HIV Specialist - March 2021 - 52

CLIN ICAL RESEARCH

UPDATE

JEFFREY T. KIRCHNER, DO, AAHIVS

Outgoing AAHIVM Chief Medical Officer

Beginning 2021, Dr. Carolyn Chu assumed the role of Chief Medical Officer (CMO) for the Academy.
We would like to thank retiring CMO Dr. Jeffrey Kirchner for his guidance and contribution over the years!
This following Clinical Research Update consists of literature reviewed by both Dr. Kirchner and Dr. Chu.
Pilkington, V. et al. Tenofovir alafenamide vs. tenofovir disoproxil
fumarate: an updated meta-analysis of 14,894 patients across 14
trials. AIDS 2020, 34:2259-2268

Lake JE et al. Risk Factors for Weight Gain Following Switch to Integrase
Inhibitor-Based Antiretroviral Therapy. Clin Infect Dis. 2020 Dec 3;71(9):
e471-e477. doi: 10.1093/cid/ciaa177. PMID: 32099991.

Tenofovir disoproxil fumarate (TDF) along with the newer
formulation tenofovir alafenamide (TAF) are both highly effective
treatments for HIV. There are concerns regarding the impact of TDF
on bone mineral density and risk of nephrotoxicity. TAF produces
higher intracellular concentrations but is thought safer due to lower
plasma concentrations of tenofovir. In addition, when ritonavir or
cobicistat are used as part of an ART regimen, they increase the
concentration of TDF. This study is an update of a prior systematic review of 14 clinical trials looking at efficacy and safety of TDF vs TAF
when used with and without boosted co-formulations. Differences in
efficacy were based specifically on viral suppression. Safety endpoints
included grades 3-4 adverse events and related drug discontinuation.
Lastly, specific markers of bone and renal function were assessed.
There was a statistically significant difference in efficacy seen in the
boosted subgroup in favor of TAF but the difference was small (94%
vs. 92%   HIV RNA < 50 copies/mL) and there was no difference in the
unboosted subgroup (89% vs 90% < 50 copies/mL). For renal outcome
there was no difference in renal tubular events between patients
taking TAF and TDF or the number of discontinuations due to renal
adverse events. Overall, there were no significant differences between
TAF and TDF for any of the key safety endpoints analyzed which
included both bone markers and renal tubular events.

The majority of persons with HIV (PWH) are now being treated
with integrase strand transfer inhibitors (INSTIs) as part of their
ART regimens. Although highly effective, this class of drugs has been
increasingly associated with excess weight gain. This study looked at
weight gain in PWH who were virologically suppressed then switched
to an INSTI - most from a PI or NNRTI. The authors included 691 patients (81% male, 50% non-white, median age 50 years) from two longitudinal ACTG cohorts who were in care from 1997-2017. The study
adjusted for various factors including age, sex, race, baseline BMI,
smoking, diabetes, nadir and current CD4+ count, and follow-up time
with suppressed HIV-RNA. Weight and waist circumference change
before and after ART switch were assessed at various time intervals.
Looking at those with undetectable VLs at the time of changing to
an INSTI, Black people, women, and persons ≥60 years of age had
significantly greater weight gain in the two years after changing to an
INSTI. In adjusted models, women who were of White or Black race,
age > 60 years, and BMI of 30 kg/m2 or greater were associated with
significantly greater annualized weight gain (0.9 - 2.0 kg/yr.). With
men, age > 60 was the greatest risk factor for weight gain (0.8 kg/yr.)
after switching to an INSTI. Dolutegravir appeared to be associated
with the greatest increase in yearly weight gain and raltegravir the
least. Concomitant increases seen in waist circumference suggest
that this weight gain is associated with an increase in fat mass.

DR. JEFFREY KIRCHNER'S COMMENTARY:

These studies included almost 15,000 patients with about 24,000 patient-years of follow up. Across all main safety endpoints, no significant
differences between TAF and TDF were seen. Although there were some
differences in patients on boosted regimens, these are now less commonly used with the majority of patients now taking INSTIs.  Regarding
the concern for renal tubular events, there were only 3 across these studies and the overall risk difference was zero percent. Another point of this
TDF vs TAF discussion should include lipid abnormalities and weight
gain seen with TAF.  For the majority of patients who need tenofovir as
part of their ART regimen or for PrEP these data support TDF as a safe,
effective, and more affordable option. Generic " Truvada " (tenofovir disoproxil fumarate/emtricitabine) became available in the U.S. in October
although the current retail price is about $1500 which is not significantly
lower than the branded formulation.

52 

MARCH 2021   HIVSPECIALIST  WWW.AAHIVM.ORG

DR. JEFFREY KIRCHNER'S COMMENTARY:

This study adds to the data from other clinical trials and observational cohorts which have found INSTIs cause weight gain in many patients. The
mechanism(s) remains uncertain and it is not clear if this is a class effect.
This study also saw worsening in lipid and glucose levels among those
with weight gain. When raltegravir was approved for use in 2007 and
dolutegravir in 2013 the issue of weight gain was thought to be a " return
to health " phenomenon. However, with the increased use of INSTIs, this
trend has become more apparent, especially in women. It may be prudent
for providers to risk-stratify certain patients who have been stable on a PI
or NNRTI- based regimen before deciding to change to an INSTI. In addition, nutritional assessment and counseling regarding diet and exercise
for PWH should be part of every clinical visit to help mitigate weight gain
and adverse metabolic effects seen with INSTIs and other antivirals.


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HIV Specialist - March 2021

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