First-line ART with dolutegravir plus 3TC: 24-week early results

1 December 2015. Related: Conference reports, Antiretrovirals, Treatment strategies, EACS 15 Barcelona 2015.

Simon Collins, HIV i-Base

EACS 2105 also included studies of dolutegravir-based dual therapy.

Early results were presented from an ongoing pilot study using dolutegravir plus lamivudine (3TC) as first-line ART. Participants became undetectable within four weeks and remained suppressed for six months. [1]

These early results from a pre-planned analysis of a secondary endpoint were presented at EACS 2015 by Pedro Cahn from Fundacion HUESPED, Buenos Aires.

This was a single arm, open label study in 20 HIV positive treatment-naive adults. Entry criteria included CD4 count >200 cells/mm3 and viral load <100,000 copies/mL and being HB(s)Ag negative. Dolutegravir (50 mg) and 3TC (300 mg) were taken together, once daily.

Given the preliminary nature of this strategy, the study was carefully designed to ensure that intensive viral monitoring would detect any early signal of sub-optimal therapy.

Viral load was monitored at baseline, at days 2, 4, 7, 19 and 14 and then at weeks 4, 8, 12 and 24. The primary endpoint was viral suppression <50 copies/mL at week 48 (by FDA snapshot ITT analysis). Enrolment was in two stages, dependent on successful viral outcomes at week 8 for the first ten participants, with predetermined discontinuation rules for the study based on suboptimal viral responses.

Median (IQR) approximate baseline characteristics of the 19 men and one woman included age 34 years (IQR: 31 to 43), CD4 count 507 cells/mm3 (IQR: 296 to 517) and viral load 24,000 copies/mL (IQR: 12,000 to 37,000).

By day 14, mean (+/ SD) viral load dropped by 2.54 log/copies/mL (+/– 0.27).

All participants had viral load <50 copies/mL by week 12 that was sustained to week 24.

Although the entry criteria excluded high baseline viral load, four participants had viral load increases to >100,000 copies/mL (range 105,000 to 273,000) between screening and baseline. Although these four people took slightly longer to suppress viral load, 3/4 reached <50 copies by week 4 and the fourth by week 8.

CD4 changes were reported as mean increase of 194 cells/mm3 (+/– 160) by week 12 that remained stable out to week 24.

The only side effects were generally mild with single reports of somnolence, epigastric pain, headache, diarrhoea and nausea (all grade 1) and one report of grade 2 headache. There were no serious side effects or grade 3/4 laboratory abnormalities.

Planned follow up will continue until week 96.

Comment

The inclusion of 20% people during likely primary infection (in this otherwise very well-designed study) could perhaps have been detected with exposure risk history, with or without symptoms. 

However, in a question after the presentation, the results from the four cases >100,000 copies/mL were used to suggest that future studies might not require an upper viral load exclusion criteria.

Clearly these results need to be confirmed in larger randomised studies, several of which are either ongoing or due to start shortly. [2, 3, 4, 5]

Several switch studies in treatment-experienced participants were also presented at EACS with similar virological results  using dolutegravir as monotherapy. [6, 7]

The low toxicity and cost of 3TC has also been used in dual therapy to overcome the lower rates of virological efficacy from studies of boosted-PI monotherapy. The 96-week results of the GARDEL study showed that dual therapy with lopinavir/r plus 3TC was non-inferior to lopinavir/r plus two NRTIs were also reported by Pedro Cahn at EACS 2015. [8]

The data supporting safety for a French study switching people to maintenance therapy with only tenofovir DF/FTC is unclear given the history of early dual-NRTI being suboptimal treatment. [9]

References:

Unless stated otherwise, references are to the programme and abstracts of the 15th European AIDS Conference (EACS), 21-24 October 2015, Barcelona.

http://www.professionalabstracts.com/eacs2015/iplanner

1. Cahn P et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE Trial. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/1.
2. Dolutegravir-based dual therapies in HIV-infected patients with virological suppression (DOLBI). clinicaltrials.gov. NCT02491242.
   https://clinicaltrials.gov/ct2/show/NCT02491242
3. clinicaltrials.gov. NCT02582684. Dolutegravir plus lamivudine dual therapy in treatment naïve HIV-1 patients
   https://clinicaltrials.gov/ct2/show/NCT02582684
4. A trial evaluating maintenance therapy with lamivudine (Epivir) and dolutegravir (Tivicay) in human immunodeficiency virus 1 (HIV-1) infected patients virologically suppressed with triple Highly Active Antiretroviral Therapy (HAART) (ANRS 167 Lamidol). clinicaltrials.gov. NCT02527096.
   https://clinicaltrials.gov/ct2/show/NCT02527096
5. Dolutegravir antiretroviral strategy to promote improvement and reduce drug exposure (ASPIRE). clinicaltrials.gov. NCT02263326.
   https://clinicaltrials.gov/ct2/show/NCT02263326
6. Rojas J et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
7. Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
8. Cahn P et al. Durability of dual therapy (DT) with lopinavir/ritonavir (LPV/r) and lamivudine (3TC) in comparison to standard triple drug therapy (TT): 96-week results of the GARDEL study. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS10/1
9. Trial to evaluate the interest of a reductive anti retroviral strategy using dual therapy inspite of triple therapy (TRULIGHT). clinicaltrials.gov. NCT02302547.
   https://clinicaltrials.gov/ct2/show/NCT02302547