacy were similar. Findings in adolescents from another study¹⁵ to week 24 were consistent with those in adults. These data led to the US and European approval of the first fixed-dose combination containing tenofovir alafenamide (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) in adults and adolescents, which is now a recommended initial regimen by the US Department of Health and Human Services guidelines for ART-naive patients with an estimated creatinine clearance of at least 30 mL/min.¹⁶ In this study, we aimed to investigate the safety, efficacy, and pharmacokinetics of this combination in treatment-naive adolescents.

Section snippets

Study design and participants

We did an open-label, single-arm, two-part trial. We enrolled participants from ten hospital clinics in South Africa (two sites), Thailand (three), Uganda (one), and the USA (four). The trial protocol, amendments and other documents were reviewed and approved by independent ethics committees or institutional review boards.

Eligibility criteria included being treatment naive, HIV-1 infected individuals aged 12–18 years, plasma HIV-1 RNA 1000 copies per mL or higher, CD4 count 100 cells per μL or

Results

Between May 22, 2013, and July 22, 2014, we screened 63 participants and enrolled 50 (figure 1), of whom 24 participated in the intensive pharmacokinetic assessment. 13 were excluded because they were ineligible. This report includes data up to August, 2015, by which time all enrollees had either completed their week 48 visit or discontinued the study drug. At baseline, four participants (8·0%) had CD4 counts of less than 200 cells per μL, and most participants had been infected by vertical

Discussion

The results of this ongoing, single-arm study in HIV-1-infected, treatment-naive adolescents through week 48 showed that the elvitegravir,

References (26)

PE Sax 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)
C Wyatt et al.
Tenofovir alafenamide for HIV infection: is less more?
Lancet
(2015)
Centers for Disease Control and Prevention
HIV surveillance report
(2014)
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Developed by the DHHS panel on antiretroviral guidelines for adults and adolescents–a working group of the office of AIDS research advisory council
SL Reisner et al.
A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth
Top HIV Med
(2009)
Guidelines for the use of antiretroviral agents in pediatric HIV infection
G Sterrantino et al.
Self-reported adherence supports patient preference for the single tablet regimen (STR) in the current cART era
Patient Prefer Adherence
(2012)
ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets. US Prescribing Information. Gilead Sciences...
Gilead Sciences Inc. GENVOYA (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) tablets, for oral use. US...
HJ Stellbrink et al.
Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study
Clin Infect Dis
(2010)

SK Gupta

Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system

AIDS Patient Care STDS

(2008)

GA McComsey et al.

Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202

J Infect Dis

(2011)

PJ Ruane et al.

Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults

J Acquir Immune Defic Syndr

(2013)

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Fractures in children and adolescents living with perinatally acquired HIV
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A case-control study found no difference in fracture rates by TDF exposure in adults [38]. At the time of analysis, none of the children/adolescents in our cohort were receiving tenofovir alefenamide (TAF) which has less effect on BMD than TDF in adults [39,40] and adolescents [41]. We observed significantly higher fractures rates in PHIV children/adolescents exposed to TDF and those exposed to RTV.
Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS).
Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr).
PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis.
Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood.
Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.
Single oral dose for HIV pre or post-exposure prophylaxis: user desirability and biological efficacy in macaques
2020, eBioMedicine
Citation Excerpt :
The clinically-relevant doses of TAF (1•5 mg/kg) and FTC (20 mg/kg) in macaques have been previously defined [17,19]. Table 3 shows that median maximum drug concentration in plasma (Cmax) and area under the curve values over 24h (AUC0-24h) for FTC (1328 [range=341–5093] ng/ml and 16,937 [7147–62,064] ngxh/ml, respectively), and median plasma Cmax and AUC0-24h values for TFV (29 [range=24–96] ng/ml and 494 [371–1,591] ngxh/ml, respectively) were within the range of those seen in humans treated with 25 mg of TAF and 200 mg of FTC [20]. The pharmacoenhancer COBI was co-administered since high (50 mg/kg) doses of EVG in macaques without a booster results in low plasma EVG concentrations (Cmax of 280 ng/ml and AUC0-24h of 4000 ngxh/ml) ([15] and supplementary Fig. 1).
Daily oral pre- or post-exposure prophylaxis (PrEP or PEP) is highly effective in preventing HIV infection. However, many people find it challenging to adhere to a daily oral regimen. Chemoprophylaxis with single oral doses of antiretroviral drugs taken before or after sex may better adapt to changing or unanticipated sexual practices and be a desirable alternative to daily PrEP or PEP. We investigated willingness to use a single oral pill before or after sex among men who have sex with men (MSM) and assessed the biological efficacy of a potent antiretroviral combination containing elvitegravir (EVG), emtricitabine (FTC), and tenofovir alafenamide (TAF).
Data on willingness to use single-dose PrEP or PEP were obtained from the 2017 cycle of the American Men's Internet Survey (AMIS), an annual online behavioral surveillance survey of MSM in the United States. Antiretroviral drug levels were measured in humans and macaques to define drug distribution in rectal tissue and identify clinically relevant doses for macaque modeling studies. The biological efficacy of a single dose of FTC/TAF/EVG as PrEP or PEP was investigated using a repeat-challenge macaque model of rectal HIV infection.
Through pharmacokinetic assessment in humans and macaques we found that EVG penetrates and concentrates in rectal tissues supporting its addition to FTC/TAF to boost and extend chemoprophylactic activity. Efficacy estimates for a single oral dose given to macaques 4h before or 2h after SHIV exposure was 91•7%[35•7%-98•9%] and 100%, respectively, compared to 80•1%[13•9%-95•4%] and 64•6%[-19•4%-89•5%] when single doses were given 6 and 24h post challenge, respectively. A two-dose regimen at 24h and 48h after exposure was also protective [77•1%[1•7%-94•7%].
Informed by user willingness, human and macaque pharmacokinetic data, and preclinical efficacy we show that single-dose prophylaxis before or after sex is a promising HIV prevention strategy. Carefully designed clinical trials are needed to determine if any of these strategies will be effective in humans.
Funded by CDC intramural funds, CDC contract HCVJCG2-2016-03948 (to CFK), and a grant from the MAC AIDS Fund and by the National Institutes of Health [P30AI050409] – the Emory Center for AIDS Research (to MZ and TS).
Bone mineral density in virologically suppressed people aged 60 years or older with HIV-1 switching from a regimen containing tenofovir disoproxil fumarate to an elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide single-tablet regimen: a multicentre, open-label, phase 3b, randomised trial
2019, The Lancet HIV
Citation Excerpt :
By contrast, tenofovir alafenamide is associated with 90% lower plasma tenofovir concentrations compared with tenofovir disoproxil fumarate, and increases delivery of active intracellular tenofovir, resulting in improved efficacy and a reduced effect on measures of renal and bone safety.7,8 In treatment-naive people living with HIV and those switching from regimens containing tenofovir disoproxil fumarate, the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide has been shown to be effective and safer than tenofovir disoproxil fumarate-based therapy across several different populations of people living with HIV, including adults,7–9 adolescents (aged 12–18 years),10 children (aged 6–11 years),11 women,12 and various racial and ethnic groups. The US Food and Drug Administration (FDA) and European Medicines Agency approved the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide single-tablet regimen in 2015.
Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older.
We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA <50 copies per mL), aged 60 years or older, on a tenofovir disoproxil fumarate-containing regimen and were randomly assigned (2:1) via an interactive web-response system to open-label elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) daily or continued therapy containing tenofovir disoproxil fumarate (300 mg). Participants were stratified by spine and hip bone mineral density categories. Primary endpoints were change from baseline to week 48 in spine and hip bone mineral density with a null hypothesis of zero between-group difference tested at a significance level of 0·05. This study was registered with ClinicalTrials.gov, NCT02616783.
Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (n=111 [66%]) or tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2·24% (SD 3·27) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and −0·10% (3·39) in the tenofovir disoproxil fumarate group (between-group difference 2·43% [95% CI 1·34–3·52]; p<0·0001), and mean percentage change in hip bone mineral density was 1·33% (2·20) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and −0·73% (3·21) in the tenofovir disoproxil fumarate group (difference 2·04% [1·17–2·90]; p<0·0001). The most common adverse events were nasopharyngitis (12 [11%]), back pain (nine [8%]), and diarrhoea (eight [7%]) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and bronchitis (six [11%]), vitamin D deficiency (four [7%]), and arthralgia (four [7%]) in the tenofovir disoproxil fumarate group. 22 (20%) participants in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and one (2%) participant in the tenofovir disoproxil fumarate group had an adverse event that was considered to be related to treatment. No treatment-related serious adverse events were observed. The proportions of adverse events leading to premature treatment discontinuation were similar between groups (four [4%] in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and one (2%) in the tenofovir disoproxil fumarate group).
The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older.
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Pharmacology of Symtuza<sup>®</sup> (DRV/c/FTC/TAF)
2018, Enfermedades Infecciosas y Microbiologia Clinica
Symtuza® es el primer y único tratamiento del VIH-1 que combina 2 análogos de nucleós(t)idos (emtricita-bina y tenofovir alafenamida) junto con un inhibidor de la proteasa potenciado (darunavir/cobicistat) en un solo comprimido una vez al día. Esta combinación es activa frente a una gran variedad de cepas del VIH y, a su vez, evita la toxicidad renal y ósea asociada con el uso de tenofovir disoproxil fumarato, y aúna eficacia, conveniencia, tolerabilidad y elevada barrera genética. Los estudios farmacocinéticos de sus componentes demuestran un perfil favorable que permite su uso en una gran variedad de pacientes y situaciones clínicas. Aunque, como en toda combinación potenciada, es necesario considerar posibles interacciones con medicación concomitante, el potenciador cobicistat inhibe más selectivamente el citocromo P-450 y no posee ningún efecto inductor, por lo que su perfil de interacciones es más predecible que el de ritonavir.
Información sobre el suplemento: este artículo forma parte del suplemento titulado «Darunavir, cobicistat, emtricitabina y tenofovir alafenamida coformulados en el tratamiento de la infección por el VIH», que ha sido patrocinado por Janssen.
Symtuza^® is the first and only treatment for HIV-1 that combines 2 nucleos(t)ide analogues (emtricitabine and tenofovir alafenamide) together with a boosted protease inhibitor (darunavir/cobicistat) in a once-daily single tablet regimen (STR). This combination is active against a wide variety of HIV strains and, in turn, avoids bone and renal toxicity associated with the use of tenofovir disoproxil fumarate, combining efficacy, convenience, tolerability and high genetic barrier. Pharmacokinetic studies of its components show a favourable profile, allowing its use in a wide variety of patients and clinical situations. Although, as in any boosted combination, possible interactions with concomitant medication should be borne in mind, cobici-stat inhibits cytochrome P-450 more selectively and has no inducing effect, so it has a more predictable interaction profile than ritonavir. Supplement information: This article is part of a supplement entitled “Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection”, which is sponsored by Janssen.
Role of tenofovir alafenamide (TAF) in the treatment and prophylaxis of HIV and HBV infections
2018, Biochemical Pharmacology
Citation Excerpt :
Through 48 weeks, more than 90% of the patients given E/C/F/TAF had plasma HIV-1 RNA levels less than 50 copies per mL, while the patients had significantly smaller mean serum creatinine increases, significantly less proteinuria and a significantly smaller decrease in spine and hip mineral density than those given E/C/F/TDF [21]. Similar data were obtained in HIV-infected adolescents [22]. The E/C/F/TAF single-tablet regimen should be recommended for adults and adolescents with HIV-1 infection, particularly those with an estimated creatinine clearance of ≥30 to <50 mL/min or an increased risk of TDF-related bone toxicity [23].
Tenofovir (TFV) is the cornerstone of the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((−)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophylaxis of HIV infection is momentarily based upon Truvada®, the combination of F with TDF, which in the future may also be replaced by TAF. TAF (Vemlidy®) has also replaced TDF (Viread®) for the treatment of hepatitis B virus (HBV) infections. Both TDF and TAF offer little or no risk for virus-drug resistance. As compared to TDF, TAF limits the risk for nephrotoxicity and loss of bone mineral density. What remains to be settled, however, before the universal use of TAF could be recommended, is its safety during pregnancy and its applicability in the treatment of tuberculosis, in combination with rifampicin.

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ArticlesSafety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Lancet

Lancet

Centers for Disease Control and Prevention

HIV surveillance report

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Developed by the DHHS panel on antiretroviral guidelines for adults and adolescents–a working group of the office of AIDS research advisory council

A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth

Top HIV Med

Guidelines for the use of antiretroviral agents in pediatric HIV infection

Self-reported adherence supports patient preference for the single tablet regimen (STR) in the current cART era

Patient Prefer Adherence

Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study

Clin Infect Dis