The two-drug antiretroviral combination dolutegravir and lamivudine is virologically effective and safe in people starting HIV therapy for the first time, according to US research led by B O Taiwo at the division of infectious diseases and Centre for Global Health, Northwestern University, Chicago.
The phase 2 pilot study recruited 120 antiretroviral-naïve adults. After 24 weeks of treatment, 90% of participants had viral suppression and none of the participants discontinued therapy because of side-effects. There were few virological failures, and these were linked to poor adherence.
Modern antiretroviral therapy usually consists of three separate drugs and is highly effective. Safety and cost considerations mean there is interest in identifying effective two drug combinations. Dolutegravir and lamivudine performed well in a small study with high rates of virological suppression over 96 weeks.
Investigators in the US wanted to build on this research. They therefore designed a pilot, phase 2, open-label study (ACTG A5353) involving adults with a viral load between 1000 and 500,000 copies/ml who were starting antiretroviral therapy for the first time. Key exclusion criteria were infection with hepatitis B virus and antiretroviral resistance.
Viral load was measured at regular intervals over 24 weeks. The main outcome was viral suppression (below 50 copies/ml) at week 24. Virological failure was defined as a viral load above 400 copies at weeks 16/20 or above 200 copies/ml at week 24. People experiencing virological failure underwent therapeutic drug level monitoring and resistance testing. Data were gathered on adherence and safety.
The participants had a median age of 30 years and 87% were male. Median baseline viral load and CD4 cell count were 40,000 copies/ml and 387 cells/mm3, respectively. Seven people were lost to follow-up or withdrew from the study before week 24. Overall, 108 people (90%) had an undetectable viral load at week 24. Rates of viral suppression were similar for people with baseline viral loads above and below 100,000 copies/ml (90 vs 89%).
Three people experienced virological failure. Drug level monitoring showed undetectable levels of dolutegravir, therefore suggesting poor treatment adherence. One person with virological failure developed the M184V mutation, which confers resistance to lamivudine, and also the R263R/K mutation, potentially limiting the effectiveness of dolutegravir. Adherence was excellent, with 90% reporting taking all their doses.
The median increase in CD4 cell count over the study was 167 cells/mm3. Ten people reported grade 3/4 adverse events, but only two were considered possibly related to therapy (grade 3 reduction in creatinine clearance and grade 3 palpitation). There were also two cases of mild rash. None of the participants stopped treatment early because of side-effects.
“The two-drug regimen of dolutegravir and lamivudine was generally safe and well-tolerated consistent with the known favourable toxicity profiles of these two agents,” comment the authors. “No participant discontinued the regimen because of adverse events. Notably, the combination of dolutegravir and lamivudine has the potential to be co-formulated into a single pill without dietary restrictions. Antiretroviral regimens must be well-tolerated and convenient to support long-term adherence.”
On the basis of current drug prices, the investigators calculated that widespread use of this two-drug combination in the US could save at least $3bn over five years. “The week 24 results of the…study showed that the two-drug antiretroviral regimen of dolutegravir and lamivudine was virologically potent and generally safe and well-tolerated in individuals with pre-treatment HIV-1 RNA up to 500,000 copies/ml,” conclude the researchers. “Fully-powered phase 3 studies in progress will provide needed comparative data versus dolutegravir-based three-drug therapy in treatment-naïve individuals.”
Background: Limited data exist on initial HIV-1 treatment with dolutegravir plus lamivudine , particularly for pre-treatment HIV-1 RNA >100,000 copies/mL.
Materials and Methods: A5353 is a phase II, single-arm, pilot study of once-daily dolutegravir (50mg) plus lamivudine (300 mg) in treatment-naïve participants with HIV-1 RNA ≥1000 and < 500,000 copies/mL. Exclusion criteria included active hepatitis B, or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was proportion with HIV-1 RNA < 50 copies/mL (FDA snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20, or >200 copies/mL at/after week 24. Dolutegravir levels and drug resistance testing were performed at VF.
Results: One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA > 100,000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm 3. Virologic efficacy by FDA snapshot at week 24 was 108/120 (90%, CI [83%, 95%]) with comparable results in the >100,000 copies/mL and ≤100,000 copies/mL strata: 89% [75%, 97%] and 90% [82%, 96%], respectively. Three participants had VF, each with undetected plasma dolutegravir at ≥1 timepoints; the M184V reverse transcriptase and R263R/K integrase mutations developed in one participant. Two participants experienced Grade 3 possibly/probably treatment-related adverse events; none discontinued treatment due to adverse events.
Conclusion: Dolutegravir plus lamivudine demonstrated efficacy in individuals with pre-treatment HIV-1 RNA up to 500,000 copies/mL in this pilot trial, but a participant selected resistance mutations to lamivudine and dolutegravir.
Taiwo BO, Zheng L, Stefanescu A, Nyaku A, Bezins B, Wallis CL, Godfrey C, Sax PE, Acosta E, Haas D, Smith KY1, Sha B, Van Dam C, Gulick RM