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Background: Adolescents living with HIV tend to
experience worse immunological and viral suppression outcomes compared to
adults, which in turn contributes to their higher mortality. In fact, adherence
to antiretroviral therapy (ART) can be challenging for adolescents and then,
poor adherence can increase their risk of drug resistance and virological
failure. This is why single-tablet, once-daily HIV-treatment regimens with
proven efficacy and effectiveness might address some of their adherence
challenges in adolescents. Tenofovir alafenamide has favorable pharmacokinetic
characteristics that offer the potential for a better safety profile, efficacy
and it may be used in adolescents.
Objective: To investigate the effectiveness and
efficacy of tenofovir alafenamide based regimens in adolescents. To determine
the safety of tenofovir alafenamide contained regimens in adolescents. To
verify short term adherence of tenofovir alafenamide based regimens in
adolescents.
Methods: We conducted an electronic search on
CENTRAL (Cochrane Central Register of Controlled Trials), Scopus, Web of
science, EMBASE, PubMed, CINAHL and MEDLINE. We conducted a meta-analysis for
outcomes with baseline data and we reported narratively other outcomes.
Selection
criteria: Average age 6 to 18:
·
HIV positive,
·
On or initiating ART,
·
ART safety and
pharmacokinetics
·
Reported adherence, viral
load and/or CD4 count and eGFR creatinine outcomes,
·
Randomized controlled
trial (RCT) or trials.
Main results: Of 248 articles, 5 met inclusion
criteria. The results have demonstrated both HIV-1 RNA and CD4 cells count were
statistically enhanced in initiation stage. However eGFR improved in both
adolescents who were switched to tenofovir alafemide contained regimens and
those on initiation stage. Besides tenofovir alafemide based regimens have
shown good pharmacokinetics, it has improved BMD and the sides effects were
minimized in adolescents.
Conclusion: Based on the results, tenofovir
alafemide based regimens could be efficient in ART initiation in adolescents.
Therefore, this review should be taken in a context of limitations because of
low sample sizes studies.
Keywords: Tenofovir alafenamide, Adolescents, HIV
INTRODUCTION
Adolescents and young people represent a growing share of people living
with HIV worldwide [1]. In 2017, 590,000 young people between the ages of 15 to
24 were diagnosed infected with HIV, of whom 250,000 of them were adolescents
between the ages of 15 and 19 [1]. To compound this, most recent data indicate
that only 23% of adolescent girls and 17% of adolescent boys aged 15-19 in
Eastern and Southern Africa which are the region most affected by HIV [1].
Despite the increasing access to ART, numerous studies have demonstrated
suboptimal levels of viral suppression in different populations in many
low-resource settings [2,3]. In particular, adolescents living with HIV tend to
experience worse immunological and viral suppression outcomes compared to
adults [3-5], which in turn contributes to their higher mortality [3,6,7]. The
current low rates of HIV diagnosis and treatment initiation among adolescents
and young people ages 15-24 continues to present a significant challenge to the
epidemic control of HIV [8]. With a ‘business as usual’ approach to HIV testing
and linkage to treatment, new infections among adolescents and youth will
likely increase, with the burden compounded by the increasing number of youth
in Africa, expected to reach 293 million by 2025 [8]. In fact, adherence to
antiretroviral therapy (ART) can be challenging for adolescents [9-11] and
then, poor adherence may increase their risk of drug resistance and virological
failure [11]. Maintaining medication adherence is vital to ensuring that
adolescents living with HIV/AIDS receive the benefits of antiretroviral therapy
(ART), although this group faces unique challenges to adherence [12]. Relevant
studies revealed few consistent relationships between measured factors and
adherence while highlighting potentially important themes for ART adherence
including the impact of:
1.
Adolescent factors such as gender and knowledge of sero-status,
2.
Family structure,
3.
The burdensome ART regimens, route of administration, and attitudes
about medication, and
4.
Health care and environmental factors, such as rural versus urban
location and missed clinic appointments [12]. This is why single-tablet,
once-daily HIV-treatment regimens with proven efficacy, effectiveness, safety
and good pharmacokinetics might address some issue of the adherence challenges
in adolescents.
Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that is
converted intracellularly to the active form; the resulting concentrations of
tenofovir diphosphate in circulating lymphocytes are higher than those achieved
with tenofovir disoproxil fumarate (TDF). TAF has a similar antiviral efficacy
to TDF at a lower dose, resulting in 91% lower plasma tenofovir exposures [13].
Additionally, TAF results in roughly four times higher intracellular
concentrations of the active metabolite tenofovir-diphosphate compared with
TDF, allowing for much lower doses of TAF versus TDF.11 Because of TAF’s
reduced dose and the improved stability, plasma exposure of tenofovir is 90%
lower with TAF than with TDF, which is believed to reduce the risk of renal and
bone toxicity [14]. TAF has favorable pharmacokinetic characteristics that
offer the potential for a better safety profile than TDF and then it may be
used in children and adolescents. Studies have shown that more than 90% of
patients receiving TAF had virological suppression at week 48, but renal and
bone abnormalities were significantly reduced in patients allocated to TAF
compared with those allocated to TDF [14,15]. A recent review demonstrated that
Evidence for the benefit of TAF over TDF in reducing HIV-RNA and HBV DNA,
increasing CD4 cells, preventing CKDs and loss of bone mineral density should
be recommended in HIV or/and Hepatitis B therapy and preventing TDF related
toxicity [16].
The switch to TAF also resulted in improvements in renal function,
including decreases in serum creatinine (those switching from a boosted
regimen), decreases in dipstick proteinuria, decreases in quantitative tests of
total urine protein, and total urine albumin, decreases in specific proximal
renal tubular proteins, and improvements in tests of proximal renal tubular
function (fractional excretion of uric acid, fractional excretion of phosphate,
and renal tubular maximum reabsorption rate of phosphate to the glomerular
filtration rate). Proteinuria, albuminuria, and specific proximal tubular
proteinuria have been shown to increase risk of mortality or cardiovascular
events in both the general population and in HIV-1 infected individuals
[15,17,18]. Several studies on TAF based regimens have been conducted in
adults, however data are scared in adolescents and this is the first review in
this field that has conducted in this adolescents HIV infected.
METHODS
The review protocol was registered with international prospective
register of systematic reviews (PROSPERO) (identification number:
CRD42017070486). This protocol could be found online at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017070486
Electronic search
We conducted an electronic search on CENTRAL (Cochrane Central Register
of Controlled Trials), Scopus, Web of science, EMBASE, PubMed, CINAHL and
MEDLINE. Additionally, HIV conferences web sites such as the Conference on
Retroviruses and Opportunistic Infections (CROI), the International AIDS
Conference (IAC), and the International AIDS Society Conference on HIV
Pathogenesis, Treatment and Prevention (IAS) The following search strategy was
used: HIV explode all trees AND (HIV OR HIV-1* OR HIV-2* OR HIV1 OR HIV2 OR HIV
infect* OR human immunodeficiency virus OR human immune-deficiency virus OR
human immuno-deficiency virus OR human immun* deficiency virus OR acquired
immunodeficiency syndrome) AND (Adolescents OR young adults OR teenages) AND
(Tenofovir alafenamide OR tenofovir prodrug OR TAF OR GENVOYA OR DESCOVY®)
AND (Randomized controlled trial) OR (controlled clinical trial) OR (randomized
controlled trials) OR (random allocation) OR (double-blind method) OR
(single-blind method) OR (clinical trial) OR (trial) OR (clinical trials) OR
(clinical trial) OR (singl* OR doubl*) OR (trebl* OR tripl*) AND (mask* OR
blind*) OR (placebos) OR (placebo*) OR (random*). We identified works published
through October 11, 2018. Inclusion criteria were focus on the following:
1.
Average age 6 to 18,
2.
HIV positive,
3.
On or initiating ART,
4.
ART safety
5.
Reported adherence, viral load and/or CD4 count and eGFR creatinine
outcomes,
6.
Randomized controlled trial (RCT) or trials.
Selection of
articles for review
Data extraction
Each article that met selection criteria was critically appraised for
baseline characteristics of the population included in the research (e.g. age,
sample size, viral load, CD4 count, eGFR, weight and ART regimens), study
design (e.g. Phase 2/3, open-label, multicenter, multi-cohort, single-arm
study), intervention characteristics/adherence strategies in treatment
condition (e.g. TAF contained regimen, duration, dosage and targets), outcomes
measured (HIV-1 RNA, CD4, eGFR, changes in bone mineral density,
pharmacokinetics, adverse events and adherence), methodology for and frequency
of outcomes measurement, overall outcome of evaluation as reported in article.
Those information were extracted by two authors (JT and VK) and recorded in an excel
worksheet database. Additionally, the risk of bias was assessed in each study
and reported in the excel worksheet.
Data synthesis
In on hand, meta-analysis was undertaken for studies with less
diversity. The baseline characteristics were roughly considered when we
conducted data synthesis. We reported binary outcome (HIV-1 RNA) by using the
odds ratio and its 95% CI. And, continuous outcomes (CD4 count and eGFR) were
reported with the mean difference and the 95% CI. We used the Cochrane’s Review
Manager Software (RevMan 2014) to conduct meta-analysis. When interventions and
study populations were sufficiently similar across the different studies, we
pooled the data across studies and estimate summary effect sizes using both
fixed- and random effects models.
GRADE evidence profiles and
summary of findings tables was generated with GRADEpro software. Diversity
between included studies was assessed with the I2 test. The results were
considered as statistically significant when P-value <0.05. In the other hand,
we reported narratively four outcomes (any AE, serious AE, ART adherence,
Changes in Bone Mineral Density (BMD) and pharmacokinetics (PK) parameter. Data
extracted from each trial were summarized and iteratively reviewed by both
authors (JT and VT) to identify common themes and limitations in the current
evidence base.
RESULTS
Populations
Study designs
This review included 2 trials with phase 2/3, open-label, multicenter,
multi-cohort, single-arm study, an open-label, single-arm, two-part trial,
Phase 2/3, single-arm, open-label and a two-part study. Most of the
interventions conducted repeated measures from baseline, generally including 2,
4, 8, 16 and 24 weeks assessments of outcomes. Only one trial measured the
outcomes until 48 weeks.
Interventions
Interventions and the length of interventions incorporated in different
studies varied, even though all trials encompassed TAF. FTC/TAF 200/10 mg qd
with boosted or 200/25 mg qd with unboosted 3rd ARVs for 24 weeks[19], 150 mg
elvitegravir, 150 mg cobicistat, 200 mgemtricitabine, and 10 mg tenofovir
alafenamide for 48 weeks [11]. E/C/F/TAF for 24 weeks [20] and
Bictegravir/F/TAF for 24 weeks [21] were different TAF contained regimens
included in this study.
Outcomes
Meta-analysis
HIV1-RNA<50
copies/ml: 2 trials with
HIV1-RNA>10000 copies/ml in the baseline were included. From 24 to 48 weeks,
the random effects meta-analysis of HIV-infected adolescents from the baseline
to 24 to 48 weeks on TAF contained regimens reduced the HIV1-RNA by 20% with
95% CI 10% to 70%. This result was statistically significant with p-value
<0.00001 (Figure 2).
HIV1-RNA<50
copies/ml: 3
trials included HIV1-RNA<50 copies/ml in the baseline. In fact, Kizito [20] included
both adolescents with HIV1-RNA<50 and >10000 copies/ml. The effect of TAF
contained regimens from the baseline to 24 weeks was not statistically
significant with OR 1.07 (95% CI 0.21 to 5.45, 7 studies, P=0.93) (Figure 3).
CD4 cells count/µL: 2 studies included CD4 count cells
and HIV1-RNA baseline characteristics were quite similar [19,21]. At 24 weeks,
TAF contained regimens improved the mean difference of CD4 count cells (MD
115.07 95% CI 22.64 to 207.50, P-value=0.01) (Figure 4).
CD4 Cells count/µL: 2 studies included CD4 count cells
and HIV1-RNA baseline characteristics were quite similar [11,20]. From 24 to 48
weeks, TAF contained regimens decreased the mean difference of CD4 count cells
(MD -161.36 95% CI -279.15 to -43.58, P-value=0.007) (Figure 5).
eGFR ml/min/1.73 m2
Schwartz:
For 4 trials included in estimated glomerular filtration rate from the baseline
and 24 weeks post TAF contained regimens. The baseline characteristics were
homogenous enough and then, we conducted meta-analysis. The inverse variance
and the random-effects meta-analysis of glomerular filtration rate yielded a
pooled MD estimate of 16.10 (95% CI 8.41to 23.80, P<0.01) with I2=72% (Figure 6).
DISCUSSION
This review was conducted in a population aged from 6 to 18 years. In
fact, tenofovir alafenamide regimens in this range of age are a new approach of
HIV-1 treatment. Until now, they are not many trials undertaken in this field.
Nonetheless, our review provides further evidence that TAF based regimens could
be a new perspective of HIV treatment from 6 to 18 years old. Improvements in
HIV-1 RNA, CD4 count, eGFR and BMD have proven the efficacy of TAF based
regimens in adolescents after 24 to 48 weeks of treatment. Additionally, the AE
and serious AE were minimized with low percent. Lastly, AUCtau was quite
similar to adults in two studies. This suggests that TAF contained regimens
have same pharmacokinetics both in adolescents and adults. The results were
mostly superior when the baseline characteristics were adolescents in ART initiation
stage. We did not find any statistical significant results in adolescents
switched from other ARV regimens to TAF based regimens. This may induce
immunological failure. This is why, in clinical practice, we suggest that TAF
based regimens should be switched with precaution in adolescents. Comparatively
to adults, switching to ART regimens to TAF based regimens has demonstrated
many benefits in HIV outcomes [16].
This present review should be taken in a context of several
limitations. As the fact, the study was graded from moderate to low evidence.
In fact, the sample sizes were low in all trials, resulting to low powers.
Furthermore, the variations between the baseline characteristics and different
TAF contained regimens included in trials implied indirectness between studies.
Besides, the applicability could face some challenges as all studies were
conducted in US. Knowing Sub Saharan African has the highest HIV adolescents
HIV prevalence, and this rate is expected to increase in the future even though,
other HIV infected class group is decreasing. Thus, large trials in this field
should be conducted in Sub Saharan African so that TAF based regimens may find
its clear applicability in adolescents.
CONCLUSION
In summary, TAF based regimens could play an important role in ART
initiation, as first line in adolescents. Those regimens have demonstrated
their efficacy in improving HIV outcomes in adolescents. But, large trials
should be done to prove long term clinical significance of TAF based regimens
in adolescents and also, to increase the study powers.
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