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Why Dolutegravir Might Get Us Closer to Ending AIDS: Next Step, Further Research

October 26, 2015

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Over 24 weeks, all participants except one person maintained an undetectable viral load (this time defined as being less than 37 copies/mL). One person had viral load rebound to low levels at week 4 (155 copies/mL) and despite modifying treatment (changing to a higher twice-daily dolutegravir dose) viral load remained detectable at week 24. This was complicated by poor adherence. Tolerability was good and laboratory monitoring tests for cholesterol and kidney function both improved.

A second monotherapy study, also presented as an oral presentation was a French study in 28 people who were treatment-experienced.6

This group were stable on current treatment but had long and complex HIV treatment histories having used ART for an average of 17 years. Although 25/28 people maintained undetectable viral load over 24 weeks, three people had their viral load rebound, in one case to over 2,000 copies/mL.

In these three cases, adherence was confirmed with good drug levels, but drug resistance developed against dolutegravir. This might have been linked to previous use of integrase inhibitor treatment, even though integrase resistance wasn't detected in tests before the switch.

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These three cases tempered the hope that dolutegravir monotherapy is without risk and they were the focus of many of the questions after the presentation.

The third study reporting dolutegravir monotherapy, was a poster in which 21 treatment-experienced French people switched from currently stable treatment to dolutegravir monotherapy.4 (This was the study that also reported on 31 people using dolutegravir dual therapy with a range of different drugs, but only three cases where this was 3TC).

Over 24 weeks of follow-up, all participants on dolutegravir monotherapy, maintained undetectable viral load below 50 copies/mL, with 96% of results less than 20 copies/mL. The study included some people who had used other integrase inhibitors before, although all the details for these people were not shown. One person using dual therapy with dolutegravir and maraviroc with previous resistance to raltegravir, experienced viral load rebound, with new resistance to dolutegravir.

Finally, a small study from the Netherlands, reported results about five treatment-experienced people who switched to dolutegravir monotherapy due serious complications with alternative drugs. Fewer details are available for this study, but although viral load remained undetectable in four people, it rebounded to clinically significant levels in a fifth.7


Is This the First Time Using Fewer Drugs Has Been Studied?

No, the interest in reducing the drugs to treat HIV has been around for a long time. Almost as soon at the first studies in 1996/7 showing that combination therapy worked, there was interest in whether people could start with one combination and then cut back later to a reduced maintenance combination later. But these studies -- including the ACTG 343 in the US, the Trilege study in France and the Adam study in the Netherlands failed very quickly. Viral load quickly rebounded when 3 drugs were reduced to one or two drugs and most people developed drug resistance.8

About a decade later -- through the noughties -- monotherapy was studied again using boosted protease inhibitors, especially lopinavir/ritonavir (Kaletra) and then more recently the PIVOT study used darunavir/ritonavir monotherapy. Although these later results were much better that the first maintenance studies, dropping the use of other drugs -- especially NRTIs (nukes) generally led to higher rates of viral rebound and certainly were never as good as combinations with three active drugs.9,10


Why Are the New Results So Surprising -- and Exciting?

The results with dolutegravir are surprising because they would not have been possible with any other single drug.

For the last 30 years, the vulnerability of HIV drugs to develop resistance has been a serious limitation of every HIV drug. This was why early studies using single and dual combinations only produced very short-term benefits. HIV is a rapidly evolving virus and unless viral load is reduced to less than 50 copies/mL, resistance is nearly always inevitable. With some drugs and combination resistance takes time to accumulate slowly but with others this can occur within a few weeks. The results with dolutegravir could change everything, with some researchers, including Professor Mark Weinberg, thinking this might play a role in strategies for a cure.11

In theory, because the results shouldn't have happened the researchers face new challenges in trying to explain them.

Looking further forward, a similar drug to dolutegravir (called cabotegravir) is already in development as a long-acting injection. Until now this drug was believed to need support from other long-acting injections. The new results with dolutegravir might mean that cabotegravir monotherapy injections might be effective on their own.

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This article was provided by HIV i-Base. Visit HIV i-Base's website to find out more about their activities, publications and services.
 

 

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