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Dolutegravir + 3TC for the initial treatment of HIV

As mentioned earlier in this issue of TreatmentUpdate, researchers are testing simplified regimens for maintenance treatment for HIV. Results from pilot studies of dual drug regimens have suggested that dolutegravir (Tivicay) and 3TC (lamivudine) can help about 90% of people who initiate treatment with this combination to achieve a viral load less than 50 copies/mL.

To explore the potential of dolutegravir + 3TC as initial dual drug therapy, researchers conducted two randomized, placebo-controlled clinical trials called Gemini 1 and Gemini 2, comparing the following regimens for initial treatment:

  • dolutegravir + 3TC
  • dolutegravir + Truvada (tenofovir DF + FTC)

At the 48th week of the study, similar proportions of participants on both regimens had a viral load less than 50 copies/mL:

  • dolutegravir + 3TC – 90%
  • dolutegravir + Truvada – 93%

Further details appear later in this report. The 96-week trial results from Gemini 1 and 2 are awaited. Should the results be similar to those seen in week 48, it is likely that a single pill containing dolutegravir + 3TC for the initial treatment of HIV infection will be approved in the U.S. in the spring of 2019 and in Canada in mid-summer 2019.

Study details

Participants for Gemini 1 and 2 were recruited from North and South America, Europe, South Africa, South Korea and Taiwan. The data from the two trials were pooled for analysis, as the trials were identical in design.

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

  • age – 32 years; about 10% of participants were 50 years or older
  • 85% males, 15% females
  • major ethno-racial groups: white – 68%; black – 13%; Asian – 10%
  • HIV viral load – 28,000 copies/mL (Note that 20% of participants had a viral load of 100,000 copies/mL. Furthermore, about 4% of participants had a viral load greater than 500,000 copies/mL.)
  • CD4+ count – 430 cells/mm3
  • no participants had hepatitis B or C virus co-infection
  • no participants had HIV that was resistant to the study drugs

A total of 716 people received dolutegravir + 3TC and 717 people received dolutegravir + Truvada.

Results—Focus on viral loads and CD4+ cell counts

At the 48th week of the study, the results were as follows:

The proportions of participants with a viral load less than 50 copies/mL (undetectable) were distributed as follows:

  • dolutegravir + 3TC – 91%
  • dolutegravir + Truvada – 93%

This difference was not statistically significant and shows that the regimen of dolutegravir + 3TC is similarly effective to a standard three-drug regimen of dolutegavir + Truvada.

Among other participants, no virological data was available at week 48 for the following proportions of participants:

  • dolutegravir + 3TC – 6%
  • dolutegravir + Truvada – 5%

Finally, the proportions of participants who were unable to achieve an undetectable viral load at week 48 were distributed as follows:

  • dolutegravir + 3TC – 3%
  • dolutegravir + Truvada – 2%

High vs. low viral loads

There was no significant difference in the proportions of participants able to achieve a suppressed viral load at week 48 when analysed by their viral load levels at the start of the study. However, among participants who entered the study with a low CD4+ count (200 or fewer cells/mm3), there appeared to be a difference in the proportions who achieved an undetectable viral load, as follows:

  • dolutegravir + 3TC – 79% (50 out of 63 people)
  • dolutegravir + Truvada – 93% (51 out of 55 people)

The overall number of participants with a CD4+ count of 200 or less was relatively small, so statistically robust conclusions cannot be drawn from this difference in outcome. However, it is possible, likely even, that people with 200 or fewer cells/mm3 who start a dual drug regimen will not do as well as people with that cell count who start a standard triple-drug regimen.

There were relatively few people who developed virological failure (less than 1% of participants), distributed as follows:

  • dolutegravir + 3TC – 6 people (less than 1%)
  • dolutegravir + Truvada – 4 people (less than 1%)

Among these people, there were no cases of HIV resistant to the classes of drugs used in this study—nucleoside analogues and integrase inhibitors.

Changes in CD4+ cell counts

Participants’ average CD4+ cell counts rose by about 220 cells/mm3 regardless of the study regimen used. That is, their average CD4+ count rose from 430 cells/mm3 at the start of the study to 650 cells/mm3 about a year later.

Focus on complications and side effects

The term adverse events is used by researchers to describe a range of unfortunate events that can occur to people in a clinical trial. Those events may be caused by drug side effects, the underlying disease process or circumstances outside of the clinical trial.

In the analysis of Gemini 1 and 2, adverse events judged by investigators to be related to the study drugs were distributed as follows:

  • dolutegravir + 3TC – 18% (126 people)
  • dolutegravir + Truvada – 24% (169 people)

Most of these drug-related adverse events were graded as mild and included the following issues:

  • headache
  • diarrhea
  • nausea

Side effects that were of at least moderate intensity, such as headache, were distributed as follows:

  • dolutegravir + 3TC – 6%
  • dolutegravir + Truvada – 7%

Adverse events leading to premature departure from the study were distributed as follows:

  • dolutegravir + 3TC – 2%
  • dolutegravir + Truvada – 2%

There was no clear pattern of side effects leading to premature withdrawal from the study.

Focus on the brain

Previous randomized studies with dolutegravir found that a relatively small proportion of participants developed brain-related side effects that likely led them to leave the study prematurely. These side effects include problems with sleep, mood (anxiety and depression) and concentration. The distribution of brain-related side effects that caused people to prematurely leave the present studies were as follows:

  • dolutegravir + 3TC – 6 people (less than 1%)
  • dolutegravir + Truvada – 4 people (less than 1%)

There was no clear pattern to the distribution of brain-related side effects that caused some people to leave the Gemini studies prematurely. The distribution was as follows:

Depression

  • dolutegravir + 3TC – 1 person
  • dolutegravir + Truvada – 1 person

Sleeping problems

  • dolutegravir + 3TC – 2 people
  • dolutegravir + Truvada – 0 people

Thoughts of self-harm

  • dolutegravir + 3TC – 1 person
  • dolutegravir + Truvada – 1 person

Attempted suicide

  • dolutegravir + 3TC – 1 person
  • dolutegravir + Truvada – 1 person

Psychotic disorder

  • dolutegravir + 3TC – 1 person
  • dolutegravir + Truvada – 0 people

Psychosis due to harmful intake of alcohol

  • dolutegravir + 3TC – 0 people
  • dolutegravir + Truvada – 1 person

Street drug overdose

  • dolutegravir + 3TC – 0 people
  • dolutegravir + Truvada – 1 person

Looking at kidney and bone health

Truvada contains tenofovir DF, the older formulation of tenofovir. In a minority of people, use of tenofovir DF is associated with an increased risk of kidney injury. In the data from Gemini 1 and 2, serious kidney injury or serious kidney dysfunction was not common. However, assessments of blood and urine samples suggested better overall kidney health among people who used dolutegravir + 3TC vs. dolutegravir + Truvada.

A similar trend was seen for proteins in the blood associated with bone health. That is, participants who used dolutegravir + 3TC were less likely than participants who used dolutegravir + Truvada to have proteins associated with reduced bone density. However, these findings are not definitive and a subset of participants should have undergone low-dose X-ray scans (DEXA) of their bones to give a clear analysis of the effects of the study drugs on bone health.

Two people died in the Gemini study—one from a heart attack and the other from complications related to cancer (lymphoma). Both participants were taking dolutegravir + 3TC and were enrolled in Gemini 2. However, investigators considered their deaths unrelated to the study drugs.

Bear in mind

The combination of dolutegravir + 3TC is more or less as effective as standard triple therapy (dolutegravir + Truvada) for the initial treatment of HIV infection in people who have more than 200 CD4+ cells/mm3. Overall, there were fewer side effects with dolutegravir + 3TC than with dolutegravir + Truvada.

Gemini 1 and 2 are ongoing studies that will continue for about three years.

—Sean R. Hosein

REFERENCE:

  1. Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week-48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2018; in press.
  2. Cahn P, Madero JS, Arribas JR, et al. Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) vs DTG Plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment–naive adults with HIV-1 infection—week 48 results rrom the GEMINI studies. In: Program and abstracts of the 22nd International AIDS Conference, 23-27 July 2018, Amsterdam, Netherlands, abstract TUAB0106LB.