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First-line integrase inhibitors for HIV—prices versus benefits
Comment
First-line integrase inhibitors for HIV—prices versus benefits WHO guidelines recommend first-line treatment for HIV with tenofovir, lamivudine (or emtricitabine), and either the non-nucleoside efavirenz or the integrase strand inhibitor dolutegravir.1 Many antiretrovirals are now becoming available worldwide as low-cost generics. Patents have already expired for efavirenz, nevirapine, abacavir, and lamivudine, whereas the basic patents on tenofovir, atazanavir, and ritonavir-boosted lopinavir will expire by 2018.2 In low-income countries, voluntary licensing and mass generic production has already enabled millions of people infected with HIV to access antiretroviral treatment at low prices.3 Generic combination treatment with tenofovir, lamivudine, and efavirenz is available in low-income countries for between US$110 and $184 per person-year.4 As patents expire, middle-income and high-income countries are also accessing generic antiretrovirals at very low prices. In low-income countries, integrase inhibitors should become available in the future, at low prices, through voluntary licensing. However, in middle-income and high-income countries, the patents on integrase strand inhibitors such as dolutegravir will remain in place for at least another 10 years, which could keep their prices high. The launch price for the patented combination of abacavir, lamivudine, and dolutegravir in the USA was $32 000 per person-year (average wholesale price).5 New first-line treatments for HIV could offer some clinical benefits over low-cost generic alternatives, but do these benefits justify the high prices being charged? The most recent International Antiviral Society-USA HIV treatment guidelines6 state “although relative efficacy in viral suppression is lower with an efavirenz-based regimen than with integrase-based regimens, the differences are modest and driven by tolerability rather than potency. Where resource constraints limit the ability of a health system to provide widespread treatment to all HIV-infected persons, a strategy of using generic formulations of recommended regimens first with use of more expensive drugs for those who demonstrate intolerance may be reasonable.” In The Lancet HIV, Steve Kanters and colleagues7 present results from a network meta-analysis, which compares the efficacy and safety of different first-line treatments for HIV infection. They conclude that integrase inhibitors—in particular dolutegravir—are
associated with significantly higher rates of long-term HIV RNA suppression than standard-dose efavirenz. Both integrase inhibitors and low-dose efavirenz (assessed in the ENCORE1 trial8) were associated with lower risks of treatment discontinuation than standard-dose efavirenz. However, this meta-analysis7 has a methodological issue, which limits the applicability of the results. In the meta-analysis,7 the most common endpoints used to define viral suppression classified virological failures as discontinuation of their randomly assigned drug for any reason (eg, the US Food and Drug Administration Snapshot method). In most clinical trials with these endpoints, only a minority of the failures are truly virological; most people have undetectable HIV RNA when they discontinue treatment, doing so because of adverse events or other reasons, and can then be switched onto alternative treatments to sustain long-term virological suppression.9,10 In the meta-analysis,7 the conclusion is that virological failure rates are significantly higher for efavirenz than dolutegravir. However, in the SINGLE trial,11 the largest head-to-head study comparing dolutegravir and efavirenz (table), the virological failure rate at week 144 was actually slightly higher for dolutegravir (10%) than for efavirenz (7%). More discontinuations because of adverse events or other reasons occurred in the efavirenz group (30%) than in the dolutegravir group (18%). The trial reported a small, non-significant difference in the risk of treatment-emergent resistance between the groups. So what is the value of a new treatment like dolutegravir that is better tolerated than standard dose efavirenz and has a higher barrier to resistance, but does not improve virological suppression rates? Dolutegravir is significantly more expensive than generic efavirenz
Lancet HIV 2016 Published Online September 6, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30154-0 See Online/Articles http://dx.doi.org/10.1016/ S2352-3018(16)30091-1
ABC/3TC/DTG
TDF/FTC/EFV
Sample size
414
419
HIV RNA <50 copies per mL (NC=F)
296 (71%)
265 (63%)
Virological non-responders
43 (10%)
30 (7%)
Discontinuation of treatment
75 (18%)
124 (30%)
Drug resistance
0
7 (2%)
ABC/3TC/DTG=abacavir/lamivudine/dolutegravir. TDF/FTC/EFV=tenofovir disproxil fumarate/emtricitabine/efavirenz. NCF=non-completer equals failure.
Table: Summary week 144 results from the SINGLE trial of first-line dolutegravir versus efavirenz11
www.thelancet.com/hiv Published online September 6, 2016 http://dx.doi.org/10.1016/S2352-3018(16)30154-0
1
Comment
in most middle-income and high-income countries—is it worth the additional cost? In a US analysis published in 2015,12 dolutegravir did not show cost-effectiveness versus efavirenz, even at branded prices. This issue of cost-effectiveness will become far more pronounced when the value of dolutegravir is compared with lowcost generic versions of efavirenz. One option, as proposed by the International Antiviral Society-USA treatment guidelines panel,6 if budgets are limited, would be to start patients on low-cost generic drugs, and only to switch to more expensive integrase inhibitors in case of adverse events. National Health authorities need to carefully assess how universal access programmes for HIV prevention, testing, treatment, and care can be achieved within realistic budgets. Difficult decisions will need to be taken if we are to achieve the UNAIDS targets for antiretroviral treatment coverage. *Anton L Pozniak, Andrew M Hill St Stephens AIDS Trust, Chelsea and Westminster Hospital, London SW10 9NH, UK [email protected] ALP has received consultancy payments from Gilead, Janssen, BMS, Merck, ViiV, and Cipla, not connected with this project. AMH has received consultancy payments from Janssen, Gilead, ViiV, BMS, Merck, and Cipla, not connected with this project.
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1
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3
4
5 6
7
8
9 10 11
12
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach, 2nd edn. http://www.who.int/hiv/pub/arv/arv-2016/en/ (accessed Oct 22, 2016). Medecins San Frontieres Access Campaign. Untangling the web of antiretroviral price reductions. www.msfaccess.org/utw (accessed Aug 18, 2016). Vitoria M, Hill AM, Ford N, Doherty M, Khoo SH, Pozniak AL. Choice of antiretroviral drugs for continued treatment scale-up in a public health approach: what more do we need to know? J Int AIDS Soc 2016; 19: 20504. Gotham D, Smith R, Hill A, Simmons B, Pozniak A. Differences in antiretroviral drug prices between countries within and outside sub-Saharan Africa. World AIDS conference; Durban, South Africa; July 18–22, 2016. TUPEE624. Positively aware. A new triple threat against HIV. http://positivelyaware. com/articles/a-new-triple-threat (accessed Aug 21, 2016). Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults. 2016 Recommendations of the International Antiviral Society–USA Panel. JAMA 2016; 316: 191–210. Kanters S, Vitoria M, Doherty M, et al. Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis. Lancet HIV 2016; published online Sept 6. http://dx.doi.org/10.1016/S2352-3018(16)30091-1. ENCORE-1 study group. Efficacy and safety of efavirenz 400mg daily versus 600mg daily: 96 week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE-1 study. Lancet Infect Dis 2015; 15: 793–802. Hill A, DeMasi R. Discordant conclusions from HIV efficacy trials—an evaluation of efficacy endpoints. Antivir Ther 2005; 10: 367–74. Hill A, Sabin C. Designing and interpreting HIV noninferiority trials in naïve and experienced patients. AIDS 2008; 22: 913–21. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naïve patients: Week 96 and Week 144 results from the SINGLE randomised clinical trial. J Acquir Immune Defic Syndr 2015; 70: 515–19. Peng S, Tafazzoli A, Dorman E, Rosenblatt L, Vilassis-Keever A, Sorensen S. Cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States. J Med Econ 2015; 18: 763–76.
www.thelancet.com/hiv Published online September 6, 2016 http://dx.doi.org/10.1016/S2352-3018(16)30154-0
First-line integrase inhibitors for HIV—prices versus benefits WHO guidelines recommend first-line treatment for HIV with tenofovir, lamivudine (or emtricitabine), and either the non-nucleoside efavirenz or the integrase strand inhibitor dolutegravir.1 Many antiretrovirals are now becoming available worldwide as low-cost generics. Patents have already expired for efavirenz, nevirapine, abacavir, and lamivudine, whereas the basic patents on tenofovir, atazanavir, and ritonavir-boosted lopinavir will expire by 2018.2 In low-income countries, voluntary licensing and mass generic production has already enabled millions of people infected with HIV to access antiretroviral treatment at low prices.3 Generic combination treatment with tenofovir, lamivudine, and efavirenz is available in low-income countries for between US$110 and $184 per person-year.4 As patents expire, middle-income and high-income countries are also accessing generic antiretrovirals at very low prices. In low-income countries, integrase inhibitors should become available in the future, at low prices, through voluntary licensing. However, in middle-income and high-income countries, the patents on integrase strand inhibitors such as dolutegravir will remain in place for at least another 10 years, which could keep their prices high. The launch price for the patented combination of abacavir, lamivudine, and dolutegravir in the USA was $32 000 per person-year (average wholesale price).5 New first-line treatments for HIV could offer some clinical benefits over low-cost generic alternatives, but do these benefits justify the high prices being charged? The most recent International Antiviral Society-USA HIV treatment guidelines6 state “although relative efficacy in viral suppression is lower with an efavirenz-based regimen than with integrase-based regimens, the differences are modest and driven by tolerability rather than potency. Where resource constraints limit the ability of a health system to provide widespread treatment to all HIV-infected persons, a strategy of using generic formulations of recommended regimens first with use of more expensive drugs for those who demonstrate intolerance may be reasonable.” In The Lancet HIV, Steve Kanters and colleagues7 present results from a network meta-analysis, which compares the efficacy and safety of different first-line treatments for HIV infection. They conclude that integrase inhibitors—in particular dolutegravir—are
associated with significantly higher rates of long-term HIV RNA suppression than standard-dose efavirenz. Both integrase inhibitors and low-dose efavirenz (assessed in the ENCORE1 trial8) were associated with lower risks of treatment discontinuation than standard-dose efavirenz. However, this meta-analysis7 has a methodological issue, which limits the applicability of the results. In the meta-analysis,7 the most common endpoints used to define viral suppression classified virological failures as discontinuation of their randomly assigned drug for any reason (eg, the US Food and Drug Administration Snapshot method). In most clinical trials with these endpoints, only a minority of the failures are truly virological; most people have undetectable HIV RNA when they discontinue treatment, doing so because of adverse events or other reasons, and can then be switched onto alternative treatments to sustain long-term virological suppression.9,10 In the meta-analysis,7 the conclusion is that virological failure rates are significantly higher for efavirenz than dolutegravir. However, in the SINGLE trial,11 the largest head-to-head study comparing dolutegravir and efavirenz (table), the virological failure rate at week 144 was actually slightly higher for dolutegravir (10%) than for efavirenz (7%). More discontinuations because of adverse events or other reasons occurred in the efavirenz group (30%) than in the dolutegravir group (18%). The trial reported a small, non-significant difference in the risk of treatment-emergent resistance between the groups. So what is the value of a new treatment like dolutegravir that is better tolerated than standard dose efavirenz and has a higher barrier to resistance, but does not improve virological suppression rates? Dolutegravir is significantly more expensive than generic efavirenz
Lancet HIV 2016 Published Online September 6, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30154-0 See Online/Articles http://dx.doi.org/10.1016/ S2352-3018(16)30091-1
ABC/3TC/DTG
TDF/FTC/EFV
Sample size
414
419
HIV RNA <50 copies per mL (NC=F)
296 (71%)
265 (63%)
Virological non-responders
43 (10%)
30 (7%)
Discontinuation of treatment
75 (18%)
124 (30%)
Drug resistance
0
7 (2%)
ABC/3TC/DTG=abacavir/lamivudine/dolutegravir. TDF/FTC/EFV=tenofovir disproxil fumarate/emtricitabine/efavirenz. NCF=non-completer equals failure.
Table: Summary week 144 results from the SINGLE trial of first-line dolutegravir versus efavirenz11
www.thelancet.com/hiv Published online September 6, 2016 http://dx.doi.org/10.1016/S2352-3018(16)30154-0
1
Comment
in most middle-income and high-income countries—is it worth the additional cost? In a US analysis published in 2015,12 dolutegravir did not show cost-effectiveness versus efavirenz, even at branded prices. This issue of cost-effectiveness will become far more pronounced when the value of dolutegravir is compared with lowcost generic versions of efavirenz. One option, as proposed by the International Antiviral Society-USA treatment guidelines panel,6 if budgets are limited, would be to start patients on low-cost generic drugs, and only to switch to more expensive integrase inhibitors in case of adverse events. National Health authorities need to carefully assess how universal access programmes for HIV prevention, testing, treatment, and care can be achieved within realistic budgets. Difficult decisions will need to be taken if we are to achieve the UNAIDS targets for antiretroviral treatment coverage. *Anton L Pozniak, Andrew M Hill St Stephens AIDS Trust, Chelsea and Westminster Hospital, London SW10 9NH, UK [email protected] ALP has received consultancy payments from Gilead, Janssen, BMS, Merck, ViiV, and Cipla, not connected with this project. AMH has received consultancy payments from Janssen, Gilead, ViiV, BMS, Merck, and Cipla, not connected with this project.
2
1
2
3
4
5 6
7
8
9 10 11
12
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach, 2nd edn. http://www.who.int/hiv/pub/arv/arv-2016/en/ (accessed Oct 22, 2016). Medecins San Frontieres Access Campaign. Untangling the web of antiretroviral price reductions. www.msfaccess.org/utw (accessed Aug 18, 2016). Vitoria M, Hill AM, Ford N, Doherty M, Khoo SH, Pozniak AL. Choice of antiretroviral drugs for continued treatment scale-up in a public health approach: what more do we need to know? J Int AIDS Soc 2016; 19: 20504. Gotham D, Smith R, Hill A, Simmons B, Pozniak A. Differences in antiretroviral drug prices between countries within and outside sub-Saharan Africa. World AIDS conference; Durban, South Africa; July 18–22, 2016. TUPEE624. Positively aware. A new triple threat against HIV. http://positivelyaware. com/articles/a-new-triple-threat (accessed Aug 21, 2016). Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults. 2016 Recommendations of the International Antiviral Society–USA Panel. JAMA 2016; 316: 191–210. Kanters S, Vitoria M, Doherty M, et al. Comparative efficacy and safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis. Lancet HIV 2016; published online Sept 6. http://dx.doi.org/10.1016/S2352-3018(16)30091-1. ENCORE-1 study group. Efficacy and safety of efavirenz 400mg daily versus 600mg daily: 96 week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE-1 study. Lancet Infect Dis 2015; 15: 793–802. Hill A, DeMasi R. Discordant conclusions from HIV efficacy trials—an evaluation of efficacy endpoints. Antivir Ther 2005; 10: 367–74. Hill A, Sabin C. Designing and interpreting HIV noninferiority trials in naïve and experienced patients. AIDS 2008; 22: 913–21. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naïve patients: Week 96 and Week 144 results from the SINGLE randomised clinical trial. J Acquir Immune Defic Syndr 2015; 70: 515–19. Peng S, Tafazzoli A, Dorman E, Rosenblatt L, Vilassis-Keever A, Sorensen S. Cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States. J Med Econ 2015; 18: 763–76.
www.thelancet.com/hiv Published online September 6, 2016 http://dx.doi.org/10.1016/S2352-3018(16)30154-0