HTB

Remarkable results with dolutegravir monotherapy

NOTE: AT CROI 2017, A HIGHER RISK OF VIRAL REBOUND AND DEVELOPMENT OF INTEGRASE INHIBITOR DRUG RESISTANCE MEANS THAT DOLUTEGRAVIR MONOTHERAPY IS NOT RECOMMENDED. ANYONE USING DOLUTEGRAVIR IS RECOMMENDED TO SWITCH TO DUAL OR TRIPLE THERAPY. 
http://i-base.info/htb/31289

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Simon Collins, HIV i-Base

15th EACS graphicEACS 2015 presented the first evidence that dolutegravir, the most recently approved integrase inhibitor, might have a resistance profile that enables monotherapy.

More surprisingly, several research groups reported similar results, with people maintaining viral suppression for up to six months without eveidence of low level blips that were seen with bossted PI monotherapy. Something special was reported: these results would not happen with any other HIV drug.

Two small, uncontrolled, open label studies were presented as oral abstracts, using dolutegravir as a single drug monotherapy in similar groups of treatment-experienced patients.

The first study was presented by Esteban Martinez from University of Barcelona. [1] It included 33 people who had been diagnosed for a median of 19 years and who had been on suppressive HIV treatment for a median of 8 years (IQR 4 to 13 years).

Median age was 56 years (IQR 50-62), 40% had a history of AIDS-related complications, and half the group were women. At the start of the study, 11 people were using PI-based treatment, 9 were using NNTRI-based treatment and two people were already using an integrase inhibitor (one on raltegravir and one on elvitegravir).

After 24 weeks of dolutegravir monotherapy, 32/33 study participants still had an undetectable viral load (using a test sensitive to <37 copies/mL).

The single case of viral load rebound was in a person with a history of viral failure on a previous integrase inhibitor-based combination, This occurred at week 4, with a viral rebound to 88 copies/mL (and confirmed at 155 copies/mL). This person reported low adherence, including to the subsequent dose increase to twice-daily dolutegravir. At week 24, viral load remained detectable at 101 copies/mL with evidence of dolutegravir resistance (118R was detected in integrated DNA in 7% PBMCs, but not in blood).

There was no indication that reduction to dolutegravir monotherapy was associated with reduced viral pressure or potency. A post hoc analysis of viral dynamics below the 37 copy/mL cut-off showed that at baseline 11/33 people had a positive signal of viral replication that was unquantifiable below 37 copies/mL. Of these 11 people, 6 became PCR negative at week 24 and 5 remained with a positive signal. Of the 22 people with negative PCR results at baseline, 20 remained negative at week 24 and 2 became positive but were unquantifiable <37 copies/mL.

The second dolutegravir monotherapy study was reported by Christine Katlama from Pitié-Salpêtrière Hospital in Paris as a single arm observational study in 28 people with a similar HIV and history and level of treatment experience as the Spanish study. [2] Median time since diagnosis was 20 years (IQR 15-21) with median viral suppression of 6.6 years (IQR 3.5 to 7.9 years). Median age was also similar at 48 (IQR 43 to 57) with equal balance of men and women (15/13).

After 24 weeks of dolutegravir monotherapy, 25/28 people still had undetectable viral load using a <50 copy/mL test and 24/25 were undetectable using a <20 copy/mL test, with one result at 37 copies/mL.

However, three participants had viral failure. One person had early viral rebound to 138 copies/mL at week 1 (confirmed at 469 copies/mL) and two cases of late rebound at week 24, to 2220 copies/mL and 291 copies/mL, respectively. These three cases were all in people who had previously used integrase inhibitors. The clinical implications for these cases were serious because they occurred under good adherence (optimal dolutegravir drugs levels were confirmed in all three) and because resistance to dolutegravir developed that was not detectable when baseline samples were subsequently tested.

One person who experienced viral rebound to 300 copies/mL at week 12 still had low level but detectable viral load (at 41 copies/mL) 14 weeks after switching back to triple therapy with rilpivirine/tenofovir/FTC. With longer follow-up this person has since become detectable. [3]

A poster from a second French group reported similarly impressive results for 52 treatment-experienced patients using either dolutegravir monotherapy (n=21) or dual therapy with another drug (n=31). [4]

This cohort included 9 people with previous integrase-inhibitor experience. Over a median follow-up of 27 weeks (IQR 24 to 40) and 45 weeks (IQR 25 to 70), in the mono and dual therapy groups respectively, all except one participant maintained viral suppression to less than 50 copies/mL (with 96% of viral load results <20 copies/mL). The single case of viral rebound was in a patient with low adherence who was using dolutegravir plus maraviroc dual therapy.

The strategy of using dolutegravir with 3TC as initial dual therapy was presented in the same session at EACS and these dual therapy studies are reported later in a separate HTB article below. [5, 6]

Comment

Although these results are from small, uncontrolled studies, maintaining such low levels of viraemia for 24 weeks in people naive to integrase inhibitors has not been seen with any other single drug.

The results are preliminary because the data is still short-term, but the expected dynamics of viral replication – basically how quickly HIV would be expected to respond under similar circumstances with other drugs – mean that something appears to be special about dolutegravir in terms of both potency and the lack of drug resistance.

Just as importantly – and fortunately – dolutegravir has fewer side effects and drug interactions than many other commonly used HIV drugs. So simplifying treatment has the potential to reduce underlying side effects and laboratory abnormalities (including impact on lipids and renal function). 

Looking even further forward, cabotegravir, the follow up compound to dolutegravir, has a long-acting injectable formulation in development that might only require quarterly injections.

If the 24-week results are sustained out to 48 weeks, treatment simplification might become an option for many, questioning the future role of the three most widely used drug classes: nukes (NRTIs), non-nukes (NNRTIs) and protease inhibitors (PIs).

However, simplification to dolutegravir monotherapy failed in 3 out of 28 people, perhaps because of earlier use of integrase inhibitors. In these cases, viral rebound occurred in people who had otherwise been stable on treatment with an undetectable viral load for more than six years. These three people developed resistance to dolutegravir.

Until the longer term risk of viral rebound is understood, together with the mechanism for control and any impact this has on the structure of HIV, the caution to study simplification as dual therapy with 3TC is probably warranted. This should involve larger, well designed, controlled studies. 

The registry at clinicaltrials.gov already lists at least five studies using dolutegravir monotherapy or  in dual therapy with 3TC that are either already ongoing or due to start shortly.  

One of these studies is from a Dutch group that reported using dolutegravir monotherapy at a meeting the day before EACS. This included a case of clinically significant viral rebound on dolutegravir monotherapy that might have involved an interaction with multivitamins. [7] This larger study is already now enrolled. [8]

Although the results only generated limited, Professor Mark Wainberg, who has reported on the resistance profile of dolutegravir for several years, is more optimistic for the potential role in overlapping  strategies for remission and a cure. [9]

Several mechanisms have been suggested for the why resistance to dolutegravir is difficult. One hypothesis is that dolutegravir remains bound to the viral integrase for longer than first-line integrase inhibitors (8 x longer than raltegravir and 26 x longer than elvitegravir). Also, any resulting changes must dramatically impair viral fitness. However, in the continued presence of drugs that bind for shorter periods – ie with good adherence – the binding site would not be unoccupied for long and yet resistance to both raltegravir and elvitegravir easily occurs in conditions of suboptimal viral suppression (>50 copies/mL) on treatment. [10]

Another explanation, perhaps more likely, it that dolutegravir specifically targets a highly conserved section of viral integrase that remains constant even when mutational changes occur elsewhere. Integrase is critical for survival and would be unable to function after structural changes of the responsible proteins. Any mutations involving conserved sequences would result in either non-viable virus, or one with reduced replicative capacity. [11]

Theoretically, resistance is unlikely to develop to any drug that targets a highly-conserved sequence  including in other regions than integrase (ie RT and protease). [12] Dolutegravir is just the first antiretroviral that has this profile that is supported by clinical data. 

These dolutegravir studies appear to be a proof of concept – at least in integrase-naive people – that such regions can not only be effectively targeted, but that this prevents the development of drug resistance.

Resistance to dolutegravir can develop with prior use of raltegravir or elvitegravir and this is a critical caution for future studies. [13]

Some of the many ongoing research questions might also be able to be answered in animal studies. [14]

Thanks to Joseph Sonnabend for additional comments.

References:

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

http://www.professionalabstracts.com/eacs2015/iplanner

  1. Rojas J et al. Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression: a 24-week pilot study. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
  2. Katlama C et al. Dolutegravir monotherapy in HIV-infected patients with suppressed HIV viremia. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/2.
  3. Personal communication with the author.
  4. Hocqueloux L 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, 21-24 October 2015, Barcelona. Poster abstract PE8/37.
  5. Cahn P et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: first results of the PADDLE Trial. 15th EACS, 21-24 October 2015, Barcelona. Oral abstract LBPS4/1.
  6. Collins S. Two-drug first-line ART with dolutegravir plus 3TC: 24-week early results. HTB November/December 2015.
    http://i-base.info/htb/29212
  7. Rokx et al. Dolutegravir as maintenance monotherapy: first experience in four consecutive HIV-1 infected patients. 1st HIV forum: integrase inhibitors, 20 October 2015, Barcelona. Abstract: CC_08 and personal communication.
  8. The Dolutegravir Antiretroviral Mono-Therapy for HIV Trial (DOMONO). clinicaltrials.gov.
    https://clinicaltrials.gov/ct2/show/NCT02401828
  9. 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.
  10. 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
  11. 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
  12. Conserved sequence. Wikipaedia. Accessed 27 October 2015.
    https://en.wikipedia.org/wiki/Conserved_sequence
  13. Marceli A-G et al. Cross-resistance to elvitegravir and dolutegravir in 502 patients failing to raltegravir. International Workshop on Antiviral Drug Resistance, 3-7 June 2014, Berlin. Abstract 88. Antiviral Therapy 2014; 19 Suppl 1:A128.
  14. Hassounah S et al. SIVmac239 integrase as a model of HIV drug resistance against integrase inhibitors. International Workshop on Antiviral Drug Resistance, 21-22 February 2015, Seattle. Abstract 58. Global Antiviral Journal Vol 11 (Supplement 1): p61.

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