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Dovato (dolutegravir + 3TC) in initial HIV treatment

In late August 2019, a pill called Dovato (containing dolutegravir + 3TC) was approved for the treatment of HIV in Canada and other high-income countries. The approval of Dovato was based on data from a clinical trial called Gemini conducted by Dovato manufacturer ViiV Healthcare.

Gemini is ongoing and aims to study the effectiveness of starting HIV treatment with a combination of two drugs: the integrase inhibitor dolutegravir and the nucleoside analogue 3TC. Results after one year found that the two-drug regimen was similarly effective to standard three-drug therapy. The detailed two-year results from Gemini reveal that dolutegravir + 3TC continues to show similar effectiveness and safety as standard three-drug therapy. 

Study details

For Gemini, doctors and nurses recruited HIV-positive people who had never previously used HIV treatment (ART) from countries in North and South America, Europe, South Africa and Taiwan.

The average profile of participants upon entering the study was as follows:

  • age – 32 years
  • 85% men, 15% women
  • major ethno-racial groups: white – 68%; black – 13%; Asian – 10%
  • viral load – 32,000 copies/mL (about 20% of participants had a viral load greater than 100,000 copies/mL)
  • CD4+ count – 433 cells/mm3 (about 9% of participants had CD4+ count of 200 cells/mm3 or lower)
  • no participants had hepatitis B virus infection
  • no participants had HIV with the ability to significantly resist drugs such as 3TC, FTC (emtricitabine) or protease inhibitors

Participants were randomly assigned to receive one of the following regimens:

  • dolutegravir + 3TC (dolutegravir dual therapy)
  • dolutegravir + tenofovir DF + FTC (dolutegravir triple therapy)

The trial was double blind; that is, neither participants nor most of the study team knew which participant received which combination. This masking of the study medicines continued to the 96th week of the study.

Results—viral load

The proportions of participants who achieved and maintained an undetectable viral load (less than 50 copies/mL) were as follows:

Week 48

  • dolutegravir dual therapy – 86% (616 of 716 participants)
  • dolutegravir triple therapy – 90% (642 of 717 participants)

These differences in viral load at week 48 were not statistically significant. The regimen of two drugs was considered to be roughly equivalent to the regimen of three drugs. The technical term for this is “non-inferior.”

The proportions of participants with a viral load of 50 copies/mL or higher were distributed as follows:

  • dolutegravir dual therapy – 3%
  • dolutegravir triple therapy – 2%

Participants with no virological data available were distributed as follows:

  • dolutegravir dual therapy – 11%
  • dolutegravir triple therapy – 9%

(Note that percentages do not total 100% due to rounding.)

The main reasons that participants did not have virological data available was due to withdrawal from the study due to side effects, distributed as follows:

  • dolutegravir dual therapy – 3%
  • dolutegravir triple therapy – 3%

Some participants discontinued the study for other reasons, such as loss of contact with the clinic, failure to follow study procedures, withdrawal by a physician, or withdrawal based on personal reasons. The distribution of these participants was as follows:

  • dolutegravir dual therapy – 8%
  • dolutegravir triple therapy – 5%

One person who was taking dolutegravir triple therapy left the study prematurely because their regimen wasn’t working.

Viral loads and CD4+ cell counts

Researchers assessed the response to treatment based on participants’ viral loads or CD4+ cell counts upon entering the study. Here are their analyses:

Viral load of 100,000 copies/mL or less

  • dolutegravir dual therapy – 87% achieved an undetectable viral load at week 96
  • dolutegravir triple therapy – 90% achieved an undetectable viral load at week 96

Viral load greater than 100,000 copies/mL

  • dolutegravir dual therapy – 84% achieved an undetectable viral load at week 96
  • dolutegravir triple therapy – 86% achieved an undetectable viral load at week 96

CD4+ count greater than 200 cells/mm3

  • dolutegravir dual therapy – 88% achieved an undetectable viral load at week 96
  • dolutegravir triple therapy – 90% achieved an undetectable viral load at week 96

CD4+ count of 200 or less cells/mm3

  • dolutegravir dual therapy – 68% achieved an undetectable viral load at week 96
  • dolutegravir triple therapy – 87% achieved an undetectable viral load at week 96

Although there were not large numbers of people in the last subgroup, dolutegravir + 3TC appeared at first glance to be less powerful among people who had low CD4+ cell counts. However, this difference in the proportions of participants with an undetectable viral load at week 96 was driven by people dropping out of the study for many different reasons, not because of virological failure. When the lack of virological failure is taken into account, there was no major difference in outcome between dual and triple treatment in people who entered the study with low CD4+ cell counts.

Side effects and complications

In general, there was a low risk for side effects and complications in the study. The overall proportions of participants who experienced a side effect of at least moderate intensity were distributed as follows:

  • dolutegravir dual therapy – 7%
  • dolutegravir triple therapy – 8%

Premature departure from the study

The proportions of overall participants who experienced a side effect that led to premature departure from the study were distributed as follows:

  • dolutegravir dual therapy – 3%
  • dolutegravir triple therapy – 3%

 Other reasons for premature withdrawal from the study were as follows:

Neuro-psychiatric issues

  • dolutegravir dual therapy – 1%
  • dolutegravir triple therapy – 1%

Kidney-related issues

  • dolutegravir dual therapy – less than 1%
  • dolutegravir triple therapy – 1%

Severe thinning of bones (osteoporosis)

  • dolutegravir dual therapy – 0%
  • dolutegravir triple therapy – less than 1%

Weight gain

  • dolutegravir dual therapy – 1.8%
  • dolutegravir triple therapy – 1.4%

Three participants died from the following causes:

  • heart attack
  • Burkitt’s lymphoma
  • coronary artery disease

All three of these participants were taking dolutegravir dual therapy. However, investigation revealed that the study drugs did not play a role in their deaths.

Focus on kidney and bone health

Overall, participants who took dolutegravir dual therapy had significantly better kidney health results than people who took dolutegravir triple therapy. This difference largely arose because triple therapy included tenofovir DF (TDF). This formulation of tenofovir is associated with kidney injury in some people. The results also showed that the combination of dolutegravir + 3TC is generally safe for the kidneys.

Similar trends were seen in assessments of bone health based on blood tests for certain proteins and peptides.

Lipids—cholesterol and triglycerides

Overall, changes in lipid levels were very modest and favoured the dual-drug regimen.

Overall

The 96-week findings from Gemini confirm the beneficial effects of a powerful dual-drug regimen based on dolutegravir. Importantly, no participant developed HIV that was resistant to the study medicines.

Both study regimens were generally safe but dolutegravir dual therapy was better tolerated and had favourable effects on bone and kidney health.

For the future

As mentioned earlier, a pill called Dovato (containing dolutegravir + 3TC) has been approved for the treatment of HIV in Canada. In the autumn, the leading HIV treatment guidelines produced under the aegis of the U.S. Department of Health and Human Services (DHHS) will assess the data on Dovato and consider its place in recommendations for the use of initial HIV treatment; that is, whether it is a preferred or alternative regimen for the initial treatment of HIV.

—Sean R. Hosein

REFERENCE:

Cahn P, Madero JS, Arribas J, et al. Durable efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment-naïve adults with HIV-1 infection – 96-week results from the GEMINI studies. In: Proceedings and abstracts of the 10th IAS Conference on Science, 21–24 July 2019. Mexico City, Mexico. Abstract WEAB0404LB.