Dolutegravir non-inferior to low dose efavirenz in real-life African study conducted in Cameroon  

13 November 2018. Related: Conference reports, Antiretrovirals, Treatment strategies.

Polly Clayden, HIV i-Base

Dolutegravir-based first-line ART was non-inferior, but not superior, to that with efavirenz 400 mg at week 48 in the NAMSAL study – according to findings presented at Glasgow 2018. [1]

Overall, approximately 70% of participants achieved viral load suppression to <50 copies/mL. But people with high viral load at baseline (>500,000 copies/mL) had poor virological response with less than 60% achieving <50 copies/mL in both arms.

NAMSAL ANRS 12313 is a phase 3 study designed to assess the safety and efficacy of a dolutegravir (DTG)- versus an efavirenz 400 mg (EFV-400)-based first-line regimen in a low-income country. Cameroon, is known for high HIV-1 genetic diversity, and has an increasing rate of NRTI- and NNRTI-transmitted resistance.

It is a randomised, open label, multicentre trial conducted at three sites in Yaoundé. HIV positive, ART-naive adults with viral load >1000 copies/mL were randomly assigned (1:1) to DTG or EFV-400, both with tenofovir disoproxil fumarate (TDF)/lamivudine (3TC).

The primary endpoint was the proportion of participants with viral load <50 copies/mL at week 48 (FDA ITT snapshot algorithm, 10% non-inferiority margin). A superiority test was planned if non-inferiority was demonstrated.

A total of 820 participants were screened: 204 were ineligible and 616 were randomised. Of these, 613 received at least one dose of study medication: 310 and 303 participants in the DTG and EFV-400 arms respectively.

Baseline characteristics were similar across both arms: 68% of participants were women, median age was 36 years (IQR: 29 to 43), CD4 count was 281 cells/mm³(IQR: 154 to 444), and viral load was 5.3 log copies/mL (IQR: 4.8 to 5.8). A considerable proportion of participants had high viral load at baseline: 66% had >100,000 copies/mL and 30% had >500,000 copies/mL.

At week 48, the proportion of participants with viral load <50 copies/mL was 74.5% in the DTG arm and 69.0% in the EFV-400 arm: difference +5.5% (95% CI –1.6 to +12.7); p=0.13 for the superiority test.

Among participants with baseline viral load <100,000 copies/mL, the respective proportions were 91.3% and 83.5%: difference +7.8% (95% CI –1.2 to +16.8).

And for participants with >100,000 copies/mL at baseline, the respective proportions were 66.2% and 61.5%: difference +4.7% (95% CI –4.6 to +14.0).

Of participants with >500,000 copies/mL at baseline only 54.8% and 57.9% in the DTG and EFV-400 arms respectively, achieved viral load <50 copies/mL at 48 weeks.

In ITT analysis for viral load <200 copies/mL the proportion were 89% for the DTG arm and 83.5% for the EFA-400 arm; and for <1000 copies/mL the respective proportions were 91.9% and 86.5%.

In multivariate analysis, viral load >100,000 copies (p<0.0001), CD4 count <200 cells/mm³(p=0.024) and male sex (p=0.017) were associated with viral load >50 copies/mL at week 48.

Among 19 participants with virological failure >1000 copies/mL and genotype results: 0/3 in the DTG arm had resistance at baseline or at virological failure and 6/16 in the EFV-400 arm had baseline resistance and 3/16 participants who were susceptible at baseline had resistance at virological failure.

Overall 9% of participants had AIDS-defining events and there were no discontinuations of study medication due to intolerance.   

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NAMSAL results have been eagerly awaited as this is the first study to look at DTG in a real-life African setting. Unlike registrational studies, participants reflect the population that will be treated in a low-income country, including those with high baseline viral load who were less likely to achieve fully suppressed viral load.

Among participants presenting with high viral load at baseline, the investigators observed persistently low viral replication rates in both arms. The discussion following the presentation mainly focused on explanations for this, particularly in the DTG arm.

Principal investigator Eric Delaporte of the University of Montpellier noted that adherence was good in the study – greater than 80% in both arms.

Anton Pozniak of the Chelsea and Westminster Hospital, London explained that viral suppression with an integrase inhibitor usually occurs by about week 16 to 24 and asked if it was likely that it could take longer with very high viral loads and this is just the first time we have seen data from a large number of people in this group. Dr Delaporte remarked that this is “not an exceptional figure” in west and other parts of Africa and that there are a lot of further analyses to do.  

NAMSAL will continue until 2021 to ensure long-term monitoring of participants who started DTG – hoping to confirm the absence of resistance mutations to this drug. [2]

References

1. Cournil A et al. Dolutegravir- versus an efavirenz 400 mg-based regimen for the initial treatment of HIV-infected patients in Camer- oon: 48-week efficacy results of the NAMSAL ANRS 12313 trial. HIV Glasgow. 
28–31 October 2018. Glasgow, UK. Oral abstract O342.
2. ANRS/Unitaid press release. Dolutegravir, an alternative first-line HIV treatment for low and middle-income countries. 31 October 2018.
   https://unitaid.org/news-blog/dolutegravir-an-alternative-first-line-hiv-treatment-for-low-and-middle-income-countries/#en