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

October 26, 2015

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What Are the Cautions?

Although resistance didn't develop to dolutegravir in studies of people starting treatment -- and a poster at EACS is helpful for summarising these data12 -- the resilience to resistance was still thought to be due to the other drugs in the combination.

Also, although dolutegravir can sometime overcome drug resistance to other integrase inhibitors if used early enough -- notably to raltegravir and elvitegravir -- this is not always the case, even using a higher dose of 50 mg twice daily.

Whether the mono and dual therapy results are sustained will depend on why dolutegravir is special and the mechanism for this protection. Resistance might be developing, but just at a very slow rate. Or dolutegravir might be causing a type of resistance that changes the structure of HIV in a way that makes it difficult to replicate -- and this is why viral load stay so low.

If dolutegravir causes HIV to mutate in a way that makes other current drugs less effective this could actually be a serious complication. Careful research is essential to look at this possibility as HIV has a history of escaping from effective treatment and mutating so that it ultimately becomes more difficult to treat.

Another concern is that many people in the dolutegravir mono and dual therapy studies were on stable treatment. Unpredictable viral load rebound in a few cases -- whether in the first weeks or in several years time -- might come with a risk of seroconversion symptoms and of becoming infectious to partners. This risk is at a time when treatment as prevention is only just getting established as a real and reliable strategy to prevent HIV transmission.

We need to understand the few cases where people had viral rebound, together with the relationship this has to previous use of integrase inhibitor treatment.


Why It Is Essential to Wait for Further Research

For all the potential benefits, the following bullet list show why further research is needed before this can be tried outside a study setting.

  • With longer follow-up, dolutegravir monotherapy might not be enough.
  • With longer follow-up, dual therapy with dolutegravir and 3TC might not be enough.
  • The short term results may not last. Maybe not until a year, maybe not until a few years. Resistance might be developing, but just very slowly in a few people -- or in everyone.
  • Using only one or two drugs might cause HIV to change into a virus that is more difficult to treat, even for people without resistance to current drugs.
  • A few cases have already been reported where monotherapy has not worked. Some of these people were stable on their previous combination but now have cross-resistance to all integrase inhibitors and cannot use them in the future.
  • Current cases where monotherapy failed have involved earlier use of integrase inhibitors but this could also relate to transmitted drug resistance and natural mutations.
  • Current resistance testing only has a limited sensitivity. Usually at least 20% of your virus needs to be resistant, or at least 1% in more specialized research tests.
  • The unpredictability of viral rebound could be associated with serious symptoms similar to seroconversion.
  • The unpredictability of viral rebound would reduce the impact of treatment as prevention and in the risk of transmission to sexual partners if condoms were not routinely used.
  • Very few people have a clinical urgency to reduce treatment. Within a year or two, much more data will be available. Historically, maintenance therapy doesn't have a great history of successful results.
  • Although the implications of less expensive treatment are important, the first focus should be on whether this strategy is both safe and effective for treatment. ART is already one of the most cost effective medical implications, in all countries and at current prices.

Given these cautions, for people wanting to join a research study, the early data is encouraging, especially if there are clinical reasons for needing to use fewer drugs. If this is the case, then the most cautious approach would be to include 3TC as dual therapy, and have very close monitoring.

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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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