Why dolutegravir might get us closer to ending AIDS: next step, further research

1 December 2015. Related: Research studies.

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

Simon Collins, HIV i-Base

Introduction

3-2-1

Several research groups – from Argentina, France, Spain and the Netherlands – presented results at the 15th European AIDS Conference (EACS) in Barcelona 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 quality of life by using fewer drugs associated with fewer side effects. Perhaps only one drug might be needed which already has one of the lowest reports 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. It might be possible to use one injection every three months. Until now, the concern to avoid drug resistance to cabotegravir (very similar to dolutegravir) has meant that researchers have been preoccupied with developing two injectable 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 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 on its own. Three of the studies were in the same session at the conference and these talks will hopefully soon be available as a webcast. [1]

Dolutegravir belongs to a class of drugs called integrase inhibitors and it 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 or 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 two HIV drugs is not a new idea – but until now results have never been able to match results using three active drugs. So the current studies were carefully designed to include very close and frequent monitoring, especially for viral load. The people taking part often had complications with the 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 dolutegravir (50 mg) in a two-drug combination with 3TC (300 mg). Both drugs were taken together, once daily, with or without food. One of these studies was in people starting treatment for the first time and two were in people switching treatment, who had already been undetectable for some time. Four other studies used dolutegravir as a single drug – ie 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 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 in the dolutegravir and 3TC dual therapy studies?

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 involved close monitoring and a lot of clinic visits. As an additional caution, the researchers only expanded the study to 20 people after the first 10 people had shown good responses over the first 8 weeks.

Also importantly, nearly everyone started ART 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 to undetectable (less than 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 viral load response surprising, this was expected. 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 participants 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 less than 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 and 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 dolutegravir 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 33 people who were on stable treatment, having had an undetectable viral load on ART for an average of eight years. These were people with a long and complex history of treatment, but with who had no evidence of integrase inhibitor resistance. 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 case was complicated by poor adherence. In the study overall, tolerability was good and results of laboratory monitoring tests for cholesterol and kidney function both improved.

A second monotherapy study, also 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 of the 28 people had undetectable viral load for 24 weeks, three people had their viral load rebound, one to over 2,000 copies/mL.

In these three cases, adherence was confirmed with good drug levels, but drug resistance still developed against dolutegravir. This might have been linked to previous use of integrase inhibitor treatment, even though integrase resistance was not detected when this was checked at the start of the study.

These three cases temper 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 had undetectable viral load below 50 copies/mL, with 96% of test results being less than 20 copies/mL. The study included some people who had previously used other integrase inhibitors, although all the details for these people were not shown.

One person with previous drug resistance to raltegravir and who used dual therapy with dolutegravir plus maraviroc, experienced viral load rebound and developed 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 showed that combination therapy worked, there were studies looking at whether people could start treatment 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 therapy only produced very short-term benefits. HIV is a rapidly evolving virus and unless viral load is reduced on ART to less than 50 copies/mL and kept this low, the development of drug resistance is nearly always inevitable. With some drugs and combinations, drug resistance takes time to accumulate slowly. But with others, resistance can occur within a few weeks. These results with dolutegravir could change everything, and some prominent researchers, including Professor Mark Weinberg, who has reported on this aspect of dolutegravir over several years, thinking this might play an additional 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 follow-on drug to dolutegravir with a similar structure (called cabotegravir) is in development with the same manufacturer as a long-acting injection. Until now, cabotegravir was believed to need support from other long-acting injectable HIV drugs. The new results with dolutegravir could mean that cabotegravir monotherapy injections might be effective on their own.

What are the cautions?

Although resistance didn’t develop to dolutegravir in the large phase 3 registrational treatment-naive studies this was thought to be because dolutegravir was used in combination with NRTIs. A poster at EACS summarises these data. [12]

Also, although dolutegravir – if used early enough – can sometimes overcome drug resistance to other integrase inhibitors (notably to raltegravir and elvitegravir), this is not always the case, even using a higher double dose (50 mg twice-daily rather than once-daily).

Whether the mono and dual therapy results are sustained will depend on why dolutegravir is special and the mechanism for this protection is not yet understood. Drug 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 might actually be a serious problem. Careful research is essential to look at this possibility as HIV has a long 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 after several years – might come with a risk of seroconversion symptoms and of becoming infectious again to sexual partners. This risk is at a time when the impact of 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 bulleted list shows why further research is needed before these mono and dual strategies 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 specialised 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 interventions, 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 for someone, then the most cautious approach would be to include 3TC with dolutegravir as dual therapy, and have very close monitoring.

Comment

Although these studies generated interest at EACS, many people were cautious about the results.

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

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

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

Even if turns out that dolutegravir monotherapy can only be relied on safely for 24 weeks with frequent monitoring, a fixed-time maintenance period might have extensive potential. This might be able to cover short periods where drug interactions, for example with chemotherapy, include an increased risk of side effects relating to NRTIs.

For many people, six months on dolutegravir monotherapy might get very close to the long outdated concept (and horrible term) of a drug holiday.

For global access, manufacturers ViiV Healthcare have already agreed to dolutegravir being included in the Patent Pool for generic companies to be able to produce. [13]

Several possible explanations have been suggested for why dolutegravir has not lead to resistance. One hypothesis is that the active drug attaches to the binding site on the virus for longer than other integrase inhibitors. Another is that resistance might be occurring, but the resulting virus is so dramatically changed that it is too unfit to replicate. [14]

More likely, is that the dolutegravir targets a section of the HIV genome that is both highly conserved and essential for replication. Again, if a change is taking place, the reduced fitness mean that it appears as if no ongoing replication is occurring. [15, 16]

References:

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

Oral abstract session. Antiretroviral Therapy I. PS1. 22 October 2015, 14:00 – 16:00, 15th EACS, Barcelona 2015.
Figueroa MI et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of he PADDLE trial. 15th EACS, Barcelona 2015. Oral abstract LPBS 4/1.
Reynes J et al. Dual therapy with dolutegravir and lamivudine maintains virologic suppression in HIV-infected HAART-treated patients: DOLULAM pilot study. 15th EACS, Barcelona 2015. Poster abstract PE 8/81.
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 abstract PE 8/37.
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.
Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15th EACS, Barcelona 2015. Oral abstract PS 4/4.
Rokx et al. 1st HIV forum: integrase inhibitors, 20 October 2015, Barcelona. Personal communication. Full reference to follow.
See: Maintenance Therapy with Less than Three Drugs Doesn’t Work. DrFax 40 (16th February 1998).
https://i-base.info/dffax/df40.html
Collins S. Kaletra monotherapy: small studies and early data. HTB September 2004.
https://i-base.info/htb/8989
Paton N et al. Randomised controlled trhttps://i-base.info/htb/24897al of a PI monotherapy switch strategy for long-term HIV management. 21st CROI, 2014, Boston. Late breaker poster abstract 550LB. See HTB March 2014.
https://i-base.info/htb/24897
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.
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.
Clayden P. Medicines Patent Pool adds dolutegravir. HTB South, June 2014.
https://i-base.info/htb-south/2632
Kulkosky J et al. Residues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases. Molecular and Cellular Biology, May 1992, p.2331-2338
15.Wainberg M and Han Y-S. Will drug resistance against dolutegravir in initial therapy ever occur? Front Pharmacol. 2015; 6: 90. (29 Apr 2015). doi: 10.3389/fphar.2015.00090.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413831
Conserved sequence. Wikipaedia. Accessed 27 October 2015.
https://en.wikipedia.org/wiki/Conserved_sequence