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Dual antiretroviral regimen maintains durable HIV suppression after switch
Liz Highleyman, 2017-02-15 05:30:00
People who switched from standard antiretroviral
therapy to a two-drug regimen of dolutegravir (Tivicay) plus rilpivirine (Edurant) were able to maintain an undetectable viral load for 48 weeks in a pair
of late-stage clinical trials, according to a late-breaking report on Wednesday
at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in
As long as people with HIV face the prospect of
lifelong treatment, researchers will continue to look for antiretroviral
regimens that are easier to take and more affordable, while remaining highly
effective and well tolerated. If this can be accomplished with two instead of
three or more drugs, treatment could be simpler and the cost could be lower.
But simplifying therapy too much raises the risk of treatment failure and drug
Josep Llibre of University Hospital Germans Trias in Barcelona presented findings from the SWORD-1 and -2
trials, which evaluated whether dolutegravir plus rilpivirine
could maintain viral suppression in treatment-experienced people who switched
from a three- or four-drug regimen with undetectable virus.
been a long-term dream to try to find safe strategies that can control the
disease with a reduced number of drugs," Dr Llibre said at a CROI press
ViiV Healthcare's dolutegravir is a potent integrase
inhibitor with a high barrier to resistance, making it a good candidate for
simplified therapy. Janssen's rilpivirine is a well tolerated second-generation
non-nucleoside reverse transcriptase inhibitor (NNRTI).
Prior studies suggested
that this approach is feasible.As reported at the International
AIDS Conference last July, the PADDLE pilot study showed
that a dual regimen of dolutegravir plus the
inexpensive nucleoside reverse transcriptase inhibitor (NRTI)
lamivudine (3TC or Epivir) led to sustained undetectable viral load in most people starting ART for the first time (the
phase 3 GEMINI trial is evaluating this regimen in a larger study). Another small study suggested that dolutegravir alone might be enough to maintain viral
suppression in some highly treatment-experienced patients. Previous studies
looked at monotherapy or dual therapy using boosted protease inhibitors, but these
agents have more side effects and drug-drug interactions than integrase
SWORD-1 and SWORD-2 were identical
multicentre randomised trials with enrolment from Europe, Russia, North and
South America, and Asia. Together the studies included 1024 people with HIV who
had been on standard ART with undetectable viral load (HIV RNA <50
copies/ml) for at least a year - with a median of four years - and had no
history of virological failure or evidence of drug resistance.
More than three-quarters were men, most were white,
the median age was 43 years and the baseline CD4 T-cell count was approximately
600 cells/mm3. At study entry they were on regimens containing at
least three drugs: an integrase inhibitor (20%), NNRTI (54%) or protease
inhibitor (26%) plus two NRTIs; 73% used tenofovir disoproxil fumarate. People
with chronic hepatitis B co-infection were excluded.
Participants in these open-label studies were randomly
assigned (1:1) either to switch to the dual regimen of once-daily dolutegravir
plus rilpivirine or to stay on their current regimen. The primary endpoint was continued
undetectable viral load at 48 weeks.
Most participants in both treatment arms maintained
viral suppression; 95% of people in the dolutegravir plus rilpivirine arm and
95% in the unchanged regimen arm had HIV RNA below 50 copies/ml at 48 weeks,
showing that switching to the dual regimen was non-inferior to staying on
Virological failure was rare, <1% in the dual
therapy arm and 1% in the unchanged regimen arm. Among those who underwent
viral sequencing, one person taking dolutegravir plus rilpivirine had a NNRTI
resistance mutation, but no one in either arm had integrase resistance
Treatment was generally safe and well tolerated. No
unexpected drug-related adverse events were reported. Serious adverse events
were comparable in both arms, but discontinuations due to adverse events occurred
more often in the dual therapy arm (3% vs <1%). The most common adverse events were
nasopharyngitis (inflammation of the nose and throat), headache, upper
respiratory tract infections and diarrhoea. Although the frequency of more
severe (grade 3-4) adverse events did not differ between the two arms, there
were more mild to moderate (grade 1-2) events reported in the dolutegravir plus
rilpivirine arm (17% vs 2%).
Joseph Eron of the University of North
Carolina at Chapel Hill suggested at the press conference that this may
reflect the fact that people who switch drugs often blame any symptoms on their
new medications, while those who stay on the same treatment might not bother to
report common minor symptoms such as headache or sore throat.
Switching to the dual regimen had a beneficial effect in terms of bone health biomarkers and
a neutral effect on lipids, according to Dr Llibre. The former may be due to
the fact that many people switched away from tenofovir DF, which is known to cause bone
is the first time we can prove [a two-drug regimen] is non-inferior in a
once-daily regimen with no booster, no protease inhibitor and no NRTIs."
Dr Llibre said.
studies are continuing through 148 weeks. A new trial will assess a fixed-dose
coformulation of dolutegravir plus rilpivirine -- described as a very small
pill -- as once-daily single-tablet regimens are now the standard of care for a
majority of people with HIV. This study will enrol some people with
pre-existing drug resistance, to better reflect a 'real world' population.