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 at Viiv Healthcare and GlaxoSmithKline believe their findings support interim World Health Organisation (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 – 48-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.
DAWNING is a non-inferiority study comparing dolutegravir (DTG) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) with lopinavir/ritonavir (LPV/r) + 2 NRTIs in HIV-1 infected adults failing first-line therapy (HIV-1 RNA ≥400 copies [c]/mL) of a non-nucleoside reverse transcriptase inhibitor + 2 NRTIs.
Subjects were randomised (1:1, stratified by Screening HIV-1 RNA and number of fully active NRTIs) to 52 weeks of open-label treatment with DTG or LPV/r + 2 investigator-selected NRTIs, including at least one fully active NRTI based on Screening resistance testing. The primary endpoint was the proportion of subjects with HIV 1 RNA <50 c/mL at Week 48 (Snapshot algorithm). Post-hoc efficacy analyses were performed based on baseline NRTI resistance profile and NRTI use in the second-line background regimen (BR).
Of 624 subjects randomised and treated, 499 (80%) received <2 active NRTIs at baseline. Overall, 84% (261/312) of subjects on DTG versus 70% (219/312) on LPV/r achieved HIV-1 RNA <50 c/mL at Week 48 (adjusted difference 13.8%, 95% CI: 7.3% to 20.3%, p<0.001 for superiority). This difference was consistent regardless of the use of <2 or 2 fully active NRTIs in the BR. NRTI resistance was present in 561 subjects (90%) at baseline, M184V/I (alone or plus additional NRTI resistance-associated mutations [RAMs]) in 513 (82%), K65R in 187 (30%), and ≥1 thymidine-analogue mutations (TAMs) in 152 subjects (24%). Of subjects with M184V/I alone or plus ≥1 NRTI RAMs, 430 subjects (84%) took lamivudine (3TC) or emtricitabine (FTC) as part of their BR. Tenofovir disoproxil fumarate (TDF) was included in BR in the presence of K65R in 15 subjects while 86 subjects with 1 or more TAMs took zidovudine (AZT). Among subjects receiving 3TC or FTC in the presence of M184V/I, 85% (187/220) of subjects on DTG versus 72% (152/210) on LPV/r had HIV-1 RNA <50 c/mL at Week 48 (difference 12.6%, 95% CI: 4.9% to 20.3%). High responses were also observed in the DTG arm, when AZT or TDF were included in the BR in the presence of TAMs or K65R, respectively; however, subject numbers in these subgroups were small (Table 1).
In DAWNING, response rates were high in subjects receiving DTG+2NRTIs regardless of pre-existing resistance to one of the NRTIs in the BR, including in subjects using 3TC or FTC in the presence of M184V/I. In WHO interim guidance on HIV treatment, DTG+2NRTIs is now a recommended second-line treatment option for patients failing an NNRTI-based regimen.
Dannae Brown, Ruolan Wang, Mark Underwood, Judy Hopking, Maria Claudia Nascimento, Michael Aboud, Jörg Sievers