Virological
response rates were excellent among patients receiving second-line antiretroviral
therapy (ART) based on dolutegravir, even when regimens included a nucleoside/nucleotide
reverse transcriptase inhibitor (NRTI) to which there was pre-existing
resistance, according to research presented to the Conference on Retroviruses and Opportunistic Infections (CROI 2019).

The research was
conducted in middle- and low-income countries and was designed to help guide
second-line treatment choices.

Regardless of the
presence of background NRTI resistance, approximately 85% of people taking dolutegravir
had an undetectable viral load at the end of follow-up, including patients
who took emtricitabine or lamivudine despite having resistance to
these drugs.

The investigators
believe their findings support interim World Health Organization (WHO) guidance
to use dolutegravir and two NRTIs in second-line ART.

An increasing
proportion of people in low- and middle-income countries are experiencing the virological
failure of their first-line ART regimens and therefore require second-line
treatments. Recommended first-line treatment is based on a non-nucleoside
reverse transcriptase inhibitor (NNRTI), usually efavirenz. Until recently,
WHO guidance recommended the protease inhibitor lopinavir/ritonavir for
second-line treatment.

Second-line NRTIs are
selected using an algorithm that takes into account previous treatment history.
In essence, patients whose first-line treatment included tenofovir with
emtricitabine or lamivudine switch to zidovudine with lamivudine, with patients
who took first-line zidovudine and lamivudine changing to tenofovir with
emtricitabine or lamivudine.

The DAWNING study was
designed to establish whether a regimen based on the integrase inhibitor dolutegravir
was non-inferior to lopinavir/ritonavir in second-line treatment. Forty-eight
week follow-up data showed the superiority of the integrase inhibitor, with 84%
of dolutegravir patients having an undetectable viral load (below 50 copies/ml)
at the end of follow-up, compared to 70% of individuals in the
lopinavir/ritonavir study arm.

Drug resistance is common
among patients experiencing the failure of their first-line therapy, especially
to the key NRTI drugs emtricitabine, lamivudine, tenofovir and zidovudine. It
is often necessary to recycle drugs from a failed first-line regimen in
subsequent therapy. Investigators from the DAWNING study therefore examined
virological outcomes for different NRTI combinations in the presence of NRTI
resistance.

Participants were
screened for drug resistance at enrolment and were only recruited to the study if
their HIV was sensitive to at least one NRTI.

A total of 624
participants were randomised. Approximately a third were women and a fifth had a
viral load above 100,000 copies/ml. As regards first-line therapy, 78% of
participants received an efavirenz-based regimen and previous tenofovir and
zidovudine therapy was documented in 59% and 29% of individuals, respectively.

Drug resistance was highly
prevalent, with 90% having resistance to some NRTIs. This included the M184V/I mutation which confers resistance to emtricitabine and lamivudine,
present in approximately 82% of patients. The K65R mutation, associated with
tenofovir resistance, was detected in 29% of individuals and a quarter of
individuals had resistance to zidovudine.

The most common
background NRTI regimens used for second-line therapy were zidovudine and
lamivudine (41%) and tenofovir with emtricitabine or lamivudine (42%). Just
over half (56%) received an NRTI combination consistent with WHO algorithms.

Over two-thirds of
patients with the M184V/I mutation continued to receive emtricitabine or
lamivudine (71% with dolutegravir; 67% with lopinavir/ritonavir).

Virological outcomes
were not affected by the presence of M184V.

Rates of virological
suppression at week 48 among patients with baseline M184V were identical to
those observed in the study overall (84% dolutegravir vs 72%
lopnavir/ritonavir). This was also the case when second-line therapy included
emtricitabine or lamivudine (85% dolutegravir vs 72% lopinavir/ritonavir).

Outcomes
were also unaffected by the presence of background tenofovir resistance (viral suppression:
84% dolutegravir vs 74% lopinavir/ritonavir) or resistance to zidovudine
(undetectable at week 48: 87% dolutegravir vs 75% lopinavir/ritonavir).

The presence of
emtricitabine or lamivudine resistance at baseline did not increase the risk of
virological failure during second-line therapy, even when these drugs continued
to be used. No new NRTI-associated resistance mutations emerged in the
dolutegravir-treated patients with confirmed virological failure, though two
individuals did have emergent integrase inhibitor resistance.

The investigators
therefore conclude that patients treated with dolutegravir had high virological
response rates, regardless of pre-existing resistance to a drug used in the
NRTI backbone, including when emtricitabine or lamivudine were used in the
presence of M184V/I. The data support interim WHO guidance for the use of
dolutegravir and two NRTIs as second-line ART in resource-limited settings.