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Dolutegravir—a promising antiretroviral in development
Comment
Dolutegravir—a promising antiretroviral in development Published Online October 21, 2011 DOI:10.1016/S14733099(11)70291-2 See Articles page 111
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Combination antiretroviral therapy (cART) has transformed the lives of people living with HIV.1 Studies suggest that treatment with cART might lead to the normal to near-normal life expectancy.2,3 However, the era of cART has not been without problems. The early years were characterised by prescription of intolerably complex regimens of multiple pills taken three times daily, restricted by food and fluid provisions as well as toxic effects, which soon led to recommendations that cART be withheld until crucial for preservation of immunocompetence.4 Over the past decade our understanding of the toxic effects of cART has improved and new, convenient, seemingly less toxic, and more tolerable antiretroviral drugs in old and new classes have become available. Once or twice daily regimens—in particular fixed-dose oncedaily combinations of two or three drugs—have simplified cART and made lifelong prescription far more acceptable. In The Lancet Infectious Diseases, Jan van Lunzen and colleagues5 describe the results of a phase 2b doseranging study of dolutegravir, a new HIV integrase strand transfer inhibitor. Three different doses of dolutegravir given once daily (10 mg, 25 mg, or 50 mg) were compared with efavirenz in a randomised, partly blinded study in treatment-naive patients with HIV. All study groups received a backbone nucleoside combination of tenofovir plus emtricitabine or abacavir plus lamivudine. The key findings were that all doses of dolutegravir induced rapid virological decline, and more patients had plasma HIV RNA viral load of less than 50 copies per mL at week 16 in the dolutegravir groups (93%) than in the efavirenz group (60%). At week 48, 90% of patients receiving dolutegravir versus 82% of those receiving efavirenz had a viral load less than 50 copies per mL. Dolutegravir was well tolerated, not associated with any specific adverse or serious adverse event, and was associated with a more favourable lipid profile. Although the rapid viral decline from baseline in all dolutegravir groups is impressive, this is a characteristic of all integrase strand transfer inhibitors studied so far and does not seem to be associated with any greater chance of long-term virological control compared with other recommended first-line cART regimens.
The findings suggest that dolutegravir will probably be non-inferior to a benchmark first-line competitor such as efavirenz in fully powered phase 3 studies. The two other integrase strand transfer inhibitors either licensed (raltegravir) or in late-phase development (elvitegravir) have both proven their non-inferiority in combination with backbone nucleoside and nucleotide reverse transcriptase inhibitors to a recommended first-line regimen containing efavirenz.6,7 Prescribers and patients seek simple cART regimens with a low pill burden that are potent, durable, tolerable, and safe. Dolutegravir seems at this stage to fulfil these criteria. It is the first integrase strand transfer inhibitor that seems to be a genuinely stand-alone once daily drug. Raltegravir is a twice daily drug—a randomised trial that tested once daily dosing did not show non-inferiority with twice daily dosing.8 Elvitegravir can be given once daily only in the presence of a pharmacokinetic booster to inhibit its metabolism by the cytochrome P450 enzyme system, thus prolonging its half-life. This comes at the cost of increased potential for drug interactions and long-term inhibition of cytochrome P450, the effects of which are unknown. The last hurdle for dolutegravir is the completion of phase 3 randomised trials. This raises some intriguing possibilities. Dolutegravir is a drug developed by GlaxoSmithKline, which owns the fixed-dose backbone nucleoside combination of abacavir plus lamivudine. It would seem natural for the company to partner dolutegravir with abacavir plus lamivudine in phase 3 studies to create a single fixed-dose, once daily, triple-combination tablet. GlaxoSmithKline has announced that the 50 mg dose of dolutegravir has been selected for phase 3 testing. Given this low dose, a tablet combining dolutegravir, abacavir, and lamivudine would probably be little bigger than the present abacavir plus lamivudine once daily pill. The ClinicalTrials.gov website lists a study assessing the relative bioavailability of two new fixed-dose tablets containing 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (NCT01366547), suggesting that this is the preferred strategy. However, abacavir plus lamivudine has had a difficult run over the past few years—abacavir has been associated with an www.thelancet.com/infection Vol 12 February 2012
Comment
increased risk of myocardial infarction compared with other nucleoside and nucleotide reverse transcriptase inhibitors, although this finding remains controversial.9,10 Abacavir plus lamivudine also confers inferior antiretroviral potency when compared with tenofovir plus emtricitabine in participants started on cART with baseline viral loads greater than 100 000 copies per mL.11 So, although dolutegravir seems to be a promising and valuable drug, how will GlaxoSmithKline design the phase 3 studies to convince the abacavir sceptics to prescribe it in a fixed-dose combination with abacavir plus lamivudine in preference to alternative regimens containing tenofovir plus emtricitabine? The design and results of the definitive phase 3 studies are awaited with great interest. Mark Boyd University of New South Wales, The Kirby Institute for infection and immunity in society, Room 217, CC4 East Wing, 45 Beach Street, Coogee, NSW 2034, Australia [email protected] I have received honoraria for HIV advisory board services and presentations provided to Abbott, Bristol Myers Squibb, Janssen-Cilag, and Merck. 1
Correll PK, Law MG, McDonald AM, Cooper DA, Kaldor JM. HIV disease progression in Australia in the time of combination antiretroviral therapies. Med J Aust 1998; 169: 469–72.
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4 5
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Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372: 293–99. van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 2010; 24: 1527–35. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356: 1423–30. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2011; published online Oct 21. DOI:10.1016/S1473-3099(11)70290-0. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravirbased versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796–806. Gilead. Press release: Gilead’s investigational antiretroviral quad regimen meets 48-week primary objective in pivotal phase 3 clinical study 102. http://www.gilead.com/pr_1596378 (accessed Oct 10, 2011). Eron JJ Jr, Rockstroh JK, Reynes J, et al. 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; published online Sept 19. DOI:10.1016/S1473-3099(11)70196-7. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–26. Ding X, Andraca-Carrera E, Cooper C, et al. No association of myocardial infarction with ABC use: an FDA meta-analysis. 18th Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; Feb 27–March 2, 2011. Abstr 808. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 2009; 361: 2230–40.
Dampening the effect of drug resistance in HIV: a leap forward Antiretroviral therapy (ART) inhibits viral replication, allows for recovery of normal immune function, and prevents progression to AIDS in millions of people with HIV. However, if inhibition of viral replication is incomplete, the residual antiviral pressure will select for drug-resistant virus1–2 and increase the risk of disease progression.3 Although drug regimens are designed to prevent these outcomes, some people initiating ART since 1998 have acquired extensively drug-resistant HIV since the treatment’s introduction 14 years ago.4,5 In The Lancet Infectious Diseases, findings6 are reported from the Pursuing Later Treatment Options II (PLATO II) collaboration; this group analyses data from European cohorts to assess outcomes in people with HIV infection with a history of failure of drugs from the three main classes.4,5 The PLATO II collaboration’s analysis6 of this impressive dataset focuses on time trends since 1998 and reports that the ability of ART to obtain durable control of HIV has improved greatly. Furthermore, this www.thelancet.com/infection Vol 12 February 2012
trend was associated with an expected reduction in risk of AIDS. A combination of several factors probably explains these favourable outcomes. First, our understanding of the mechanisms leading to resistance has improved. Technologies providing molecular evidence of the exact areas of the viral genome where resistance might emerge became available around 2000. This technology allowed for an understanding of factors associated with continued viraemia during ART (ie, the role played by true drug resistance rather than merely poor compliance). Furthermore, it aided selection of the next ART regimen in case of resistance. Second, the focus in HIV clinics on education of patients to improve compliance is rapidly increasing.7 The positive results from such behavioural interventions have been reinforced by innovations allowing for a reduction in pill burden and more flexibility in the interval between doses. This reduction and increased flexibility is due to
Published Online October 10, 2011 DOI:10.1016/S14733099(11)70278-X See Articles page 119
91
Dolutegravir—a promising antiretroviral in development Published Online October 21, 2011 DOI:10.1016/S14733099(11)70291-2 See Articles page 111
90
Combination antiretroviral therapy (cART) has transformed the lives of people living with HIV.1 Studies suggest that treatment with cART might lead to the normal to near-normal life expectancy.2,3 However, the era of cART has not been without problems. The early years were characterised by prescription of intolerably complex regimens of multiple pills taken three times daily, restricted by food and fluid provisions as well as toxic effects, which soon led to recommendations that cART be withheld until crucial for preservation of immunocompetence.4 Over the past decade our understanding of the toxic effects of cART has improved and new, convenient, seemingly less toxic, and more tolerable antiretroviral drugs in old and new classes have become available. Once or twice daily regimens—in particular fixed-dose oncedaily combinations of two or three drugs—have simplified cART and made lifelong prescription far more acceptable. In The Lancet Infectious Diseases, Jan van Lunzen and colleagues5 describe the results of a phase 2b doseranging study of dolutegravir, a new HIV integrase strand transfer inhibitor. Three different doses of dolutegravir given once daily (10 mg, 25 mg, or 50 mg) were compared with efavirenz in a randomised, partly blinded study in treatment-naive patients with HIV. All study groups received a backbone nucleoside combination of tenofovir plus emtricitabine or abacavir plus lamivudine. The key findings were that all doses of dolutegravir induced rapid virological decline, and more patients had plasma HIV RNA viral load of less than 50 copies per mL at week 16 in the dolutegravir groups (93%) than in the efavirenz group (60%). At week 48, 90% of patients receiving dolutegravir versus 82% of those receiving efavirenz had a viral load less than 50 copies per mL. Dolutegravir was well tolerated, not associated with any specific adverse or serious adverse event, and was associated with a more favourable lipid profile. Although the rapid viral decline from baseline in all dolutegravir groups is impressive, this is a characteristic of all integrase strand transfer inhibitors studied so far and does not seem to be associated with any greater chance of long-term virological control compared with other recommended first-line cART regimens.
The findings suggest that dolutegravir will probably be non-inferior to a benchmark first-line competitor such as efavirenz in fully powered phase 3 studies. The two other integrase strand transfer inhibitors either licensed (raltegravir) or in late-phase development (elvitegravir) have both proven their non-inferiority in combination with backbone nucleoside and nucleotide reverse transcriptase inhibitors to a recommended first-line regimen containing efavirenz.6,7 Prescribers and patients seek simple cART regimens with a low pill burden that are potent, durable, tolerable, and safe. Dolutegravir seems at this stage to fulfil these criteria. It is the first integrase strand transfer inhibitor that seems to be a genuinely stand-alone once daily drug. Raltegravir is a twice daily drug—a randomised trial that tested once daily dosing did not show non-inferiority with twice daily dosing.8 Elvitegravir can be given once daily only in the presence of a pharmacokinetic booster to inhibit its metabolism by the cytochrome P450 enzyme system, thus prolonging its half-life. This comes at the cost of increased potential for drug interactions and long-term inhibition of cytochrome P450, the effects of which are unknown. The last hurdle for dolutegravir is the completion of phase 3 randomised trials. This raises some intriguing possibilities. Dolutegravir is a drug developed by GlaxoSmithKline, which owns the fixed-dose backbone nucleoside combination of abacavir plus lamivudine. It would seem natural for the company to partner dolutegravir with abacavir plus lamivudine in phase 3 studies to create a single fixed-dose, once daily, triple-combination tablet. GlaxoSmithKline has announced that the 50 mg dose of dolutegravir has been selected for phase 3 testing. Given this low dose, a tablet combining dolutegravir, abacavir, and lamivudine would probably be little bigger than the present abacavir plus lamivudine once daily pill. The ClinicalTrials.gov website lists a study assessing the relative bioavailability of two new fixed-dose tablets containing 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (NCT01366547), suggesting that this is the preferred strategy. However, abacavir plus lamivudine has had a difficult run over the past few years—abacavir has been associated with an www.thelancet.com/infection Vol 12 February 2012
Comment
increased risk of myocardial infarction compared with other nucleoside and nucleotide reverse transcriptase inhibitors, although this finding remains controversial.9,10 Abacavir plus lamivudine also confers inferior antiretroviral potency when compared with tenofovir plus emtricitabine in participants started on cART with baseline viral loads greater than 100 000 copies per mL.11 So, although dolutegravir seems to be a promising and valuable drug, how will GlaxoSmithKline design the phase 3 studies to convince the abacavir sceptics to prescribe it in a fixed-dose combination with abacavir plus lamivudine in preference to alternative regimens containing tenofovir plus emtricitabine? The design and results of the definitive phase 3 studies are awaited with great interest. Mark Boyd University of New South Wales, The Kirby Institute for infection and immunity in society, Room 217, CC4 East Wing, 45 Beach Street, Coogee, NSW 2034, Australia [email protected] I have received honoraria for HIV advisory board services and presentations provided to Abbott, Bristol Myers Squibb, Janssen-Cilag, and Merck. 1
Correll PK, Law MG, McDonald AM, Cooper DA, Kaldor JM. HIV disease progression in Australia in the time of combination antiretroviral therapies. Med J Aust 1998; 169: 469–72.
2
3
4 5
6
7
8
9
10
11
Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372: 293–99. van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 2010; 24: 1527–35. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356: 1423–30. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2011; published online Oct 21. DOI:10.1016/S1473-3099(11)70290-0. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravirbased versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796–806. Gilead. Press release: Gilead’s investigational antiretroviral quad regimen meets 48-week primary objective in pivotal phase 3 clinical study 102. http://www.gilead.com/pr_1596378 (accessed Oct 10, 2011). Eron JJ Jr, Rockstroh JK, Reynes J, et al. 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; published online Sept 19. DOI:10.1016/S1473-3099(11)70196-7. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–26. Ding X, Andraca-Carrera E, Cooper C, et al. No association of myocardial infarction with ABC use: an FDA meta-analysis. 18th Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; Feb 27–March 2, 2011. Abstr 808. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 2009; 361: 2230–40.
Dampening the effect of drug resistance in HIV: a leap forward Antiretroviral therapy (ART) inhibits viral replication, allows for recovery of normal immune function, and prevents progression to AIDS in millions of people with HIV. However, if inhibition of viral replication is incomplete, the residual antiviral pressure will select for drug-resistant virus1–2 and increase the risk of disease progression.3 Although drug regimens are designed to prevent these outcomes, some people initiating ART since 1998 have acquired extensively drug-resistant HIV since the treatment’s introduction 14 years ago.4,5 In The Lancet Infectious Diseases, findings6 are reported from the Pursuing Later Treatment Options II (PLATO II) collaboration; this group analyses data from European cohorts to assess outcomes in people with HIV infection with a history of failure of drugs from the three main classes.4,5 The PLATO II collaboration’s analysis6 of this impressive dataset focuses on time trends since 1998 and reports that the ability of ART to obtain durable control of HIV has improved greatly. Furthermore, this www.thelancet.com/infection Vol 12 February 2012
trend was associated with an expected reduction in risk of AIDS. A combination of several factors probably explains these favourable outcomes. First, our understanding of the mechanisms leading to resistance has improved. Technologies providing molecular evidence of the exact areas of the viral genome where resistance might emerge became available around 2000. This technology allowed for an understanding of factors associated with continued viraemia during ART (ie, the role played by true drug resistance rather than merely poor compliance). Furthermore, it aided selection of the next ART regimen in case of resistance. Second, the focus in HIV clinics on education of patients to improve compliance is rapidly increasing.7 The positive results from such behavioural interventions have been reinforced by innovations allowing for a reduction in pill burden and more flexibility in the interval between doses. This reduction and increased flexibility is due to
Published Online October 10, 2011 DOI:10.1016/S14733099(11)70278-X See Articles page 119
91