Affordability of new HIV treatments
*Esteban Burrone, Greg Perry
In their overview of the recent FLAMINGO study,1 Anton Pozniak and Jose Arribas2 conclude that we might be entering the integrase inhibitor era in HIV treatment, but ask whether innovative medicines like dolutegravir will be affordable. The question is particularly relevant in developing countries, including those most affected by the epidemic. A recent agreement between the Medicines Patent Pool (MPP) and ViiV Healthcare provides hope that price will not be a barrier to the use of dolutegravir in most developing countries.3 The agreement allows for early manufacturing of quality-assured generic dolutegravir and its supply to countries that are home to 93% of adults and 99% of children living with HIV in the developing world. Through the agreement, manufacturers who obtain WHO Prequalification or approval from the Food and Drug Administration or the European Medicines Agency will be able to make affordable generic versions of the medicine, thus creating diversity of supply and price competition. In the past, market competition among generic manufacturers has led to substantial price reductions and, together with major donor funding and community mobilisation, has been key to HIV treatment scale-up in developing countries. Nevertheless, long delays in delivering new treatment options to developing countries have often hindered their rollout. Historically, it has taken between 5 and 10 years after registration in the USA for newly approved anti-retroviral drugs to become available as quality-assured generics for use in developing countries. This MPP-ViiV agreement on dolutegravir will help reduce that time substantially so that clinical considerations, rather than price, can drive HIV treatment decisions in developing countries.
1
We declare no competing interests.
www.thelancet.com Vol 384 September 6, 2014
[email protected] Medicines Patent Pool, Geneva 1202, Switzerland
2
3
Clotet B, Feinberg J, van Lunzen J, et al, on behalf of the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383: 2222–31. Pozniak AL, Arribas JR. FLAMINGO: how much rosier can antiretroviral therapy get? Lancet 2014; 383: 2191–93. Medicines Patent Pool. Medicines Patent Pool, ViiV Healthcare sign licence for the most recent HIV medicine to have received regulatory approval. http://www.medicinespatentpool. org/medicines-patent-pool-viiv-healthcaresign-licence-for-the-most-recent-hivmedicine-to-have-received-regulatoryapproval/ (accessed April 14, 2014).
Type 2 diabetes and cancer as redox diseases? We have read with great interest the hypothesis postulated by James Watson (March 1, p 841)1 that diabetes, dementias, cardiovascular disease, and some cancers are accelerated or even caused by shortages in cellular reactive oxygen species (ROS). Watson reasons that physical activity prevents these diseases by generating ROS, which are needed for redox potentials to correctly fold proteins in the endoplasmatic reticulum. Remarkably, physical activity can not only contribute to cancer prevention,2 but also prolong survival and delay recurrence in patients with cancer. 3 Therefore, Watson’s hypothesis resonates well with cancer metabolism as a driver of malignancy. By comparison with quiescent cells, proliferating cells decrease nutrient flow through the Krebs cycle and electron transport chain in favour of aerobic glycolysis (known as the Warburg effect).4 For reductive biosynthetic reactions, cells are in high demand of NADPH. 4 Because the electron transport chain is the major generator of ROS and NADPH is an important antioxidant,5 such
metabolic rewiring might contribute to ROS shortages. This contribution might non-specifically hamper the stabilisation of tumour suppressor proteins, for example, which can further contribute to oncogenesis. Therefore, we are convinced that Watson’s insights can be elaborated more explicitly into cancer by hypothesising that the therapeutic effect of physical activity in cancer relies on the restoration of the low ROS levels caused by cancerous metabolic rewiring. Watson’s proposal to unravel the molecular basis of physical activity as therapy for diabetes could also benefit cancer research and patients with cancer.
DR P Marazzi/Science Photo Library
Correspondence
For more on the Medicines Patent Pool see http://www. medicinespatentpool.org/
We declare no competing interests.
*Remco J Molenaar, Cornelis J van Noorden [email protected] Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, Netherlands 1 2
3
4
5
Watson JD. Type 2 diabetes as a redox disease. Lancet 2014; 383: 841–43. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. Can Med Assoc J 2006; 174: 801–09. Irwin ML, Smith AW, McTiernan A, et al. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008; 26: 3958–64. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 2012; 21: 297–308. Koehler A, Van Noorden CJ. Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution-induced liver cancer in female flounder. Environ Toxicol Chem 2003; 22: 2703–10.
There is a body of evidence to refute James Watson’s hypothesis suggesting that the reason for type 2 diabetes might be cellular oxidant production failure.1 Werner syndrome is characterised by the premature onset of many processes associated with ageing. Patients with Werner syndrome show hallmarks of metabolic syndrome, including visceral obesity, hypertriglyceridaemia, insulin resistant type 2 diabetes, and associated cardiovascular diseases. Remarkably, the prominent findings 853
Correspondence
Erol Project Development House for the disorders of energy metabolism, Internal medicine, Muammer Aksoy Caddesi, Elmas sokak 4, Silivri, Istanbul, Turkey
Oxidative stress
Exercise
1 Systemic DNA damage response
Genomic instability
2
3 Type 2 diabetes mellitus
4 Figure: Oxidative stress-mediated crosstalk between type 2 diabetes and exercise 5
of patients with Werner syndrome are increased reactive oxygen species (ROS) levels and genomic instability.2 Free radicals causing oxidative stress are inevitable byproducts of mitochondrial metabolism and have been proposed to exert repetitive damage to individual cells. However, exercise-induced repeated exposure to sublethal stress (ROS) has been proposed to enhance stress resistance and ultimately increased survival rates due to hormesis.3 The molecular mechanism behind the favourable effect of exercise could be linked to redox homoeostasis. The exercise-induced oxidative challenge-associated systemic adaptation mechanism is initiated by transcription factors, resulting in increased antioxidant enzymes, more effective repair and housekeeping by the DNA repair enzymes and proteasome complex. 4 Exercise-induced IGF-1 and PGC-1 production are other beneficial aspects of exercise, leading to increased production of mitochondria. They are also crucial in the maintenance of glucose, lipid, and energy homoeostasis.5 Finally, exercise-mediated stress activates the AMPK-p53 signalling pathway, which, in turn, decreases the systemic metabolic stress, inhibits mTORC1, and induces autophagy, which are considered beneficial for preventing age-associated pathologies (figure).4 I declare no competing interests.
Adnan Erol [email protected]
854
Watson JD. Type 2 diabetes as a redox disease. Lancet 2014; 383: 841–43. Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 2010; 24: 158–72. Ristow M, Zarse K, Oberbach A, et al. Antioxidant prevents health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 2009; 106: 8665–70. Erol A. Systemic DNA damage response and metabolic syndrome as a premalignant state. Curr Mol Med 2010; 10: 321–34. Sandri M, Lin J, Handschin C, et al. PGC1a protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 2006; 103: 16260–65.
67th WHA Resolution on violence prevention misses the mark Men and boys bear most of the mortality and morbidity burden from intentional injuries. 1 Yet the recent World Health Assembly (WHA)’s resolution to strengthen the role of the health system in addressing violence specifically requests a focus on women and children. 2 The new Resolution sets a remarkable precedent: no other WHA response to a priority health condition purposively directs prevention efforts away from the most vulnerable group. The Resolution recognises that men are among those most affected, but nearly every clause directs focus to women, girls, and children without clear justification. The distinction between girls and children further entrenches a preventive effort directed at female children. Why should boys be accorded less protection? Adverse childhood experiences including harsh physical punishment predict later violent behaviour. Preventing violence against boys should be a priority not an afterthought. Women are more vulnerable than men to certain forms of violence
such as sexual assault, intimate partner violence, and rape. The role of gender features prominently in all of these forms, but if this is what the Resolution seeks to address it should do so explicitly, and not exclude men victims by also focusing on homophobic violence. For other forms of violence men and boys feature prominently among the vulnerable: youth violence, random acts of violence, abuse of the elderly, and child abuse. It is hardly coincidental that men are more frequently both the victims and perpetrators of most violence and should be primary targets for intervention. But the Resolution stops short of condemning the acceptability and tolerance of violence against boys and men in its requests to Member States, and relegates their involvement to promoting gender equality and empowerment of women and girls. The Resolution might raise the profile of violence among the world’s pressing health and development problems, but it is not clear how this omission of men is expected to strengthen the health system’s response.3 The UN system is replete with reports, resolutions, and declarations denouncing various forms of violence against women and children. The sentiment is laudable in attempting to offer redress to groups that are traditionally equated with vulnerability. For UNICEF, children are the raison d’être and the wellbeing of mothers a natural extension. For UNDP maternal and under-five mortality are key evaluative metrics for its MDG.4 But the World Health Assembly as the highest decision making authority for global health needs to be guided by epidemiology and evidence rather than sentiment. We declare no competing interests.
*Richard Matzopoulos, Morna Cornell, Brett Bowman, Jonny Myers [email protected]
www.thelancet.com Vol 384 September 6, 2014
*Esteban Burrone, Greg Perry
In their overview of the recent FLAMINGO study,1 Anton Pozniak and Jose Arribas2 conclude that we might be entering the integrase inhibitor era in HIV treatment, but ask whether innovative medicines like dolutegravir will be affordable. The question is particularly relevant in developing countries, including those most affected by the epidemic. A recent agreement between the Medicines Patent Pool (MPP) and ViiV Healthcare provides hope that price will not be a barrier to the use of dolutegravir in most developing countries.3 The agreement allows for early manufacturing of quality-assured generic dolutegravir and its supply to countries that are home to 93% of adults and 99% of children living with HIV in the developing world. Through the agreement, manufacturers who obtain WHO Prequalification or approval from the Food and Drug Administration or the European Medicines Agency will be able to make affordable generic versions of the medicine, thus creating diversity of supply and price competition. In the past, market competition among generic manufacturers has led to substantial price reductions and, together with major donor funding and community mobilisation, has been key to HIV treatment scale-up in developing countries. Nevertheless, long delays in delivering new treatment options to developing countries have often hindered their rollout. Historically, it has taken between 5 and 10 years after registration in the USA for newly approved anti-retroviral drugs to become available as quality-assured generics for use in developing countries. This MPP-ViiV agreement on dolutegravir will help reduce that time substantially so that clinical considerations, rather than price, can drive HIV treatment decisions in developing countries.
1
We declare no competing interests.
www.thelancet.com Vol 384 September 6, 2014
[email protected] Medicines Patent Pool, Geneva 1202, Switzerland
2
3
Clotet B, Feinberg J, van Lunzen J, et al, on behalf of the ING114915 Study Team. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet 2014; 383: 2222–31. Pozniak AL, Arribas JR. FLAMINGO: how much rosier can antiretroviral therapy get? Lancet 2014; 383: 2191–93. Medicines Patent Pool. Medicines Patent Pool, ViiV Healthcare sign licence for the most recent HIV medicine to have received regulatory approval. http://www.medicinespatentpool. org/medicines-patent-pool-viiv-healthcaresign-licence-for-the-most-recent-hivmedicine-to-have-received-regulatoryapproval/ (accessed April 14, 2014).
Type 2 diabetes and cancer as redox diseases? We have read with great interest the hypothesis postulated by James Watson (March 1, p 841)1 that diabetes, dementias, cardiovascular disease, and some cancers are accelerated or even caused by shortages in cellular reactive oxygen species (ROS). Watson reasons that physical activity prevents these diseases by generating ROS, which are needed for redox potentials to correctly fold proteins in the endoplasmatic reticulum. Remarkably, physical activity can not only contribute to cancer prevention,2 but also prolong survival and delay recurrence in patients with cancer. 3 Therefore, Watson’s hypothesis resonates well with cancer metabolism as a driver of malignancy. By comparison with quiescent cells, proliferating cells decrease nutrient flow through the Krebs cycle and electron transport chain in favour of aerobic glycolysis (known as the Warburg effect).4 For reductive biosynthetic reactions, cells are in high demand of NADPH. 4 Because the electron transport chain is the major generator of ROS and NADPH is an important antioxidant,5 such
metabolic rewiring might contribute to ROS shortages. This contribution might non-specifically hamper the stabilisation of tumour suppressor proteins, for example, which can further contribute to oncogenesis. Therefore, we are convinced that Watson’s insights can be elaborated more explicitly into cancer by hypothesising that the therapeutic effect of physical activity in cancer relies on the restoration of the low ROS levels caused by cancerous metabolic rewiring. Watson’s proposal to unravel the molecular basis of physical activity as therapy for diabetes could also benefit cancer research and patients with cancer.
DR P Marazzi/Science Photo Library
Correspondence
For more on the Medicines Patent Pool see http://www. medicinespatentpool.org/
We declare no competing interests.
*Remco J Molenaar, Cornelis J van Noorden [email protected] Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, Netherlands 1 2
3
4
5
Watson JD. Type 2 diabetes as a redox disease. Lancet 2014; 383: 841–43. Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. Can Med Assoc J 2006; 174: 801–09. Irwin ML, Smith AW, McTiernan A, et al. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008; 26: 3958–64. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 2012; 21: 297–308. Koehler A, Van Noorden CJ. Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution-induced liver cancer in female flounder. Environ Toxicol Chem 2003; 22: 2703–10.
There is a body of evidence to refute James Watson’s hypothesis suggesting that the reason for type 2 diabetes might be cellular oxidant production failure.1 Werner syndrome is characterised by the premature onset of many processes associated with ageing. Patients with Werner syndrome show hallmarks of metabolic syndrome, including visceral obesity, hypertriglyceridaemia, insulin resistant type 2 diabetes, and associated cardiovascular diseases. Remarkably, the prominent findings 853
Correspondence
Erol Project Development House for the disorders of energy metabolism, Internal medicine, Muammer Aksoy Caddesi, Elmas sokak 4, Silivri, Istanbul, Turkey
Oxidative stress
Exercise
1 Systemic DNA damage response
Genomic instability
2
3 Type 2 diabetes mellitus
4 Figure: Oxidative stress-mediated crosstalk between type 2 diabetes and exercise 5
of patients with Werner syndrome are increased reactive oxygen species (ROS) levels and genomic instability.2 Free radicals causing oxidative stress are inevitable byproducts of mitochondrial metabolism and have been proposed to exert repetitive damage to individual cells. However, exercise-induced repeated exposure to sublethal stress (ROS) has been proposed to enhance stress resistance and ultimately increased survival rates due to hormesis.3 The molecular mechanism behind the favourable effect of exercise could be linked to redox homoeostasis. The exercise-induced oxidative challenge-associated systemic adaptation mechanism is initiated by transcription factors, resulting in increased antioxidant enzymes, more effective repair and housekeeping by the DNA repair enzymes and proteasome complex. 4 Exercise-induced IGF-1 and PGC-1 production are other beneficial aspects of exercise, leading to increased production of mitochondria. They are also crucial in the maintenance of glucose, lipid, and energy homoeostasis.5 Finally, exercise-mediated stress activates the AMPK-p53 signalling pathway, which, in turn, decreases the systemic metabolic stress, inhibits mTORC1, and induces autophagy, which are considered beneficial for preventing age-associated pathologies (figure).4 I declare no competing interests.
Adnan Erol [email protected]
854
Watson JD. Type 2 diabetes as a redox disease. Lancet 2014; 383: 841–43. Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 2010; 24: 158–72. Ristow M, Zarse K, Oberbach A, et al. Antioxidant prevents health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 2009; 106: 8665–70. Erol A. Systemic DNA damage response and metabolic syndrome as a premalignant state. Curr Mol Med 2010; 10: 321–34. Sandri M, Lin J, Handschin C, et al. PGC1a protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 2006; 103: 16260–65.
67th WHA Resolution on violence prevention misses the mark Men and boys bear most of the mortality and morbidity burden from intentional injuries. 1 Yet the recent World Health Assembly (WHA)’s resolution to strengthen the role of the health system in addressing violence specifically requests a focus on women and children. 2 The new Resolution sets a remarkable precedent: no other WHA response to a priority health condition purposively directs prevention efforts away from the most vulnerable group. The Resolution recognises that men are among those most affected, but nearly every clause directs focus to women, girls, and children without clear justification. The distinction between girls and children further entrenches a preventive effort directed at female children. Why should boys be accorded less protection? Adverse childhood experiences including harsh physical punishment predict later violent behaviour. Preventing violence against boys should be a priority not an afterthought. Women are more vulnerable than men to certain forms of violence
such as sexual assault, intimate partner violence, and rape. The role of gender features prominently in all of these forms, but if this is what the Resolution seeks to address it should do so explicitly, and not exclude men victims by also focusing on homophobic violence. For other forms of violence men and boys feature prominently among the vulnerable: youth violence, random acts of violence, abuse of the elderly, and child abuse. It is hardly coincidental that men are more frequently both the victims and perpetrators of most violence and should be primary targets for intervention. But the Resolution stops short of condemning the acceptability and tolerance of violence against boys and men in its requests to Member States, and relegates their involvement to promoting gender equality and empowerment of women and girls. The Resolution might raise the profile of violence among the world’s pressing health and development problems, but it is not clear how this omission of men is expected to strengthen the health system’s response.3 The UN system is replete with reports, resolutions, and declarations denouncing various forms of violence against women and children. The sentiment is laudable in attempting to offer redress to groups that are traditionally equated with vulnerability. For UNICEF, children are the raison d’être and the wellbeing of mothers a natural extension. For UNDP maternal and under-five mortality are key evaluative metrics for its MDG.4 But the World Health Assembly as the highest decision making authority for global health needs to be guided by epidemiology and evidence rather than sentiment. We declare no competing interests.
*Richard Matzopoulos, Morna Cornell, Brett Bowman, Jonny Myers [email protected]
www.thelancet.com Vol 384 September 6, 2014
