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Article Commentary: Generic Substitution of Antiretroviral Agents: Never a Problem?

Article Commentary: Generic Substitution of Antiretroviral Agents: Never a Problem? Antiviral Therapy 2019; 24:389–391 (doi: 10.3851/IMP3321) Commentary Generic substitution of antiretroviral agents: never a problem? 1 1,2 David Burger *, Piter Oosterhof Deparment of Pharmacy, Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands Department of Pharmacy, OLVG, Amsterdam, the Netherlands *Corresponding author e-mail: david.burger@radboudumc.nl More than 30 years after the first antiretroviral agents hypercholesterolaemia, and moreover it follows simi- were introduced to treat HIV infection, many of these lar patterns of more sustained preferences for innova- agents have now become available as generic formu- tor products as seen in patients treated with drugs with lations in Western countries. Initially, the first generics narrow therapeutic ranges, for instance patients with represented ‘older’ antiretroviral agents such as zido- organ transplants or epilepsy. We have various reasons vudine and nevirapine. These agents are no longer the for holding the opinion that generics in HIV are special, recommended first-line options according to DHHS [1] and we want to explain this here. and IAS-USA guidelines [2]. More recently, the most The first aspect that needs to be discussed is that the frequently used nucleoside reverse transcriptase inhibi- bioequivalence criteria for licensing a generic formula- tor backbone in Western countries, tenofovir disoproxil tion of an antiretroviral drug are similar as for any other fumarate/emtricitabine (TDF/FTC), has become generic. drug. That is, the 90% CI of the geometric mean ratio of In the Netherlands there are currently six different man- area under the curve (AUC) and maximum concentra- ufacturers, which have made it possible to reduce prices tion (C ) of the antiretroviral drug in the generic for- max in the range of 80–90% compared with the original mulation versus the innovator product should lie within price of the innovator product (Truvada®). This reduc- 80–125%. Regulatory authorities have adapted this tion is partly possible by gaining a market share due to criterion for drugs with a narrow therapeutic range to the pre-exposure prophylaxis (PrEP) indication. 90–111%, and research has demonstrated that licensed The latest generic introductions in the Netherlands generic antiretrovirals to a large extent also meet this has been darunavir and ritonavir, and we expect the more strict criterion [4]. Some physicians argue that next generic introductions, for example raltegravir, in this interval is too wide for HIV drugs and that indi- 2021. With the latest generic introductions it is now vidual differences within a patient may be larger than possible to provide triple therapy completely generic, 20%. Although theoretically this argument is valid, we for example TDF/FTC plus darunavir/ritonavir. Since think there are two arguments against this statement: health-care costs for HIV-infected patients are responsi- first, current antiretroviral agents that become generic ble for approximately 80% of total drug costs for HIV- are much more forgiving and relatively small differ- infected patients, cost savings through generic drug ences in exposure will not put the patient at increased substitution should be a priority in any national health- risk for therapy failure [5]; second, health-care provid- care system [3]. Inclusion of generic medication in the ers and patients generally do not realize that also intra- existing guidelines would also help this transition. In patient variability exists with innovator products, so addition, it would be helpful if we also spread the posi- variability has always been part of HIV treatment, also tive effects of generic medication, thereby increasing before generic formulations arrived. Research with the confidence among physicians, pharmacists and patients. antiepileptic agent gabapentin demonstrated that intra- Generic substitution is not unique for HIV treat- patient variability because of generic substitution can- ment but in contrast to other disease areas (for exam- not be distinguished from intrapatient variability while ple, hypertension, hyperlipidaemia, etc) it is a relatively continuing taking the innovator product [6]. new phenomenon for HIV-infected patients and pos- In addition to the bioequivalence demonstrated for sibly for their health-care providers too. Therefore, any licensed generic antiretroviral agent, one should we think that generic substitution in HIV treatment also realize that millions of HIV-infected patients are is more novel than for patients with hypertension or currently being treated with complete generic ART ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 389 AVT-19-COM-4539_Burger.indd 389 AVT-19-COM-4539_Burger.indd 389 22/11/2019 11:11:26 22/11/2019 11:11:26 D Burger & P Oosterhof combination, namely outside Western countries. physician instructed – understandably – the patient to Although results from cohorts in resource-limited resume taking the innovator product. countries cannot directly be compared with cohorts Many Western countries have a health-care system in Western countries, there is no indication of subop- where generic substitution is standard policy to save timal treatment because of the use of generics. It is a costs. A pitfall of this system is that patients, physi- good thing that investigators from the HIV-NAT 223 cians and pharmacists are forced to follow this system. study  [7] have presented data that generic switch of The abundance of choice may unfortunately lead to atazanavir/ritonavir showed equivalent pharmacoki- lower acceptance and confidence among physicians and netics, safety and efficacy. It is understandable that patients [11]. such studies will not be carried out for every particular Therefore, we propose that patients reporting adverse generic formulation, but the team in Thailand needs to events shortly after switching to a generic product, with be complimented that they have undertaken this study the exception of a probable or proven allergy to an that supports the uptake of generic atazanavir/ritonavir. excipient, should be asked to participate in an N-of-1 While the abovementioned arguments and data sup- study [12]. Pharmacists should be able to provide both port generic substitution also for antiretroviral agents, the innovator and the generic formulation in a blinded there are still a number of concerns that need to be fashion, for example for 1 month, and both the physi- addressed. First, generic substitution by pharmacists cian and patient are not aware which formulation has should be accompanied by sufficient patient counselling been dispensed. At the end of this period both patient and providing relevant information to the patient about and physician can decide on the optimal formulation, any change in size, colour, package etc, when a change and in case of no preference, the generic version will to a generic is conducted [8]. Furthermore, it is advis- be dispensed. In case of evidence for a preference of the able for the pharmacist to inform the other health-care innovator product over the generic (or for one generic providers of this change. As optimal adherence is cru- over another generic) this should be recorded in the cial for successful HIV therapy, patients should always electronic patient record and specified on the physician be informed about changes in drug formulations, and order. Health-care insurance providers should accept health-care providers must ascertain that patients have this preference after receiving adequate documentation understood these changes. from the prescribing physician. A second issue is that from clinical practice we In summary, we do not believe that generic substi- know that some patients present with (aspecific) side tution of an antiretroviral agent is never a problem. effects shortly after changing formulations containing However as outlined above, these problems can and the same amount of active drug [9]. The mechanisms should be addressed in a structured way. Furthermore, behind the reported side effects can be divided into at adequate counselling of patients by physicians, nurse least four subcategories, each of which may require a consultant/specialist and/or pharmacists can diminish different intervention. First, it is possible that a generic problems associated with generic substitution. As a formulation may contain excipients to which the result, we are confident that maximal cost savings will patient is allergic or experiences complaints. The phar- be achieved through generic substitution without harm- macist is the appropriate health-care provider to give ing the patient’s treatment outcome. the patient the correct generic medicine without this excipient. Second, despite proven bioequivalence, there Disclosure statement can be subtle differences in rate of absorption between formulations, leading to changes in peak concentra- DB has worked on advisory boards for Merck and tions in selected patients. Third, psychological aspects ViiV Healthcare. DB has received research grants from may play a role, where a patient has lower confidence Merck, BMS, Janssen/Tibotec, Gilead and ViiV Health- in the generic product than in the innovator product care. DB has received an educational grant and been a [10]. Therefore, he may report adverse events, some- speaker at a symposium for Merck. PO has worked on times with the intention to be allowed to resume the advisory boards for Gilead and ViiV Healthcare. innovator product. Fourth and finally, shortly after the switch to a generic drug, other factors in a patient may References change too, which can mistakenly be attributed to the 1. DHHS. Guidelines for the Use of Antiretroviral Agents generic switch. For example, we had recently a patient in Adults and Adolescents Living with HIV. (Updated 25 October 2018. Accessed 22 March 2019.) Available who acquired acute hepatitis A infection a few days from https://aidsinfo.nih.gov/contentfiles/lvguidelines/ after initiating generic abacavir/lamivudine. When adultandadolescentgl.pdf liver enzymes were increasing and serological evidence 2. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: of the viral infection was pending, the generic substi- 2018 Recommendations of the International Antiviral tution was among the potential explanations, and the Society-USA Panel. JAMA 2018; 320:379–396. 390 ©2019 International Medical Press AVT-19-COM-4539_Burger.indd 390 AVT-19-COM-4539_Burger.indd 390 22/11/2019 11:11:26 22/11/2019 11:11:26 Generic substitution of antiretroviral agents: never a problem? 3. Rwagitinywa J, Sommet A, Palmaro A, Montastruc JL, 8. Kieran JA, O’Reilly E, O’Dea S, Bergin C, O’Leary A. Generic Lapeyre-Mestre M. Utilization and costs of HIV substitution of antiretrovirals: patients’ and health care antiretroviral drugs in Europe during the last ten years: providers’ opinions. Int J STD AIDS 2017; 28:1239–1246. impact of generic antiretroviral drugs on cost reduction. 9. Rathe JØ. The effect of generic switching on concerns about Health Policy 2018; 122:237–242. medicine and non-persistence among Danish adults in a 4. Gwaza L, Gordon J, Welink J, et al. Interchangeability general practice setting. Dan Med J 2015; 62:B5148. between first-line generic antiretroviral products 10. Evers AWM, Colloca L, Blease C, et al. Implications of prequalified by WHO using adjusted indirect comparisons. placebo and nocebo effects for clinical practice: expert Antivir Ther 2017; 22:135–144. consensus. Psychother Psychosom 2018; 87:204–210. 5. Gianotti N, Poli A, Galli L, et al. Efficacy and safety of 11. Allavena C, Jacomet C, Pereira B, et al. Acceptability and switching from branded to generic antiretrovirals in confidence in antiretroviral generics of physicians and HIV- virologically suppressed HIV-infected patients. PLoS One infected patients in France. J Int AIDS Soc 2014; 17 Suppl 2017; 12:e0182007. 3:19608. 6. Yu Y, Teerenstra S, Neef C, Burger D, Maliepaard M. A 12. Pereira JA, Holbrook AM, Dolovich L, et al. Are brand- comparison of the intrasubject variation in drug exposure name and generic warfarin interchangeable? Multiple n-of-1 between generic and brand-name drugs: a retrospective randomized, crossover trials. Ann Pharmacother 2005; analysis of replicate design trials. Br J Clin Pharmacol 2016; 39:1188–1193. 81:667–678. 7. Hiransuthikul A, Thammajaruk N, Techatanawat I, et al. Pharmacokinetics and 48-week safety and efficacy of generic ritonavir tablet-boosted atazanavir in HIV-1- infected Thai adults. Antivir Ther 2018; 23:699–703. Accepted 2 June 2019; published online 7 June 2019 Antiviral Therapy 24.6 391 AVT-19-COM-4539_Burger.indd 391 AVT-19-COM-4539_Burger.indd 391 22/11/2019 11:11:26 22/11/2019 11:11:26 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Article Commentary: Generic Substitution of Antiretroviral Agents: Never a Problem?

Burger, David; Oosterhof, Piter
Antiviral Therapy , Volume 24 (6): 3 – Aug 1, 2019
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SAGE
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© 2019 SAGE Publications
ISSN
1359-6535
eISSN
2040-2058
DOI
10.3851/imp3321
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Abstract

Antiviral Therapy 2019; 24:389–391 (doi: 10.3851/IMP3321) Commentary Generic substitution of antiretroviral agents: never a problem? 1 1,2 David Burger *, Piter Oosterhof Deparment of Pharmacy, Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands Department of Pharmacy, OLVG, Amsterdam, the Netherlands *Corresponding author e-mail: david.burger@radboudumc.nl More than 30 years after the first antiretroviral agents hypercholesterolaemia, and moreover it follows simi- were introduced to treat HIV infection, many of these lar patterns of more sustained preferences for innova- agents have now become available as generic formu- tor products as seen in patients treated with drugs with lations in Western countries. Initially, the first generics narrow therapeutic ranges, for instance patients with represented ‘older’ antiretroviral agents such as zido- organ transplants or epilepsy. We have various reasons vudine and nevirapine. These agents are no longer the for holding the opinion that generics in HIV are special, recommended first-line options according to DHHS [1] and we want to explain this here. and IAS-USA guidelines [2]. More recently, the most The first aspect that needs to be discussed is that the frequently used nucleoside reverse transcriptase inhibi- bioequivalence criteria for licensing a generic formula- tor backbone in Western countries, tenofovir disoproxil tion of an antiretroviral drug are similar as for any other fumarate/emtricitabine (TDF/FTC), has become generic. drug. That is, the 90% CI of the geometric mean ratio of In the Netherlands there are currently six different man- area under the curve (AUC) and maximum concentra- ufacturers, which have made it possible to reduce prices tion (C ) of the antiretroviral drug in the generic for- max in the range of 80–90% compared with the original mulation versus the innovator product should lie within price of the innovator product (Truvada®). This reduc- 80–125%. Regulatory authorities have adapted this tion is partly possible by gaining a market share due to criterion for drugs with a narrow therapeutic range to the pre-exposure prophylaxis (PrEP) indication. 90–111%, and research has demonstrated that licensed The latest generic introductions in the Netherlands generic antiretrovirals to a large extent also meet this has been darunavir and ritonavir, and we expect the more strict criterion [4]. Some physicians argue that next generic introductions, for example raltegravir, in this interval is too wide for HIV drugs and that indi- 2021. With the latest generic introductions it is now vidual differences within a patient may be larger than possible to provide triple therapy completely generic, 20%. Although theoretically this argument is valid, we for example TDF/FTC plus darunavir/ritonavir. Since think there are two arguments against this statement: health-care costs for HIV-infected patients are responsi- first, current antiretroviral agents that become generic ble for approximately 80% of total drug costs for HIV- are much more forgiving and relatively small differ- infected patients, cost savings through generic drug ences in exposure will not put the patient at increased substitution should be a priority in any national health- risk for therapy failure [5]; second, health-care provid- care system [3]. Inclusion of generic medication in the ers and patients generally do not realize that also intra- existing guidelines would also help this transition. In patient variability exists with innovator products, so addition, it would be helpful if we also spread the posi- variability has always been part of HIV treatment, also tive effects of generic medication, thereby increasing before generic formulations arrived. Research with the confidence among physicians, pharmacists and patients. antiepileptic agent gabapentin demonstrated that intra- Generic substitution is not unique for HIV treat- patient variability because of generic substitution can- ment but in contrast to other disease areas (for exam- not be distinguished from intrapatient variability while ple, hypertension, hyperlipidaemia, etc) it is a relatively continuing taking the innovator product [6]. new phenomenon for HIV-infected patients and pos- In addition to the bioequivalence demonstrated for sibly for their health-care providers too. Therefore, any licensed generic antiretroviral agent, one should we think that generic substitution in HIV treatment also realize that millions of HIV-infected patients are is more novel than for patients with hypertension or currently being treated with complete generic ART ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 389 AVT-19-COM-4539_Burger.indd 389 AVT-19-COM-4539_Burger.indd 389 22/11/2019 11:11:26 22/11/2019 11:11:26 D Burger & P Oosterhof combination, namely outside Western countries. physician instructed – understandably – the patient to Although results from cohorts in resource-limited resume taking the innovator product. countries cannot directly be compared with cohorts Many Western countries have a health-care system in Western countries, there is no indication of subop- where generic substitution is standard policy to save timal treatment because of the use of generics. It is a costs. A pitfall of this system is that patients, physi- good thing that investigators from the HIV-NAT 223 cians and pharmacists are forced to follow this system. study  [7] have presented data that generic switch of The abundance of choice may unfortunately lead to atazanavir/ritonavir showed equivalent pharmacoki- lower acceptance and confidence among physicians and netics, safety and efficacy. It is understandable that patients [11]. such studies will not be carried out for every particular Therefore, we propose that patients reporting adverse generic formulation, but the team in Thailand needs to events shortly after switching to a generic product, with be complimented that they have undertaken this study the exception of a probable or proven allergy to an that supports the uptake of generic atazanavir/ritonavir. excipient, should be asked to participate in an N-of-1 While the abovementioned arguments and data sup- study [12]. Pharmacists should be able to provide both port generic substitution also for antiretroviral agents, the innovator and the generic formulation in a blinded there are still a number of concerns that need to be fashion, for example for 1 month, and both the physi- addressed. First, generic substitution by pharmacists cian and patient are not aware which formulation has should be accompanied by sufficient patient counselling been dispensed. At the end of this period both patient and providing relevant information to the patient about and physician can decide on the optimal formulation, any change in size, colour, package etc, when a change and in case of no preference, the generic version will to a generic is conducted [8]. Furthermore, it is advis- be dispensed. In case of evidence for a preference of the able for the pharmacist to inform the other health-care innovator product over the generic (or for one generic providers of this change. As optimal adherence is cru- over another generic) this should be recorded in the cial for successful HIV therapy, patients should always electronic patient record and specified on the physician be informed about changes in drug formulations, and order. Health-care insurance providers should accept health-care providers must ascertain that patients have this preference after receiving adequate documentation understood these changes. from the prescribing physician. A second issue is that from clinical practice we In summary, we do not believe that generic substi- know that some patients present with (aspecific) side tution of an antiretroviral agent is never a problem. effects shortly after changing formulations containing However as outlined above, these problems can and the same amount of active drug [9]. The mechanisms should be addressed in a structured way. Furthermore, behind the reported side effects can be divided into at adequate counselling of patients by physicians, nurse least four subcategories, each of which may require a consultant/specialist and/or pharmacists can diminish different intervention. First, it is possible that a generic problems associated with generic substitution. As a formulation may contain excipients to which the result, we are confident that maximal cost savings will patient is allergic or experiences complaints. The phar- be achieved through generic substitution without harm- macist is the appropriate health-care provider to give ing the patient’s treatment outcome. the patient the correct generic medicine without this excipient. Second, despite proven bioequivalence, there Disclosure statement can be subtle differences in rate of absorption between formulations, leading to changes in peak concentra- DB has worked on advisory boards for Merck and tions in selected patients. Third, psychological aspects ViiV Healthcare. DB has received research grants from may play a role, where a patient has lower confidence Merck, BMS, Janssen/Tibotec, Gilead and ViiV Health- in the generic product than in the innovator product care. DB has received an educational grant and been a [10]. Therefore, he may report adverse events, some- speaker at a symposium for Merck. PO has worked on times with the intention to be allowed to resume the advisory boards for Gilead and ViiV Healthcare. innovator product. Fourth and finally, shortly after the switch to a generic drug, other factors in a patient may References change too, which can mistakenly be attributed to the 1. DHHS. Guidelines for the Use of Antiretroviral Agents generic switch. For example, we had recently a patient in Adults and Adolescents Living with HIV. (Updated 25 October 2018. Accessed 22 March 2019.) Available who acquired acute hepatitis A infection a few days from https://aidsinfo.nih.gov/contentfiles/lvguidelines/ after initiating generic abacavir/lamivudine. When adultandadolescentgl.pdf liver enzymes were increasing and serological evidence 2. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: of the viral infection was pending, the generic substi- 2018 Recommendations of the International Antiviral tution was among the potential explanations, and the Society-USA Panel. JAMA 2018; 320:379–396. 390 ©2019 International Medical Press AVT-19-COM-4539_Burger.indd 390 AVT-19-COM-4539_Burger.indd 390 22/11/2019 11:11:26 22/11/2019 11:11:26 Generic substitution of antiretroviral agents: never a problem? 3. Rwagitinywa J, Sommet A, Palmaro A, Montastruc JL, 8. Kieran JA, O’Reilly E, O’Dea S, Bergin C, O’Leary A. Generic Lapeyre-Mestre M. Utilization and costs of HIV substitution of antiretrovirals: patients’ and health care antiretroviral drugs in Europe during the last ten years: providers’ opinions. Int J STD AIDS 2017; 28:1239–1246. impact of generic antiretroviral drugs on cost reduction. 9. Rathe JØ. The effect of generic switching on concerns about Health Policy 2018; 122:237–242. medicine and non-persistence among Danish adults in a 4. Gwaza L, Gordon J, Welink J, et al. Interchangeability general practice setting. Dan Med J 2015; 62:B5148. between first-line generic antiretroviral products 10. Evers AWM, Colloca L, Blease C, et al. Implications of prequalified by WHO using adjusted indirect comparisons. placebo and nocebo effects for clinical practice: expert Antivir Ther 2017; 22:135–144. consensus. Psychother Psychosom 2018; 87:204–210. 5. Gianotti N, Poli A, Galli L, et al. Efficacy and safety of 11. Allavena C, Jacomet C, Pereira B, et al. Acceptability and switching from branded to generic antiretrovirals in confidence in antiretroviral generics of physicians and HIV- virologically suppressed HIV-infected patients. PLoS One infected patients in France. J Int AIDS Soc 2014; 17 Suppl 2017; 12:e0182007. 3:19608. 6. Yu Y, Teerenstra S, Neef C, Burger D, Maliepaard M. A 12. Pereira JA, Holbrook AM, Dolovich L, et al. Are brand- comparison of the intrasubject variation in drug exposure name and generic warfarin interchangeable? Multiple n-of-1 between generic and brand-name drugs: a retrospective randomized, crossover trials. Ann Pharmacother 2005; analysis of replicate design trials. Br J Clin Pharmacol 2016; 39:1188–1193. 81:667–678. 7. Hiransuthikul A, Thammajaruk N, Techatanawat I, et al. Pharmacokinetics and 48-week safety and efficacy of generic ritonavir tablet-boosted atazanavir in HIV-1- infected Thai adults. Antivir Ther 2018; 23:699–703. Accepted 2 June 2019; published online 7 June 2019 Antiviral Therapy 24.6 391 AVT-19-COM-4539_Burger.indd 391 AVT-19-COM-4539_Burger.indd 391 22/11/2019 11:11:26 22/11/2019 11:11:26

Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

There are no references for this article.