- Email: [email protected]
Towards a universal second-line fixed-dose combination ART
Comment
Towards a universal second-line fixed-dose combination ART Over the 30 year history of antiretroviral therapy (ART), we have learnt the hard way that the best way to facilitate close adherence to therapy is to make ART as simple and tolerable as possible. The first years of the combination ART era were characterised by regimens of multiple tablets requiring three times daily dosing, with food and water restrictions. The drugs were frequently toxic and intolerable. By contrast, contemporary ART management is characterised by a selection of effective, well tolerated ART combinations that require people to adhere to only one or two tablets a day. These regimens include fixed-dose combinations of integrase inhibitors or non-nucleoside reverse transcriptase inhibitors combined with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs).1 This situation exists in high-income, middle-income, and low-income countries.2 In those people for whom first-line therapy fails, the situation is different. No single-tablet regimens are available for people who need second-line ART. Until recently, people who required a protease inhibitor had to take a separate ritonavir tablet to facilitate twice or once daily dosing, as well as a separate fixed-dose NRTI combination tablet. This situation is set to change. In The Lancet HIV, Chloe Orkin and colleagues report the results of the EMERALD study, in which people with HIV experiencing virological suppression with a boosted-protease inhibitor plus tenofovir disoproxil fumarate and emtricitabine were randombly assigned to maintain that multicomponent ART or to switch to a fixed-dose combination of cobicistatboosted darunavir plus tenofovir alafenamide and emtricitabine.3 After 48 weeks there was no difference between the groups in terms of the proportions of patients who maintained virological suppression. This result is unsurprising. It is likely that this all-in-one fixed dose combination tablet will become available in high-income countries within the next couple of years. Given that protease inhibitors are seen as preferred agents for second-line ART and beyond, the introduction of this combination will allow people for whom first-line ART has failed to switch to a simple fixed-dose combination as second-line ART. Will this fixed-dose combination regimen translate into the management of second-line ART in low-income
and middle-income countries? During the past 5 years, results from a set of studies4–6 have established a solid evidence base for the selection of a protease-inhibitor containing second-line ART regimen for use after failure of first-line ART containing a non-nucleoside reverse transcriptase inhibitor plus two NRTIs. This effort has facilitated extension of the public health approach to the prescription of second-line ART. The specific combination of NRTIs selected for pairing with boosted protease inhibitors (whether by use of genotypic resistance testing or by standardised algorithm) made no difference to the result of the primary outcome.6–8 Moreover, the people who did best virologically were those who had little-to-no predicted antiretroviral activity with the NRTI class compared with people with intermediate-to-full predicted activity; participants with little-to-no predicted NRTI activity did as well as those receiving two fully active drugs and far better than those who received boosted-protease inhibitor monotherapy.6–8 These findings have generally been interpreted as suggesting that people with baseline NRTI resistance were taking their first-line ART, but probably developed resistance as a result of unanticipated ART interruptions. Conversely, people with multiple NRTI options at baseline were probably non-adherent to both first-line and second-line ART. Satisfactory performance of the combination of a boosted-protease inhibitor plus two NRTIs might simply be attributable to residual activity of lamivudine or emtricitabine, which were nearly always recycled (ie, the maintenance of the relatively unfit replicationincompetent Met184Val mutant).9 This hypothesis is supported by evidence from a second-line study of people with virological control on a second-line ART combination of a boosted-protease inhibitor plus two NRTIs.10 If the NRTI combination used makes no difference to the likelihood of a patient achieving virological suppression with second-line boosted-protease inhibitor-containing ART and the activity of the NRTIs is attributable to the selection of the lamivudine resistance mutant (Met184Val), it could be postulated that an optimised universal second-line ART regimen might only need to contain a boosted-protease inhibitor plus lamivudine. Additionally, evidence suggests
www.thelancet.com/hiv Published online October 6, 2017 http://dx.doi.org/10.1016/S2352-3018(17)30180-7
Lancet HIV 2017 Published Online October 6, 2017 http://dx.doi.org/10.1016/ S2352-3018(17)30180-7 See Online/Articles http://dx.doi.org/10.1016/
S2352-3018(17)30179-0
1
Comment
that in protease inhibitor-unexposed people, the darunavir dose could be optimised from 800 mg per day to 600 mg and possibly even 400 mg.11,12 Taken together the evidence raises the possibility that an optimised universal second-line regimen might be composed of optimised darunavir plus the ritonavir boost and lamivudine. Such a combination would yield a reasonably compact fixed-dose regimen and help to bring the simplified public health approach to the prescription of second-line ART. The results of the EMERALD study herald the emergence of a protease inhibitor-containing fixeddose combination regimen suitable for use as secondline therapy after first-line failure of ART composed of either an integrase inhibitor or non-nucleoside reverse transcriptase inhibitor combined with two NRTIs. The introduction of such a regimen would translate in all settings into a simple and streamlined ART management algorithm. Findings suggest that there might be room to optimise this second-line fixed-dose combination, producing important cost savings and reducing exposure to redundant agents. As always, more research is required. *Mark A Boyd, David A Cooper, Charles F Gilks University of Adelaide, Lyell McEwin Hospital, Adelaide, SA 5112, Australia (MAB); Kirby Institute, University of New South Wales Australia, NSW, Australia (DAC); School of Public health, University of Queensland, Queensland, Australia (CFG) [email protected] MAB reports grants from Gilead and Merck and personal fees from Gilead, Janssen-Cilag, Merck, and ViiV Healthcare. The other authors declare no competing interests.
2
1
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf (accessed Sept 16, 2017). 2 WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach, 2nd edn. Geneva: World Health Organization, 2016.. 3 Orkin C, Molina J-M, Negredo E, et al, on behalf of the EMERALD study group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV 2017; published online Oct 6. http://dx.doi.org/10.1016/S2352-3018(17)30179-0. 4 SECOND-LINE Study Group. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013; 381: 2091–99. 5 Paton NI, Kityo C, Hoppe A, et al Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 2014; 371: 234-47. 6 La Rosa AM, Harrison LJ, Taiwo B, et al Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. Lancet HIV 2016; 3: e247–58. 7 Boyd MA, Moore CL, Molina JM, et al. Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis. Lancet HIV 2015; 2: e42–51. 8 Paton NI, Kityo C, Thompson J, et al. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. Lancet HIV 2017; 4: e341–48. 9 Wainberg MA, Drosopoulos WC, Salomon H, et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 1996; 271: 1282–85. 10 Ciaffi L, Koulla-Shiro S, Sawadogo, et al. Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial. Lancet HIV 2017; 4: e384–92. 11 Moltó J, Valle M, Ferrer E, et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. J Antimicrob Chemother 2015; 70: 1139–45. 12 Molina J-M, El Abassi EM, Gallien S, et al. Efficacy and safety of darunavir dose reduction from 800 to 400 mg daily with ritonavir and TDF/FTC or ABC/3TC in virologically suppressed HIV-1-infected adults: an open-label study (ANRS-165 DARULIGHT sub-study). 9th IAS Conference on HIV Science; Paris, France; July 23–26, 2017. MOPEB0313 (abstr).
www.thelancet.com/hiv Published online October 6, 2017 http://dx.doi.org/10.1016/S2352-3018(17)30180-7
Towards a universal second-line fixed-dose combination ART Over the 30 year history of antiretroviral therapy (ART), we have learnt the hard way that the best way to facilitate close adherence to therapy is to make ART as simple and tolerable as possible. The first years of the combination ART era were characterised by regimens of multiple tablets requiring three times daily dosing, with food and water restrictions. The drugs were frequently toxic and intolerable. By contrast, contemporary ART management is characterised by a selection of effective, well tolerated ART combinations that require people to adhere to only one or two tablets a day. These regimens include fixed-dose combinations of integrase inhibitors or non-nucleoside reverse transcriptase inhibitors combined with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs).1 This situation exists in high-income, middle-income, and low-income countries.2 In those people for whom first-line therapy fails, the situation is different. No single-tablet regimens are available for people who need second-line ART. Until recently, people who required a protease inhibitor had to take a separate ritonavir tablet to facilitate twice or once daily dosing, as well as a separate fixed-dose NRTI combination tablet. This situation is set to change. In The Lancet HIV, Chloe Orkin and colleagues report the results of the EMERALD study, in which people with HIV experiencing virological suppression with a boosted-protease inhibitor plus tenofovir disoproxil fumarate and emtricitabine were randombly assigned to maintain that multicomponent ART or to switch to a fixed-dose combination of cobicistatboosted darunavir plus tenofovir alafenamide and emtricitabine.3 After 48 weeks there was no difference between the groups in terms of the proportions of patients who maintained virological suppression. This result is unsurprising. It is likely that this all-in-one fixed dose combination tablet will become available in high-income countries within the next couple of years. Given that protease inhibitors are seen as preferred agents for second-line ART and beyond, the introduction of this combination will allow people for whom first-line ART has failed to switch to a simple fixed-dose combination as second-line ART. Will this fixed-dose combination regimen translate into the management of second-line ART in low-income
and middle-income countries? During the past 5 years, results from a set of studies4–6 have established a solid evidence base for the selection of a protease-inhibitor containing second-line ART regimen for use after failure of first-line ART containing a non-nucleoside reverse transcriptase inhibitor plus two NRTIs. This effort has facilitated extension of the public health approach to the prescription of second-line ART. The specific combination of NRTIs selected for pairing with boosted protease inhibitors (whether by use of genotypic resistance testing or by standardised algorithm) made no difference to the result of the primary outcome.6–8 Moreover, the people who did best virologically were those who had little-to-no predicted antiretroviral activity with the NRTI class compared with people with intermediate-to-full predicted activity; participants with little-to-no predicted NRTI activity did as well as those receiving two fully active drugs and far better than those who received boosted-protease inhibitor monotherapy.6–8 These findings have generally been interpreted as suggesting that people with baseline NRTI resistance were taking their first-line ART, but probably developed resistance as a result of unanticipated ART interruptions. Conversely, people with multiple NRTI options at baseline were probably non-adherent to both first-line and second-line ART. Satisfactory performance of the combination of a boosted-protease inhibitor plus two NRTIs might simply be attributable to residual activity of lamivudine or emtricitabine, which were nearly always recycled (ie, the maintenance of the relatively unfit replicationincompetent Met184Val mutant).9 This hypothesis is supported by evidence from a second-line study of people with virological control on a second-line ART combination of a boosted-protease inhibitor plus two NRTIs.10 If the NRTI combination used makes no difference to the likelihood of a patient achieving virological suppression with second-line boosted-protease inhibitor-containing ART and the activity of the NRTIs is attributable to the selection of the lamivudine resistance mutant (Met184Val), it could be postulated that an optimised universal second-line ART regimen might only need to contain a boosted-protease inhibitor plus lamivudine. Additionally, evidence suggests
www.thelancet.com/hiv Published online October 6, 2017 http://dx.doi.org/10.1016/S2352-3018(17)30180-7
Lancet HIV 2017 Published Online October 6, 2017 http://dx.doi.org/10.1016/ S2352-3018(17)30180-7 See Online/Articles http://dx.doi.org/10.1016/
S2352-3018(17)30179-0
1
Comment
that in protease inhibitor-unexposed people, the darunavir dose could be optimised from 800 mg per day to 600 mg and possibly even 400 mg.11,12 Taken together the evidence raises the possibility that an optimised universal second-line regimen might be composed of optimised darunavir plus the ritonavir boost and lamivudine. Such a combination would yield a reasonably compact fixed-dose regimen and help to bring the simplified public health approach to the prescription of second-line ART. The results of the EMERALD study herald the emergence of a protease inhibitor-containing fixeddose combination regimen suitable for use as secondline therapy after first-line failure of ART composed of either an integrase inhibitor or non-nucleoside reverse transcriptase inhibitor combined with two NRTIs. The introduction of such a regimen would translate in all settings into a simple and streamlined ART management algorithm. Findings suggest that there might be room to optimise this second-line fixed-dose combination, producing important cost savings and reducing exposure to redundant agents. As always, more research is required. *Mark A Boyd, David A Cooper, Charles F Gilks University of Adelaide, Lyell McEwin Hospital, Adelaide, SA 5112, Australia (MAB); Kirby Institute, University of New South Wales Australia, NSW, Australia (DAC); School of Public health, University of Queensland, Queensland, Australia (CFG) [email protected] MAB reports grants from Gilead and Merck and personal fees from Gilead, Janssen-Cilag, Merck, and ViiV Healthcare. The other authors declare no competing interests.
2
1
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf (accessed Sept 16, 2017). 2 WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach, 2nd edn. Geneva: World Health Organization, 2016.. 3 Orkin C, Molina J-M, Negredo E, et al, on behalf of the EMERALD study group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV 2017; published online Oct 6. http://dx.doi.org/10.1016/S2352-3018(17)30179-0. 4 SECOND-LINE Study Group. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013; 381: 2091–99. 5 Paton NI, Kityo C, Hoppe A, et al Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med 2014; 371: 234-47. 6 La Rosa AM, Harrison LJ, Taiwo B, et al Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study. Lancet HIV 2016; 3: e247–58. 7 Boyd MA, Moore CL, Molina JM, et al. Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis. Lancet HIV 2015; 2: e42–51. 8 Paton NI, Kityo C, Thompson J, et al. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. Lancet HIV 2017; 4: e341–48. 9 Wainberg MA, Drosopoulos WC, Salomon H, et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 1996; 271: 1282–85. 10 Ciaffi L, Koulla-Shiro S, Sawadogo, et al. Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial. Lancet HIV 2017; 4: e384–92. 11 Moltó J, Valle M, Ferrer E, et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. J Antimicrob Chemother 2015; 70: 1139–45. 12 Molina J-M, El Abassi EM, Gallien S, et al. Efficacy and safety of darunavir dose reduction from 800 to 400 mg daily with ritonavir and TDF/FTC or ABC/3TC in virologically suppressed HIV-1-infected adults: an open-label study (ANRS-165 DARULIGHT sub-study). 9th IAS Conference on HIV Science; Paris, France; July 23–26, 2017. MOPEB0313 (abstr).
www.thelancet.com/hiv Published online October 6, 2017 http://dx.doi.org/10.1016/S2352-3018(17)30180-7