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
*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
