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Home , Dolutegravir

CLINICAL BRIEF

September 2017 HIV Treatment Clinical Brief:

Clinical trials comparing dolutegravir Dolutegravir with other drugs

Trial name Drugs and Patient Results INTRODUCTION regimens population Dolutegravir (DTG) belongs to the class of antiretroviral compared medicines called inhibitors (INIs) or integrase strand transfer inhibitors (INSTIs). SPRING-2 2,3 Dolutegravir vs. Treatment-naïve At week 48, 88% on dolutegravir and 86% Integrase inhibitors work by blocking integrase, the enzyme on raltegravir had viral required for HIV to insert its viral DNA into the DNA of a host suppression. CD4 cell. DTG is a well-tolerated antiretroviral that is effective SAILING4 Dolutegravir vs. Treatment- At week 48, 71% on at suppressing HIV, can be taken once a day, and has a raltegravir experienced and dolutegravir and 64% high barrier to resistance. It is increasingly recognized as a failing therapy on raltegravir had viral potential fi rst-line treatment option for HIV. suppression (P=0.03). FLAMINGO5 Dolutegravir vs. Treatment-naïve At week 96, 80% on dolutegravir and 68% US FDA-approved integrase inhibitors on darunavir had viral Dolutegravir (DTG; Tivicay®) suppression (P=0.002). (EVG; Vitekta®) SINGLE 6 Dolutegravir Treatment-naïve At week 48, 88% Raltegravir (RAL; Isentress®) with on the dolutegravir and combination and vs. 81% on the efavirenz with combination had viral CLINICAL TRIALS tenofovir and suppression (P=0.003); In clinical trials comparing DTG to other antiretroviral 2% on dolutegravir medicines, DTG was found to be as effective as the other had to stop treatment drugs in the populations studied (see table below). A study due to side effects or using DTG among treatment-experienced patients with other adverse events pre-existing resistance showed that compared to 10% 69% of patients had on the efavirenz- undetectable viral load containing regimen. at week 24.1 IMPAACT Dolutegravir Treatment- At week 48, 61% had P10937 with an experienced viral suppression. optimized 12- to 18-year- background old adolescents regimen Tablet sizes of DAWNING8 Dolutegravir Treatment- At week 24, 78% efavirenz 600 mg with 2 experienced of subjects on (top) and 200 mg nucleoside adults failing dolutegravir vs. (middle) compared reverse fi rst-line 69% on / to dolutegravir 50 mg transcriptase therapy of achieved (bottom). inhibitors NNRTI + 2NRTIs viral suppression. The Markings on the tablet, color, and design may differ among (NRTIs) vs. Independent Data manufacturers. lopinavir/ Monitoring Committee ritonavir (LPV/ recommended RTV) with discontinuation of the 2NRTIs lopinavir/ritonavir arm Published by amfAR (P <0.001). Please Visit Us Online at www.treatasia.org In treatment-naïve women, a DTG plus abacavir (ABC) plus European Medicines Association lamivudine (3TC) regimen provided statistically superior viral suppression (HIV-1 RNA <50 copies/mL) rates at week 48 dolutegravir dosing compared to boosted with ritonavir (ATV/r) plus fumarate/emtricitabine (TDF/FTC).9 Adult dosing Adolescent dosing 50 mg once daily 50 mg once daily for adolescents aged 12 to for people without less than 18 years and weighing at least 40 INDICATIONS documented or clinically kg without resistance to integrase inhibitors DTG is used for the treatment of HIV in combination with suspected resistance to other antiretrovirals in adults and adolescents. It is a useful integrase inhibitors option for treatment-experienced patients because of its potency—its ability to control HIV levels in the body—even 50 mg twice daily for Children from 6 years to less than 12 years when there is resistance to other drugs in the treatment people with documented Body weight (kg) Dosing regimen. It is a recommended fi rst-line treatment for HIV or clinically suspected infection by the Department of Health and Human Services resistance to integrase 15 to less than 20 20 mg once daily (DHHS), the European AIDS Clinical Society (EACS), and the inhibitors (taken as two 10 mg International Antiviral Society-USA (IAS-USA). In its 2016 tablets) Consolidated Guidelines on the Use of Antiretroviral Drugs 50 mg twice daily for 20 to less than 30 25 mg once daily for Treating and Preventing HIV Infection, the World Health people who are taking 30 to less than 40 35 mg once daily Organization (WHO) included DTG in alternative fi rst-line any of these other drugs: (taken as one 25 mg antiretroviral therapy (ART) regimens (see table below). efavirenz, , tablet and one 10 mg rifampin, ritonavir- tablet) boosted WHO 2016 preferred and alternative adult 40 or greater 50 mg once daily ART regimens

Preferred fi rst-line regimens Alternative fi rst-line regimens

TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP) SIDE EFFECTS TDF + 3TC (or FTC) + DTG In registration studies, DTG was better tolerated than efavirenz TDF + 3TC (or FTC) + EFV400 (EFV) or darunavir/ritonavir (DRV/r) and although there was TDF + 3TC (or FTC) + NVP an increased risk of insomnia, more serious central nervous system (CNS) side effects such as depression and suicidal ideation were rare.10 Following marketing approvals, evidence from clinical practice has emerged suggesting that DTG is REGULATORY APPROVALS AND associated with a higher incidence of neuropsychiatric side effects than was observed in clinical trials. In a cohort study of DOSING 556 patients in the Netherlands, after a median follow up of 225 DTG was approved for use by the United States Food and days, DTG was stopped in 15.3% of the patients. The reasons Drug Administration (US FDA) in August 2013, and by the for stopping were intolerability, insomnia, sleep disturbance, European Commission in January 2014. gastrointestinal complaints, and neuropsychiatric symptoms, such as anxiety, psychosis, and depression.11 The need to US FDA dolutegravir dosing switch from DTG was observed to be more frequent when the ART regimen also contained abacavir (ABC). 50 mg once daily for adults and adolescents over 12 years who weigh 40 kg and above, and who have not previously taken antiretrovirals A retrospective study of 1950 patients in Germany starting before or have used other types of antiretrovirals, but never used an an integrase inhibitor between 2007 and 2016 estimated that integrase inhibitor the rate of any adverse event and neuropsychiatric adverse events leading to discontinuation within 12 months was 7.6% 50 mg twice daily for people who have used integrase inhibitors before and who have or are suspected to have resistance to other and 5.6% for DTG, 7.6% and 0.7% for EVG, and 3.3% and integrase inhibitors 1.9% for RAL. Neuropsychiatric adverse events leading to DTG discontinuation were observed more frequently in women, in 50 mg twice daily for people who are taking any of these other drugs patients older than 60 years, and in patients who were human (regardless of whether there has been previous exposure to integrase leucocyte antigen (HLA)-B*5701-negative who initiated ABC at inhibitors): efavirenz, rifampin, ritonavir-boosted fosamprevir, the same time.12 ritonavir-boosted tipranavir DRUG-DRUG INTERACTIONS DTG can interact with some antiretrovirals and other medications. Dose adjustment or more frequent monitoring may be required. Medicine Interaction Recommendation Decreases the concentration Dolutegravir should not be used with etravirine without co- of dolutegravir administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Efavirenz Decreases the concentration 50 mg twice daily of dolutegravir is recommended in treatment- of dolutegravir naïve or treatment-experienced, integrase inhibitor-naïve patients. Nevirapine Decreases the concentration Co-administration with nevirapine should be avoided. of dolutegravir /ritonavir, tipranavir/ritonavir Decreases the concentration 50 mg twice daily of dolutegravir is recommended in treatment- of dolutegravir naïve or treatment-experienced, integrase inhibitor-naïve patients. Oxcarbazepine, phenytoin phenobarbital, carbamazepine, Decreases the concentration Co-administration with these metabolic inducers should be St. John’s wort of dolutegravir avoided. Medications containing polyvalent cations: cation-containing Decreases the concentration Dolutegravir should be administered 2 hours before or 6 hours antacids or laxatives, sucralfate, buffered medications of dolutegravir after taking medications containing polyvalent cations. Oral calcium or iron supplements, including multivitamins Decreases the concentration Dolutegravir should be administered 2 hours before or 6 hours that contain calcium or iron of dolutegravir after taking supplements containing calcium or iron. Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food. Metformin Increases the concentration With concomitant use, limit the total daily dose of metformin of metformin to 1,000 mg either when starting metformin or dolutegravir. When stopping dolutegravir, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of dolutegravir is recommended. Rifampin Decreases the concentration 50 mg twice daily of dolutegravir is recommended in treatment- of dolutegravir naïve or treatment-experienced, integrase inhibitor-naïve patients.

CONTRAINDICATIONS ACCESS TO DOLUTEGRAVIR IN SOUTH DTG is contraindicated in patients: • with a previous hypersensitivity reaction to DTG AND SOUTHEAST ASIA • receiving dofetilide (a class III antiarrhythmic agent), In April 2014, the Medicines Patent Pool (MPP) signed an due to the potential for increased dofetilide plasma agreement with DTG’s originator company, ViiV Healthcare, to 17 concentrations and associated serious and/or life voluntarily license the production and distribution of generic threatening adverse events (such as QT prolongation and pediatric and adult formulations of the drug. The pediatric 18 polymorphic ventricular tachycardia [torsade de points]). voluntary license allows generic DTG to be sold in 121 named countries without requiring that a royalty be paid back to the originator. The adult license19 allows DTG be sold in 92 countries, 13 EVIDENCE GAPS and to additional countries where a patent is not yet granted or : No patterns of anomalies have been observed where a compulsory license20 has been issued. ViiV Healthcare- across data sets reporting safety of DTG in pregnancy, branded DTG is widely available in hospitals in China, Hong Kong including the Antiretroviral Pregnancy Registry (APR), SAR, Malaysia, Singapore, Taiwan, and Thailand. The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC), DTG registration trials, and compassionate use programs. However, the small numbers South and Southeast Asian South and Southeast Asian countries where only pediatric countries where both adult and in these datasets precludes fi rm conclusions. A study in generic formulations can be pediatric generic formulations Botswana of women initiating regimens with either EFV or marketed can be marketed DTG with TDF/FTC during pregnancy found no signifi cant differences in birth outcomes by regimen.14 Malaysia, Sri Lanka, Thailand Bangladesh, Bhutan, Cambodia, India, Indonesia, Laos, Myanmar, Nepal, Philippines, Vietnam Tuberculosis: Information on treating HIV/TB coinfection with a DTG-based regimen is limited and related studies are A full list of countries where adult or pediatric generic DTG formulations can be marketed can be accessed from footnotes 18 and 19. ongoing or planned.

Low- and Middle-Income Countries (LMICs): DTG studies Indian generic companies started producing and marketing this have included limited numbers of people in LMICs. All 624 medicine in February 2017 under voluntary licenses from the participants of the DAWNING study are from LMICs, and 106 MPP and ViiV Healthcare. The generic version has been priced of these are from Asia. Several additional studies in LMICs at 2990 Indian Rupees (approximately US$44.6021 ) for a supply are now under way (e.g., ADVANCE15 and NAMSAL16 in of 30, 50 mg tablets on the private market in India (i.e., outside South Africa and Cameroon). of government purchases). It is anticipated that larger-volume purchases to supply government-funded national HIV programs would drive down the price. REFERENCES

1. Castagna A, et al. Dolutegravir in antiretroviral- 10. Fit for Purpose, Antiretroviral treatment optimisation for experienced patients with raltegravir- and/or elvitegravir- adults and children, HIV i-Base, July 2017 resistant HIV-1: 24-week results of the phase III 11. Boer M, et al. Intolerance of dolutegravir-containing VIKING-3 study, The Journal of Infectious Diseases, combination antiretroviral therapy regimens in real-life August 2014. clinical practice, AIDS, November 2016. 2. Francois R, et al. Once-daily dolutegravir versus 12. Coffmann C, et al. Higher rates of neuropsychiatric raltegravir in antiretroviral-naive adults with HIV-1 adverse events leading to dolutegravir discontinuation in infection: 48 week results from the randomised, double- women and older patients, HIV Medicine, January 2017. blind, non-inferiority SPRING-2 study, The Lancet, March 2013. 13. Adapted from Fit for Purpose, Antiretroviral treatment optimisation for adults and children, HIV i-Base, July 3. Francois R, et al. Once-daily dolutegravir versus twice- 2017 daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a 14. Zash R, et al. Dolutegravir/tenofovir/emtricitabine (DTG/ randomised, double-blind, non-inferiority trial, The TDF/FTC) started in pregnancy is as safe as efavirenz/ Lancet Infectious Diseases, November 2013. tenofovir/emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana, abstract # 4. Cahn P, et al. Dolutegravir versus raltegravir in MOAX0202LB presented at IAS Science, 24-26 July antiretroviral-experienced, integrase-inhibitor-naive 2017, Paris, France. adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study, The Lancet, 15. ClinicalTrials.gov. ADVANCE Study of DTG + TAF + FTC August 2013. vs DTG + TDF + FTC and EFV + TDF+FTC in First-line Antiretroviral Therapy (ADVANCE). 5. Jean MM, et al. Once-daily dolutegravir versus http://www.clinicaltrials.gov/ct2/show/NCT03122262 darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a 16. ClinicalTrials.gov. Efficacy and Safety of a Dolutegravir- randomised, open-label, phase 3b study, The Lancet based Regimen for the Initial Management of HIV HIV, April 2015. Infected Adults in Resource-limited Settings (NAMSAL). http://www.clinicaltrials.gov/ct2/show/NCT02777229 6. Sharon W, et al. Dolutegravir plus abacavir/lamivudine for the initial treatment of HIV-1 infection, The New 17. A voluntary license is an agreement that an originator England Journal of Medicine, November 2013. company or a patent holder may make with other parties that provides the legal right to manufacture, import, and/ 7. Rolando V, et al. Safety and efficacy of dolutegravir or distribute the originator company’s pharmaceutical (DTG;GSK1349572) in treatment-experienced HIV-1 product. infected adolescents: 24-week results from IMPAACT P1093. IDWeek 2013, San Francisco, USA, poster 18. Medicines Patent Pool Foundation Paediatric Sublicense abstract number 172, October 2013. Agreement. http://www.medicinespatentpool.org/ wp-content/uploads/MPPF-Sublicence-Paediatric- 8. Aboud M, et al. Superior efficacy of dolutegravir (DTG) Execution-version-20140401.pdf plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 19. Medicines Patent Pool Foundation Adult Sublicense NRTIs in second-line treatment: interim data from the Agreement. http://www.medicinespatentpool.org/ DAWNING study, abstract #TUAB0105LB, presented at wp-content/uploads/ViiV-MPPF-Adult-Amended-and- IAS Science, 24-26 July 2017, Paris, France. Restated-Sublicence-Adult11.pdf 9. Orell C, et al. Superior efficacy of dolutegravir/abacavir/ 20. Compulsory licensing is when a government allows a lamivudine (DTG/ABC/3TC) fixed dose combination party other than the original patent holder to produce (FDC) compared with ritonavir (RTV) boosted atazanavir a previously patented product or process without the (ATV) plus tenofovir disoproxil fumarate/emtricitabine consent of the patent owner. (TDF/FTC) in treatment-naïve women with HIV-1 21. 1 USD=66.96 Indian Rupees. https://www.rbi.org.in/ infection (ARIA Study). Presented at the International accessed February 14, 2017. AIDS Conference (IAC), 18-22 July 2016, Durban, South Africa. Abstract #10215. www.viivhealthcare.com/media/press-releases/2016/ july/aria-study-shows-superior-efficacy-of-triumeq-for- treatment-na%C3%AFve-women-living-with-.aspx

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