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

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

This blog discusses the implications for HIV-positive people of several studies at the 15th EACS conference in October 2015.

Introduction

Last week at the 15th European AIDS Conference (EACS) in Barcelona, several research groups -- from Argentina, France, Spain and the Netherlands -- presented results from small independent pilot studies that have the potential to dramatically change HIV globally.

If the early results are supported by larger studies, the implications include the potential:

  • To improve the quality of life by using fewer drugs associated with less side effects. Perhaps only one drug might be needed which already has one of the lowest risks of side effects.
  • To reduce costs of antiretroviral treatment (ART) at a time when health budgets are being cut in many high-income countries, including the UK, and when funding programmes for low and middle-income countries have a new challenge to double the number of people accessing ART.
  • To improve the choices of treatment worldwide. This is not just related to cost but to speeding up access to better second-line and first-line drugs.
  • To speed up the option to treat HIV with a long-lasting injection instead of daily pills medication. This might be possible to use one injection every three months. Until now, the concern to avoid drug resistance to dolutegravir has meant that researchers have been preoccupied with developing two injectible drugs to use in combination.
  • To play a new and unexpected role in research into either a cure or long-term HIV remission. This is really jumping ahead but might be an outcome if the mechanism to explain the early results is that dolutegravir disables HIV in a way that makes it unable to replicate.

But these remarkably grand hopes need to be tempered with serious caution and patience. The current results are tentative, short-term and in small numbers of people. The results are exciting because our understanding of the dynamics of HIV mean that they shouldn't have happened, but they did -- and coming as a surprise means that even experts are unsure of their significance.

Further research will be essential before trying this at home or even trying this with your doctor's advice. This is because these risks are serious too: dolutegravir might for example cause HIV to mutate in a way that makes the virus more difficult to treat, even with drugs that were working beforehand.

Larger studies are already planned or ongoing. Perhaps within a year the long-term outlook for treatment might be different for a significant percentage of HIV-positive people.

What Were These Studies at EACS?

The studies all looked at whether HIV antiretroviral treatment (ART) could be simplified from standard 3- 4 drug combinations to using fewer drugs. The studies all used dolutegravir -- the most recently approved HIV drug -- either with one of the earlier HIV drugs called lamivudine (3TC), or using dolutegravir on its own. Three of the studies were in the same oral sessions that will hopefully be webcast.1

Dolutegravir belongs to a class of drugs called integrase inhibitors, which is probably one of the most effective drugs to reduce viral load and also has a low risk of side effects. 3TC is still widely used, and it is also very well tolerated with very few no side effects. Because 3TC came off patent several years ago, generic versions are available very cheaply in all countries.

Treatment with only one or drugs is not a new idea -- but until now results have never been able to matched results using three active drugs. So the current studies were therefore carefully designed to include very close and frequently monitoring, especially for viral load. The people taking part often had complications with HIV drugs that they were already taking due to difficult side effects, lack of available treatment or complicated drug interactions with other important medicines. So there were clinical reasons to consider this experimental approach based on individualised care.

Three studies at EACS 2015 used 50 mg dolutegravir in a two-drug combination with 300 mg lamivudine (3TC). Both drugs were taken together, once-daily, with or without food. On of these studies was in people starting treatment and two were in people switching. Four other studies used 50 mg dolutegravir as a single drug -- i.e., with no other HIV meds.

What Were the Early Results?

The first results -- in small numbers of people for short periods of time -- showed that viral load generally stayed undetectable for the 24 weeks. However, viral load did not stay undetectable for everyone. Some people were unlucky. And when viral load did rebound, some of these people developed drug resistance.

Although the possibility of using fewer drugs might sound tempting, the risks are also real.

What Happened With Dolutegravir and 3TC Dual Therapy?

Two studies reported on two-drug (dual) therapy using dolutegravir with 3TC.

The first was an oral presentation from Argentina called the PADDLE study.2

This study involved 20 people (average age 34) who had never used HIV drugs and who started their first treatment using dolutegravir plus 3TC. Viral load was measured eight times over the first month and then weekly. This means that the study involved close monitoring and a lot of clinic visits. As an additional caution, the researchers only expanded the study to 20 people when the first 10 people had been shown good response over the first 8 weeks.

Also importantly, nearly everyone started with a low viral load and the average was 20,000 copies/mL. However, although this was not intended when planning the study, four people started with a viral load greater than 100,000 copies/mL. These high results were because of viral load increases between the screening visit and the start of the study.

After starting treatment, viral load dropped very quickly. Within three weeks, everyone saw their viral load fall to less than 400 copies/mL, with ten people getting undetectable <50 copies/mL within 2 weeks. By 8 weeks, all 20 participants had a viral load that was less than 50 copies/mL -- with the people starting at highest viral load taking longest to reach undetectable. Although many people might find this surprising, this aspect of the study was expected by the researchers. Other studies have reported how quickly integrase inhibitors reduce viral load within the first month of treatment.

What was more remarkable was that all 20 people stayed undetectable through to week 12 and then to week 24.

Average CD4 counts increased by about 200 cells/mm3 -- as would be expected with triple combinations. Very few side effects were reported and nearly all were mild. The most serious side effect was a moderate headache (but with minimal need for medication) and there were no serious abnormalities from blood monitoring tests (ie not needing an additional intervention). The PADDLE study will continue to follow participants for two years and larger studies are already planned.

The second dual therapy study was presented as a poster in the exhibition hall and had a different design and studied people with a different HIV history.3

In this case, 27 French patients who were already on treatment and who had an undetectable viral load that was less than 50 copies/mL for at least a year, changed ART to dolutegravir plus 3TC. Everyone in the study was doing well before switching. This was defined as having undetectable viral load on treatment for at least the previous year. People were not only older than those in the PADDLE study (average age was 59) but they had a long HIV treatment history, having been on ART for an average of almost 18 years. What is unusual -- and a significant caution -- is that seven people had already used another integrase inhibitor (raltegravir) and eight had history of drug resistance to 3TC.

Over 24 weeks, viral load remained <20 copies/mL in all participants, with one blip at 52 copies/mL. Tolerability was also good, although two people changed back to their pre-switch combination because of fatigue with dolutegravir + 3TC.

A third study -- also from a French group -- reported on 31 people who were using dolutegravir as part of dual therapy with a range of other drugs but only three people used 3TC. As this third study also included 21 people using dolutegravir monotherapy, these results are described below with the single drug studies.4

What Were the Results From the Monotherapy Studies?

Although the results of dual therapy studies were very positive, several studies went a step further. Three studies at EACS showed results from using dolutegravir as a single HIV drug, with a fourth study presented at a meeting linked to the main conference.

The first of these was an oral presentation of a Spanish study in which 33 people who were on stable treatment, having been undetectable viral load for an average of eight years. These were people with a long and complex history of treatment, but with no evidence of integrase inhibitor resistance and all participants switched to dolutegravir monotherapy.

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.

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.

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.

Comment

Although these studies generated interest at EACS, many people reserved caution about the results.

These were all single arm pilot studies in small groups of people with short periods of follow-up.

They all concluded that results need to be confirmed in larger studies where follow up is just as close and where results are compared to using standard three drug treatment. The new studies will need to look into how effectively mono and dual therapy works in different body sits -- not just based on results from blood tests.

Nevertheless, for people struggling on current ART, the results offer great hope if the early promise is sustained.

For wider global access it is also significant that manufacturers ViiV Healthcare agreed to dolutegravir being available for generic manufacturers as part of the Patent Pool.13

References

Unless stated otherwise, all references are the the programme and abstracts of the 15th European AIDS Conference (EACS), 21-24 October 2015, Barcelona, Spain.

  1. Oral abstract session. Antiretroviral Therapy I. PS1. 22 October 2015, 14:00 - 16:00, 15th EACS, Barcelona2015.
  2. Figueroa MI et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE trial. 15th EACS, Barcelona 2015. Oral abstract LPBS 4/1.
  3. Reynes J et al. Dual therapy with dolutegravir and lamivudine maintains virologic suppression in HIV-infectedHAART-treated patients: DOLULAM pilot study. 15th EACS, Barcelona 2015. Poster abstract PE 8/81.
  4. Gubavu C et al. Simplification for dolutegravir as a mono- or bitherapy maintains high proportion of viral suppression even in highly-experienced HIV-1-infected patients. 15th EACS, Barcelona 2015. Poster abstractPE 8/37.
  5. Rojas J et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: A 24-weekPilot Study. 15th EACS, Barcelona 2015. Oral abstract LPBS 4/2.
  6. Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15th EACS,Barcelona 2015. Oral abstract PS 4/4.
  7. Rokx et al. 1st HIV forum: integrase inhibitors, 20 October 2015, Barcelona. Personal communication. Fullreference to follow.
  8. See: Maintenance Therapy with Less than Three Drugs Doesn't Work. DrFax 40 (16th February 1998).
  9. Collins S. Kaletra monotherapy: small studies and early data. HTB September 2004.
  10. Paton N et al. Randomised controlled trial of a PI monotherapy switch strategy forlong-term HIV management. 21st CROI, 2014, Boston. Late breaker poster abstract 550LB. See HTB March 2014.
  11. Wainberg M et al.What if a new HIV integrase inhibitor was not prone to the problem of drug resistance?15th EACS, 21-24 October 2015, Barcelona. Poster abstract PE9/8.
  12. Demarest J et al. Integrated analysis of emergent drug resistance through 96 & 144 weeks from clinical studies of HIV-1 treatment-naive subjects receiving dolutegravir based regimens. 15th EACS, Barcelona 2015. Poster abstract PE 9/21.
  13. Clayden P. Medicines Patent Pool adds dolutegravir. HTB South, June 2014.