Dolutegravir: A Powerful Drug Entering Different Research Paths

Dolutegravir, sold as Tivicay and in a pill called Triumeq (containing dolutegravir + abacavir + 3TC), belongs to a class of anti-HIV drugs called integrase inhibitors. These drugs, when used as part of potent combination anti-HIV therapy (commonly called ART), can quickly reduce the amount of HIV in the blood. Other licensed integrase inhibitors are elvitegravir (found in Genvoya and Stribild) and raltegravir (Isentress).

Dolutegravir-based regimens have performed very well in clinical trials, showing good general safety and either rough equivalence or statistical superiority to other leading regimens. Dolutegravir derives its potency, in part, because it binds very tightly to a viral enzyme called integrase. This enzyme is needed by HIV to help the virus insert its genetic material into a cell's DNA. Minor changes, or mutations, in integrase generally do not stop dolutegravir from binding to HIV. Furthermore, dolutegravir seems to bind to integrase for a relatively long period of time (hours). The relatively long time that dolutegravir binds to integrase may make it difficult for HIV to develop high-level resistance, particularly in people who are using dolutegravir-based ART for the first time, provided they take ART every day, exactly as directed.

Clinical Trials Ahead

Dolutegravir's advantages in clinical trials -- its relative potency, safety, once-daily dosing (in people who have not taken ART before), lack of food restrictions and limited drug interactions -- have caused researchers to theorize about different ways of using the drug. For instance, because dolutegravir is so powerful, some researchers are seeking to test this drug in simplification studies. In such studies, regimens are simplified from the usual four or three drugs to two or even one drug alone.

Caution Needed

While dolutegravir is indeed powerful, it is not invincible. If used improperly, treatment failure can occur, particularly in people who have previously used integrase inhibitors. Therefore, simplification regimens are best pursued by entering clinical trials. We will have details from some simplification studies later in this issue of TreatmentUpdate. These trials should be viewed as pilot studies or providing preliminary results because they are generally small and of short duration (six to 12 months). They may provide interesting results, but such results require confirmation in a larger trial of more robust statistical design.

Dolutegravir's power has also intrigued some researchers to move in the opposite direction of simplification -- intensification. In such studies, standard ART regimens are intensified by adding dolutegravir. Researchers at the Alfred Hospital in Melbourne, Australia, and elsewhere are planning such intensification studies.

References

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2. Molina JM, Clotet B, van Lunzen J, et al. 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.
3. Rhodes M, Laffan S, Genell C, et al. Assessing a theoretical risk of dolutegravir-induced developmental immunotoxicity in juvenile rats. Toxicological Sciences. 2012 Nov;130(1):70-81.
4. Hightower KE, Wang R, Deanda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrobial Agents and Chemotherapy. 2011 Oct;55(10):4552-9.
5. Anstett K, Fusco R, Cutillas V, et al. Dolutegravir-selected HIV-1 containing the N155H and R263K resistance substitutions does not acquire additional compensatory mutations under drug pressure that lead to higher-level resistance and increased replicative capacity. Journal of Virology. 2015 Oct;89(20):10482-8.
6. Malet I, Thierry E, Wirden M, et al. Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance. Journal of Antimicrobial Chemotherapy. 2015 Oct;70(10):2870-80.
7. Osman N, Mesplède T, Quashie PK, et al. Dolutegravir maintains a durable effect against HIV replication in tissue culture even after drug washout. Journal of Antimicrobial Chemotherapy. 2015 Oct;70(10):2810-5.
8. Liang J, Mesplède T, Oliveira M, et al. The combination of the R263K and T66I resistance substitutions in HIV-1 integrase is incompatible with high-level viral replication and the development of high-level drug resistance. Journal of Virology. 2015 Nov 15;89(22):11269-74.