Cardiovascular Diseases Clinical Trial
Official title:
Assessing Virologic Success and Metabolic Changes in Patients Switching From a TDF to TAF Containing Antiretroviral Therapy Regimen
Switching patients with HIV infection from tenofovir disoproxil fumarate (TDF) to a tenofovir alafenamide (TAF) based drug regimen can provide many safety benefits including preserving bone mineral density and kidney function. This study will examine metabolic changes that patients may encounter due to the switch in medication regimens and the maintenance of viral suppression.
Many providers of HIV medicine are switching patients from TDF to TAF containing ART regimens
for safety reasons including significant improvements in bone health and kidney function that
have been demonstrated in clinical trials.1-3 Multiple studies have evaluated the efficacy
and safety of switching from TDF to TAF based regimens, but most allowed other components of
the ART regimen to change in addition to TDF which may confound study results. For example, a
recent meta-analysis demonstrated that TDF accompanied by ritonavir or cobicistat boosting
was associated with higher risks of bone and renal adverse events and lower rates of
virologic suppression in comparison to TAF. In contrast, when ritonavir and cobicistat were
not used, there were not efficacy differences and only marginal safety differences between
tenofovir agents.4 Additionally, measures of treatment success aside from maintaining
virologic suppression including requirements for additional regimen changes due to
tolerability, cost and access have not been formally evaluated. Furthermore, aside from renal
function and bone health, comprehensive evaluations of metabolic changes following TDF to TAF
switches have not been performed. Specifically, alterations in weight, body mass index, and
glycemic control have not been studied in patients switching from TDF to TAF in clinical
trials and changes in cholesterol and cardiovascular disease risk have had only minimal
assessment.5 Weight gain most commonly occurs following the initiation of ART in treatment
naïve patients, but has been noted in virologically suppressed patients making certain ART
changes. Weight gain following TDF to TAF switches was not measured in clinical trials, but
has been noted anecdotally within our clinic population and is believed to warrant additional
investigation.
In terms of cholesterol and cardiovascular disease risk, previous clinical trials have
identified differences in serum cholesterol measurements in patients receiving TDF and TAF,
but formal assessments of the resulting potential differences in cardiovascular disease risk
have not occurred:
- The first trial was a phase II, randomized, double-blind, double-dummy, multi-center
study that compared the safety and efficacy of TAF and TDF.6 The active-controlled arm
received elvitegravir 150mg, cobicistat 150mg, emtricitabine 200mg, and TDF 200mg
(E/C/F/TDF). The study arm received elvitegravir, cobicistat, emtricitabine, and TAF
(E/C/F/TAF). Subjects receiving E/C/F/TAF experienced more Grade 3 or 4 increases in
low-density lipoprotein cholesterol (LDL) (9% vs. 3%). However, the median increase in
fasting LDL was similar between groups (+17 vs. +11 mg/dL, p=0.11). Significant
differences were observed for total cholesterol (+30 vs +17 mg/dL, p=0.007) and
high-density lipoprotein (HDL) (+7 vs +3 mg/dL, p=0.023), but the total cholesterol:HDL
ratio remained similar for both treatment arms.
- A second phase II, randomized, double-blind, double-dummy multicenter trial compared
darunavir 800mg/cobicistat 150mg/emtricitabine 200mg/TAF 10mg (D/C/F/TAF) to darunavir
800mg, cobicistat 150mg, and co-formulated emtricitabine 200mg/TDF 300mg (D+C+F/TDF).7
More than 230 subjects were screened, and 153 were randomized 2:1 to receive either
D/C/F/TAF (n=103) or D+C+F/TDF (n=50). The primary efficacy outcome was virologic
suppression at weeks 24 and 48. Safety and tolerability were assessed through renal,
bone, and metabolic measurements. At the end of the trial, fasting lipid changes from
baseline were greater in the TAF group at week 48 for total cholesterol (+40 vs. +5
mg/dL, p<0.001), LDL (+26 vs. +4 mg/dL, p<0.001), HDL (+7 vs. +3 mg/dL, p=0.009), and
triglycerides (+29 vs. -5 mg/dL, p=0.007). The total change in total cholesterol:HDL
ratio was again comparable between groups (0 vs. -0.2, p=0.15).
- A randomized, active-controlled, open-label study assessed the safety and efficacy of
switching virologically suppressed HIV-infected patients from their TDF-based regimen to
E/C/F/TAF.8 The study assessed 601 patients who were randomized 2:1 to receiving
E/C/F/TAF (n=402) or maintain their current regimen of FTC/TDF plus atazanavir boosted
with cobicistat or ritonavir (n=199). Again, patients receiving E/C/F/TAF had
statistically significant median increases in total cholesterol (+23 vs. + 5 mg/dL,
p<0.001) and in LDL (+9 vs -1 mg/dL, p<0.001). Additionally, the proportion of patients
who initiated lipid-modifying agents was greater in the E/C/F/TAF group but was not
statistically significant (8.5% vs. 5%, p=0.14).
In each trial, it is evident that patients receiving TAF have greater elevations in serum
cholesterol levels in comparison to TDF. However, the majority of trials also note that the
total cholesterol:HDL ratio appears to be similar among TDF and TAF recipients. This value
has been used by investigators to suggest that differences in cardiovascular disease risk are
unlikely to be present among TDF and TAF recipients despite considerable increases in total
cholesterol, LDL and triglycerides levels in TAF recipients. The current ACC/AHA guidelines
on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in
adults, do not recommend the use of the total cholesterol:HDL ratio to determine risk for
cardiovascular disease.9 Rather, they recommend using the atherosclerotic cardiovascular
disease (ASCVD) scoring system, which incorporates cholesterol values in additional to other
factors that influence cardiovascular disease risk. This level of cardiovascular disease risk
assessment has not been performed and assessed for TAF and TDF in clinical trials.
The current study is significant because it will add to the current clinical knowledge of TAF
in terms of efficacy, safety and tolerability. It will evaluate treatment success when
patients have isolated TDF to TAF switches by analyzing virologic and immunologic responses
in addition to the need for subsequent regimen changes due to poor tolerability, cost
restriction or access limitations. This study will also provide a comprehensive assessment of
potential metabolic changes following isolated TDF to TAF changes. This includes changes in
the incidence of metabolic syndrome, alterations in cholesterol and cardiovascular disease
risk, changes in weight and body mass index (BMI), and changes in glycemic control and renal
function.
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