Italian study explores dual drug regimens as maintenance treatment

The drug dolutegravir is a widely used part of combination therapy for HIV treatment. Dolutegravir belongs to a class of drugs called integrase inhibitors; it is powerful and generally well tolerated. Dolutegravir is sold under the following brand names and fixed-dose combinations:

• Tivicay – dolutegravir
• Juluca – dolutegravir + rilpivirine
• Triumeq – dolutegravir + 3TC + abacavir

Investigating dolutegravir-containing combinations

A pill containing two drugs—dolutegravir + 3TC—is currently in clinical trials for the initial treatment of HIV infection. Results from the first year of those trials suggest that the combination is very promising. It is likely that the combination of dolutegravir + 3TC will be approved by regulatory agencies in Canada and other high-income countries sometime in 2019.

A recent study from Alberta found that over the course of 20 years some long-term survivors have been taking kilograms of medicines. In light of that, maintenance or even initial therapy with just two drugs (instead of the standard three- or four-drug combinations) can reduce the burden of medicines and potentially result in fewer side effects and/or drug interactions.

Comparing dual drug regimens

Researchers at several clinics in Italy have conducted an observational study of induction-maintenance therapy for HIV. In the induction phase of this approach to treatment, patients are given standard three- and four-drug combinations. Once their viral load has been suppressed to 50 copies/mL and stays suppressed for some time afterward (usually a period of months), doctors can offer maintenance therapy by reducing their regimen to just two drugs.

In the Italian study, researchers analysed data from 419 people who had stable and suppressed viral loads on standard regimens and who were later switched to one of the following dual drug combinations:

• dolutegravir + 3TC – 229 participants
• dolutegravir + rilpivirine – 187 participants

Participants were monitored for about two years while they were on these simplified regimens.

The researchers found that around 90% of participants maintained a suppressed viral load over the course of the study. Both dual drug regimens were associated with improvements in cholesterol levels in the blood and were generally well tolerated.

An important additional finding from the Italian study was that participants who several years prior to the present clinical trial had a viral load greater than 500,000 copies/mL were at increased risk for experiencing virological failure during the present study.

Study details

The present study was retrospective in design. That is, researchers analysed data that had been collected previously for another purpose—to compare dual drug regimens. Participants were not randomly assigned to the study regimens.

The researchers defined virological failure in one of the following ways:

• having two consecutive viral load test results of 50 copies/mL or greater over a period of three months
• having a single viral load test result that was 1,000 copies/mL or greater

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

• age – 53 years
• 72% men, 28% women
• 21% of participants had been exposed to hepatitis C virus (HCV)
• 44% had one of their pre-study regimens fail
• length of time since HIV diagnosis – 16 years
• viral load – less than 50 copies/mL
• CD4+ count – 670 cells/mm³

Results

The overall proportions of participants whose viral load was suppressed and stayed suppressed two years after entering the study were distributed as follows:

• dolutegravir + 3TC – 95%
• dolutegravir + rilpivirine – 97%

So, overall, the regimens have similar effects.

However, researchers noticed one difference in the proportions of people who achieved viral suppression, and this was related to their historical viral load. That is, researchers found that participants whose highest-ever viral load prior to entering the study was 500,000 copies/mL or greater were at heightened risk for developing virological failure in the present study, regardless of which dual drug combination they took.

Among participants taking dolutegravir + 3TC who had a viral load of 500,000 copies/mL or greater at some point before entering the present study, the proportions who achieved a suppressed viral load during the study were as follows:

• week 48 – 95%
• week 96 – 87%

Among participants taking dolutegravir + rilpivirine who had a viral load of 500,000 copies/mL or greater at some point before entering the present study, the proportions who achieved a suppressed viral load during the study were as follows:

• week 48 – 92%
• week 96 – 88%

Adverse events

The term adverse events describes a range of unfortunate events that can occur in a clinical trial. These events may be due to drug side effects, the underlying disease process or issues outside of the clinical trial.

Dolutegravir + 3TC

A total of 30 participants (13%) left the study prematurely. The main reasons for their departure were as follows:

• neuropsychiatric events (including sleeping problems, anxiety, depression) – 8 people
• virological failure – 6 people
• wanting to take a single-tablet regimen – 4 people
• gastrointestinal problems – 1 person
• hypersensitivity reaction – 1 person

Dolutegravir + rilpivirine

A total of 13 participants (7%) left the study prematurely. The main reasons for their departure were as follows:

• neuropsychiatric events (including sleeping problems, anxiety, depression) – 3 people
• virological failure – 2 people
• gastrointestinal problems – 2 people
• kidney injury – 1 person

Changes to lab test results

On average, levels of total cholesterol fell after participants began taking dual drug regimens.

No significant changes in tests of kidney health occurred during the course of the study.

Bear in mind

The present study is retrospective in nature. It used data collected for one purpose in the past, then analysed that data for the purposes of this study. Conclusions drawn from retrospective studies must be taken cautiously, as such studies are not the most statistically robust. Despite this caveat, the findings from the Italian study are broadly similar to results from randomized clinical trials of dual drug regimens containing dolutegravir.

The overall range of neuropsychiatric side effects in the present study was about 4%. This is within the range reported from other studies.

The association between previously having a high viral load (500,000 copies/mL and greater) and an increased risk of virological failure while subsequently on dual drug therapy is interesting. It may serve as a cautionary note about the limits of dual therapy.

—Sean R. Hosein

REFERENCE:

Ciccullo A, Baldin G, Capetti A, et al. A comparison between two dolutegravir-based two-drug regimens as switch strategies in a multicentre cohort of HIV-1-infected patients. Antiviral Therapy. 2018; in press.