Switching to Dovato (dolutegravir + 3TC) from a TAF-based regimen

The dual-drug regimen dolutegravir + 3TC, sold in a pill called Dovato, has been approved in Canada and other high-income countries for the treatment of HIV infection. This regimen is anchored by the power of dolutegravir, a potent integrase inhibitor.

Dovato may therefore be considered for use by doctors in two ways:

intitial HIV treatment
simplification (explained below)

Some people on standard triple- or four-drug therapy whose viral load has been stably suppressed could be considered for switching to a simpler two-drug regimen of Dovato. Such people should not have pre-existing resistance to dolutegravir or 3TC, have hepatitis B virus co-infection or prior instances of virological failure

Doctors increasingly expect that many people who take HIV treatment (ART) will have a near-normal life expectancy. Given this tremendous benefit of ART, it makes sense to consider how many medicines people are taking and for how long, at least in people who are highly adherent and whose viral loads are suppressed. A study in Southern Alberta found that some patients had been taking kilograms of ART over several decades. The long-term benefits of ART are clear—survival and generally good health. However, what is less clear is whether there are drawbacks to taking ART over many decades. This concept will probably be debated among doctors and scientists in the years ahead. Later in this issue of TreatmentUpdate we discuss several issues that may be relevant to the use of dolutegravir-based dual therapy.

A phase III clinical trial called Tango is underway. This study has enrolled participants taking a standard regimen that includes TAF (tenofovir alafenamide), some of whom were switched to a reduced drug regimen of two medicines—dolutegravir + 3TC.

After 48 weeks of being on dolutegravir and 3TC, researchers found similar rates of effectiveness among the regimens. There was no development of resistance to dolutegravir or 3TC. Furthermore, the dual-drug regimen was generally safe.

Study details

Participants had a suppressed viral load on their pre-study regimen for at least six months and all such regimens included TAF.

Participants did not have the following:

hepatitis B virus co-infection
prior instances of virological failure
resistance to integrase inhibitors or nucleoside analogues

Participants were randomly assigned to be on one of the following regimens:

switch to dolutegravir + 3TC
continue taking a TAF-based regimen

The average profile of participants upon study entry was as follows:

age – 40 years
92% men, 8% women
major ethno-racial groups: white – 80%; black – 15%; Asian – 4%
CD4+ count – 700 cells/mm³

Pre-study regimens

The distribution of participants’ pre-study regimens was as follows:

80% were taking Genvoya, a fixed-dose regimen of elvitegravir, cobicistat, TAF and FTC
12% were taking Odefsey, a fixed-dose combination of rilpivirine, TAF and FTC
8% were taking darunavir (Prezista) with ritonavir or cobicistat and TAF and FTC

Tango is expected to continue for about four years.

Results

The proportions of participants with an undetectable viral load (less than 50 copies/mL) at week 48 were as follows:

dolutegravir dual therapy – 93% (344 of 369 people)
TAF-based regimen – 93% (346 of 372 people)

The study was designed to assess the non-inferiority of dolutegravir dual therapy against TAF-based regimens (usually containing three or four anti-HIV drugs). Statistically, the study found that both study regimens were similarly effective. That is, dolutegravir dual therapy was not worse than and not better than TAF-based regimens.

Side effects and complications

During clinical trials, a range of unfortunate events can occur. These events could be caused by the study drugs, the underlying disease process or issues outside of the clinical trial. Researchers refer to all of these unfortunate events as “adverse events.” The overall distribution of adverse events during the study was as follows:

dolutegravir dual therapy – 80%
TAF-based regimen – 79%

However, the distribution of adverse events of at least moderate intensity that were drug side effects were distributed as follows:

dolutegravir dual therapy – 6% (17 of 295 people)
TAF-based regimen – 1% (three of 292 people)

Examples of drug side effects that occurred in more than 0.5% of participants were as follows:

Problems with sleep

dolutegravir dual therapy – 1%
TAF-based regimen – 0%

Constipation

dolutegravir dual therapy – 1%
TAF-based regimen – 0%

Flatulence

dolutegravir dual therapy – 1%
TAF-based regimen – 0%

Headache

dolutegravir dual therapy – 1%
TAF-based regimen – 0%

The proportions of participants who left the study prematurely because of side effects were distributed as follows:

dolutegravir dual therapy – 2%
TAF-based regimen – less than 1%

Weight

At week 48, participants on both study regimens had gained about 1 kg of weight (about 2.2 lbs)—this was listed as a possible general adverse effect. However, increased weight was reported as a drug-related side effect in three people (1%) who used dolutegravir dual therapy and in six people (2%) who continued to use a TAF-based regimen.

Premature withdrawal from the study

People on both regimens left the study prematurely because of different adverse events. Note that in the cases below, which occurred in people who were using dolutegravir dual therapy, some people experienced more than one adverse event, which caused them to leave. In some cases, investigation was able to assess the cause of the problem:

anxiety – 3 cases
sleep problems – 3 cases
increased weight – 2 cases
lack of energy – 2 cases
abdominal discomfort – 1 case
heart burn – 1 case
nausea – 1 case
numbness and tingling in the mouth – 1 case
drug hypersensitivity – 1 case
gunshot wound – 1 case; this was unrelated to the study medicines
lymphoma – 1 case; this was not caused by study medicines
lung cancer – 1 case; this was not caused by study medicines
problems concentrating – 1 case
prickling, decreased sense of touch – 1 case
irritability – 1 case
thoughts of suicide – 1 case; this was not caused by the study medicines
loss of sensation in the genitals – 1 case
tingling, numbness in the genitals – 1 case
itchy skin – 1 case

Many of the cases above were not likely linked to the study medicines. They are more likely to have been related to an underlying disease process or, in some cases, other, non-HIV-related medicines that participants were taking.

Premature departure from the study among TAF users

Note that in the cases below, some people experienced more than one adverse event, which caused them to leave the study. In some cases, investigation was able to assess the cause of the problem:

weight gain – 1 person
depression – 1 person
attempted suicide – 1 person; this was unrelated to the study drug

Focus on lipids, kidneys and bones

Overall, regardless of the study regimen, many participants had generally acceptable or good levels of the following in their blood or urine samples:

lipids (cholesterol, triglycerides)
markers of bone health
markers of kidney health

A note on archived virus

Prior to entering the study, some people may have been infected with a strain of HIV that is partially or wholly resistant to drugs such as 3TC, FTC or TAF. Drug resistance can also arise when people do not adhere to their medicines. As HIV in the blood is suppressed by the use of potent regimens, infected cells with HIV that might be resistant to 3TC and FTC are not actively producing virus and are either circulating in the blood at low levels or lie deep within lymph nodes and lymphoid tissues. In the setting of a suppressed viral load, virologists say that HIV-infected cells that have the ability to partially resist treatment are “archived” somewhere in the body. This archived (and drug-resistant strain of) HIV can emerge from hiding and spread in the body if doses are skipped or missed.

In people whose viral loads are suppressed by powerful drugs such as dolutegravir dual treatment, does archived drug resistant HIV matter? To explore this issue, researchers with Tango analysed stored blood samples and found small numbers of infected cells with the ability to resist 3TC and/or FTC. HIV that has the ability to resist these drugs carries mutations in its genome called M184V and/or M184I. The distribution of people with these mutations at the start of the study was as follows:

dolutegravir dual therapy – 4 people (about 1%)
TAF-based regimen – 3 people (about 1%)

At week 48, all seven of these people had a viral load that was less than 50 copies/mL.

Among participants who did not have archived mutations associated with resistance to 3TC and/or FTC at the start of the study, the proportions with a suppressed viral load at week 48 were as follows:

dolutegravir dual therapy – 100%
TAF-based regimen – 99%

The lower figure among TAF users occurred because two people had a viral load greater than 50 copies/mL at the end of the study. However, the M184V/M184I mutation did not have an impact on treatment success in the study.

Bear in mind

Most people in Tango did not have archived mutations to 3TC; those who did were generally screened out of the study (only about 1% of people in Tango had such mutations). However, the analysis of mutations and viral load in the study is reassuring about the potency of dolutegravir + 3TC when used in the context of switching regimens among people who are virologically suppressed (having a viral load less than 50 copies/mL). Another trial called Salsa is planned. In this study, scientists will assess the effectiveness of dolutegravir + 3TC in switching patients from different regimens.

—Sean R. Hosein

REFERENCE:

van Wyk J, Ajana F, Bisshop F, et al. Switching to DTG+3TC fixed dose combination (FDC) is non-inferior to continuing a TAF-based regimen (TBR) in maintaining virologic suppression through 24 weeks (TANGO Study). In: Proceedings and abstracts of the 10^th IAS Conference on Science, 21–24 July 2019. Mexico City, Mexico. Abstract WEAB0403LB.

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