Tivi-que? Why Dolutegravir is the GOAT(Thus Far)

Stop me if I have mentioned this before, but HIV therapy is actually quite simple these days. No longer do patients have to take a “cocktail” of medications (whatever that means, I typically think of the alcoholic cocktail) with regimens being streamlined into one simple pill:

Atripla, Odefsy, Genvoya/Stribild, Triumeq, and the (relatively) new kid on the block, Biktarvy, have made it easier for patients to be compliant with their adherence (or is that, adherent to their compliance?) in regards to HIV medications. The recent guidelines have recommended that integrase inhibitors be the first-line therapy when starting someone who is treatment naive (1):

Within this class, there are 4 integrase inhibitors that are currently used:

• Raltegravir – the first one
• Elvitegravir – typically combined with cobicistat, a booster
• Dolutegravir – usually combined with either Truvada (the “TDF” version) or Descovy (the “TAF” version)
• Bictegravir – only available in combination with emtracitabine and TAF

There is a new, long acting one called cabotegravir (2), though I will not discuss this one here. As with any class of medications, not all of them are created equal, with dolutegravir and bictegravir being the preferred over raltegravir and elvitegravir. 

Why is this? As it so happens, raltegravir has a low barrier to resistance. This was seen in a randomized controlled trial (3), which evaluated once a day to twice a day raltegravir in treatment navie patients with >5000 copies of viral RNA per mL. While both groups had good response at 48 weeks, the once-daily group had a statistically significant lower virological response (<50 copies/mL):

These patients were more likely to exhibit virological failure than the twice-daily group, with more integrase mutations seen as well:

Notably, the N155H and Q148 mutations have been described for both raltegravir and elvitegravir, resulting in cross-resistance (4, 5). Thus, while fairly good medications, lack of adherence may result in quickly getting a mutation that almost knocks out an entire class of medications. Enter, dolutegravir, a second generation integrase inhibitor that dissociates slowly integrase-DNA complexes, achieving a half-life of about 14 hours and has no effect on cytochrome P450 systems. As such, this makes it an attractive option over both raltegravir and elvitegravir.

The SPRING-2 study evaluated dolutegravir and raltegravir in treatment naive patients with HIV-1 infection (6). This was a 96-week non-inferiority, RCT, multicenter study, with patients randomized in a 1:1 fashion to either dolutegravir 50mg daily or raltegravir 400mg daily along with either 2 NRTIs. Primary endpoint was the proportion of patients with viral load <50 copies/mL at week 48. 411 patients were randomized to each group, with both groups achieving similar proportion of patients with viral load <50 copies/mL:

This held true in the per-protocol population:

Notably, there were no mutations to dolutegravir at 48 weeks:

Similar results were seen at 96 weeks between groups (7):

And once again, no resistance to dolutegravir was seen (and no, I am not copying/pasting the same table above; this is literally the same set of patients seen 96 week out):

Similar findings were seen in a set of treatment-experienced patients. In a multi-center, randomized, double-blind, non-inferiority study (8), dolutegravir and raltegravir were compared in patients with >2 viral loads of at least 400 copies/mL and resistance to at least 2 or more classes of drugs. Primary endpoint were proportions of patients with VL >50 copies/mL at week 48. About half of patients had resistance to at least 3 or more classes of ARTs, so these were fairly complicated patients, and many of them had advanced disease. Patients in the dolutegravir group were more likely to have virological success at week 48 when compared to raltegravir (71% vs 64%, difference 7.4%, 95% CI 0.7 to 14.2, p-value 0.03):

Virological failure occurred earlier and more frequently in the raltegravir group (12% vs 6%) by week 48, and four of 354 patients in the dolutegravir group had integrase inhibitor resistance by week 48 compared to 17/361 in the raltegravir group (adjusted difference -3.7%, 95% CI -6.1 to -1.2, p-value 0.003).

Given that N155H, Q148H/K/R, and Y143C/H/R are mutations that can confer resistance to both raltegravir and elvitegravir, a multicenter, open-label study was done to evaluate the performance of dolutegravir with patients who had one of these raltegravir mutations (9). There were 2 cohorts, one with once-daily dolutegravir and another with twice a day dolutegravir. Patients who had a failing raltegravir-based regimen had their integrase inhibitor switched for dolutegravir for 10 days. On day 11, the dolutegravir was kept and the background therapy was changed:

Primary endpoint was the proportion of patients with viral load <400 copies/mL at day 11. 23/24 patients in the twice per day group achieved the primary endpoint vs 21/27 in the once daily group. Furthermore, 75% of patients in the twice daily group had a viral load <50 copies/mL compared to 41% in the once-per day group. Of note, a total of 5 subjects from both cohorts were found to have developed additional integrase resistance mutations or a reduction in DTG susceptibility:

A phase III study, designed similarly to the above study, evaluated twice daily dolutegravir in patients with resistance to raltegravir and elvitegravir (10). Endpoint this time around was proportion of patients with viral load <50 copies/mL at 24 weeks and mean change in viral load at day 8. 69% of patients achieved viral suppression at week 24, with a change in viral load of -1.43 log 10 copies/mL (95% CI 1.52 to -1.34):

Multivariate analysis demonstrated that baseline viral load and DTG susceptibility had strong influence on response. Furthermore, patients with Q148 mutations and secondary mutations had decrease response to dolutegravir:

Despite this, these data suggest that dolutegravir can be used even in the presence of mutations against elvitegravir/raltegravir. 

Switching regimens to a dolutegravir-based regimen is also a reasonable option if given the opportunity. Two studies suggest this is the case. A retrospective study (11) compared switching to either DTG + Truvada (TDF/FTC) or Stribild (EVG/FTC/TDF/c), and did not find a difference in time to virological failure, with 48-week efficacy being 96.1% in the dolutegravir group and 95.4% in the elvitegravir group (p-value 0.941), though more patients in the elvitegravir group had adverse events leading to discontinuation of the drug. COmpare this to a switch from Kaletra to raltegravir (12). In these 2 multi-center, randomized controlled trials, treatment experienced patients were randomized in a 1:1 fashion to continue Lopinavir/raltegravir or to switch to raltegravir. Notably, the trial was stopped at 24 weeks due to lower efficacy in viral suppression in the raltegravir group. Indeed, the overall difference between Kaletra and raltegravir in terms of treatment efficacy was -6.2% (95% CI -11.2 to -1.3):

A similar observational study was performed, where patients with prior treatment failure and who were transitioned to dolutegravir or kept on lopinavir/ritonavir were compared (13). There were more virologic failures in patients who were on a protease inhibitor-boosted regimen compared to dolutegravir, however the difference was not statistically significant:

Finally, an open-label multicenter study compared dolutegravir and lopinavir/ritonavir in those who had failed prior therapies (14), which demonstrated that more patients in the dolutegravir group achieved viral suppression at 48 weeks when compared to those in the lopinavir/ritonavir group:

Subgroup analysis in the ITT population also favored treatment with dolutegravir:

And the FLAMINGO study (15), an open-label randomized trial found that even once-daily dolutegravir was better than darunavir/ritonavir, with an adjusted difference of 7.1% (95% CI 0.9-13.2):

Overall, for both treatment experienced and naive patients, dolutegravir tends to be a good option for first line therapy, with it being favorable over the previously recommended protease-inhibitor combinations. 

References:

1. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society–USA Panel. JAMA. 2020;324(16):1651–1669. doi:10.1001/jama.2020.17025
2. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. The New England Journal of Medicine. 2020 Mar;382(12):1112-1123. DOI: 10.1056/nejmoa1904398.
3. Eron JJ Jr, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, Young B, Katlama C, Gatell-Artigas JM, Arribas JR, Nelson M, Campbell H, Zhao J, Rodgers AJ, Rizk ML, Wenning L, Miller MD, Hazuda D, DiNubile MJ, Leavitt R, Isaacs R, Robertson MN, Sklar P, Nguyen BY; QDMRK Investigators. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011 Dec;11(12):907-15. doi: 10.1016/S1473-3099(11)70196-7. Epub 2011 Sep 18. Erratum in: Lancet Infect Dis. 2011 Dec;11(12):895. Dosage error in article text. PMID: 21933752.
4. Anstett K, Brenner B, Mesplede T, Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology. 2017;14(1):36. Published 2017 Jun 5. doi:10.1186/s12977-017-0360-7
5. Quashie PK, Mesplède T, Wainberg MA. Evolution of HIV integrase resistance mutations. Curr Opin Infect Dis. 2013 Feb;26(1):43-9. doi: 10.1097/QCO.0b013e32835ba81c. Erratum in: Curr Opin Infect Dis. 2014 Aug;27(4):401. Erratum in: Curr Opin Infect Dis. 2014 Jun;27(3):302. PMID: 23242340.
6. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, Bloch M, Podzamczer D, Pokrovsky V, Pulido F, Almond S, Margolis D, Brennan C, Min S; SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013 Mar 2;381(9868):735-43. doi: 10.1016/S0140-6736(12)61853-4. Epub 2013 Jan 8. PMID: 23306000.
7. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, Baril JG, Domingo P, Brennan C, Almond S, Min S; extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35. doi: 10.1016/S1473-3099(13)70257-3. Epub 2013 Sep 25. PMID: 24074642.
8. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S; extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0. Epub 2013 Jul 3. Erratum in: Lancet. 2014 Jan 4;383(9911):30. PMID: 23830355.
9. Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, Poizot-Martin I, Richmond G, Soriano V, Ait-Khaled M, Fujiwara T, Huang J, Min S, Vavro C, Yeo J; VIKING Study Group. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013 Mar 1;207(5):740-8. doi: 10.1093/infdis/jis750. Epub 2012 Dec 7. PMID: 23225901; PMCID: PMC3563307.
10. Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, Molina JM, Chas J, Durant J, Moreno S, Doroana M, Ait-Khaled M, Huang J, Min S, Song I, Vavro C, Nichols G, Yeo JM; VIKING-3 Study Group. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014 Aug 1;210(3):354-62. doi: 10.1093/infdis/jiu051. Epub 2014 Jan 19. PMID: 24446523; PMCID: PMC4091579.
11. Baldin G, Ciccullo A, Capetti A, Rusconi S, Sterrantino G, Cossu MV, Giacomelli A, Lagi F, Latini A, Bagella P, De Luca A, Di Giambenedetto S, Madeddu G. Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentre, observational study. HIV Med. 2019 Feb;20(2):164-168. doi: 10.1111/hiv.12688. Epub 2018 Nov 20. PMID: 30457197.
12. Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, Workman C, Zajdenverg R, Fätkenheuer G, Berger DS, Kumar PN, Rodgers AJ, Shaughnessy MA, Walker ML, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Xu X, Sklar P; SWITCHMRK 1 and 2 investigators. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010 Jan 30;375(9712):396-407. doi: 10.1016/S0140-6736(09)62041-9. Epub 2010 Jan 12. PMID: 20074791.
13. Sangaré MN, Baril JG, de Pokomandy A, Ferreira Guerra S, Carabali M, Laprise C, Thomas R, Klein M, Tremblay C, Roger M, Pexos C, Greenwald ZR, Machouf N, Durand M, Hardy I, Dakouo M, Trevisan A, Laporte L, Schnitzer ME, Trottier H. Treatment Switch to Dolutegravir With 2 Nucleoside Reverse-Transcriptase Inhibitors (NRTI) in Comparison to Continuation With Protease Inhibitor/Ritonavir Among Patients With Human Immunodeficiency Virus at Risk for Prior NRTI Resistance: A Cohort Analysis of Real-World Data. Open Forum Infect Dis. 2020 Sep 4;7(11):ofaa404. doi: 10.1093/ofid/ofaa404. PMID: 33204746; PMCID: PMC7654378.
14. Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, Losso MH, Chetchotisakd P, Brites C, Sievers J, Brown D, Hopking J, Underwood M, Nascimento MC, Punekar Y, Gartland M, Smith K. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial. Lancet Infect Dis. 2019 Mar;19(3):253-264. doi: 10.1016/S1473-3099(19)30036-2. Epub 2019 Feb 4. PMID: 30732940.
15. Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, Kulagin V, Givens N, de Oliveira CF, Brennan C; FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr;2(4):e127-36. doi: 10.1016/S2352-3018(15)00027-2. Epub 2015 Mar 10. Erratum in: Lancet HIV. 2015 Apr;2(4):e126. PMID: 26424673.