The efficacy of first-line antiretroviral
therapy (ART) continues to improve, according to an analysis of outcomes in
78,000 people in 181 studies, published in AIDS by Professor Andrew Carr of St Vincent’s Hospital in Sydney and colleagues. Over three-quarters of people who
started treatment between 2011 and 2015 were still on their first regimen and
had an undetectable viral load three years later.

Outcomes in 2011-2015 were significantly
better than those recorded in people starting therapy between 2006 and 2010,
which in turn were an improvement on results seen in people who started treatment
between 2001 and 2005 and between 1994 and 2000. Moreover, there was a steady
and sustained fall in the proportion of individuals who stopped their first line
regimen because of side-effects or due to personal choice. However, the
proportion of people stopping because of virological failure flatlined at
approximately 5%.

But good as these post-2011 outcomes are, the
investigators believe that it’s still possible to do better. They note that even with the most modern ART
regimens, a fifth of people experience treatment failure (stop or change their treatment regimen, for any reason) within three years
of starting HIV therapy.

The study contained some pointers about which
regimens are likely to have the greatest success: people starting treatment with tenofovir
(either TDF or TAF)/emtricitabine and integrase inhibitors were each more likely to remain on first-line treatment over three years.
Other findings showed that baseline resistance testing and once-daily dosing
were also predictors of long-term treatment success.

findings of especial importance are highlighted by the authors:

  • Although initial ART efficacy continues to improve, more than 20% of post-2010
    patients on integrase inhibitor-based ART failed over 144 weeks.
  • Phase
    3 studies overestimate ‘real world efficacy’.
  • There are few routinely
    collected patient/clinical characteristics that predicted ART failure.
  • The rate of ART cessation for virological failure does not appear to have
    declined in over 20 years.
  • Length of study follow-up remains too short.

treatment guidelines make recommendations for the selection of first-line
therapy based on the sequential review of individual, randomised studies. To
obtain a more accurate impression of the efficacy and durability of first-line
ART, Carr and colleagues conducted a systematic review of
outcomes reported in 181 studies involving 77,999 people.

was from 1994 to 2017. A similar exercise conducted in 2008 showed that therapy
based on tenfovir/emtricitabine was more effective than treatment based on
abacavir/lamivudine when used with either a boosted protease inhibitor or a
non-nucleoside reverse transcriptase inhibitor (NNRTI). An update in 2012
showed that treatment based on an integrase inhibitor was superior to treatment
including either a boosted protease inhibitor or NNRTI. It also showed that differences in
outcomes according to baseline viral load were smaller for integrase
inhibitors than boosted protease inhibitors and NNRTIs.

randomised studies and prospective cohort studies involving people starting
first-line ART were included. The primary outcome was treatment efficacy at
weeks 48, 96 and 114, defined as an undetectable viral load reported on an
intent-to-treat basis – changing treatment for any reason was therefore regarded
as failure. 

the patients had a mean age at baseline of 37 years, 75% were men and 61% were
white. At baseline, mean CD4 cell count and viral load were 262 cells/mm3
and 63,000 copies/ml, respectively. Patients took a mean of 4.8 pills in 1.6 doses daily.

main treatment backbones were tenofovir/emtricitabine (44%), thymidine-based
(28%) and abacavir/lamivudine (10%). The principal third drugs were NNRTIs (50%), boosted protease inhibitors (28%) and integrase inhibitors (12%).

at week 48 were reported for almost all the participants. Mean efficacy was 71%. It
improved significantly over time, from 57% in studies starting between 1994 and
2000, to 69% for people initiating therapy between 2001 and 2005, to 77% for
individuals in 2006 to 2010 studies and to 84% in post-2010 studies.

at week 96 was reported in 41% of studies with an overall rate of 64%. It
increased from 52% for pre-2000 studies, to 61% for 2001 to 2005 studies, to 65%
for 2006 to 2010 studies and to 80% in studies recruiting between 2011 and

14% of studies reported on week 144 outcomes and these found an overall
efficacy of 62%. Once again, these improved over time. Efficacy rates for
the four time periods were 45%, 55%, 72% and 77%,

of efficacy included choice of drug, with outcomes favouring both tenofovir/emtricibine and integrase inhibitors. Several dosing characteristics
were also associated with greater efficacy: once-daily at week 48; dosing without
food restrictions at week 96; and fewer pills at weeks 96 and 144.

type of ART used, in particular the use of an integrase inhibitor as the anchor
drug and the use of a once-daily NRTI [nucleoside reverse transcriptase inhibitor] backbone, had a far greater impact on
efficacy than did patient characteristics,” comment the authors. “The number of
doses per day had a stronger relationship with efficacy than whether ART was
taken as one pill or more than one pill per day.”

resistance testing (p = 0.0003) and higher baseline CD4 cell count (p = 0.0003)
were also predictors of greater efficacy.

in post-licensing and “real world” studies were progressively worse than those
observed in phase three clinical trials.

outcomes were about 10% better with regimens recommended in US Department of
Health and Social Services guidelines, compared to World Health Organization recommended regimens.

However, almost
30% of people with 144 weeks of follow-up stopped their initial ART regimen
prematurely. The most common reasons were patient choice (13%), side-effects
(9%) and virological failure (5%). Most of these cessations happened by week
48. The proportion of early treatment cessations due to patient choice or
side-effects was lower in studies conducted post-2010 compared to other time
periods. However, the proportion of people stopping therapy because of
virological failure remained stable at approximately 5%.

ART efficacy continues to improve, but more than 20% of post-2010 patients
failed over 3 years,” conclude the investigators. “Real-world efficacy is lower
than in phase 3 trials. Guidelines should list non-integrase inhibitor-based
initial ART as nonpreferred. Strategies are needed to improve access to pre-ART
genotyping and to increase early initiation of once-daily ART.”