- Email: [email protected]
David Reddy—taking HIV therapy to new frontiers
Interview David Reddy—taking HIV therapy to new frontiers Interviewed by Pam Das
David Reddy graduated in cellular and molecular biology from the University of Auckland, New Zealand, in 1983. He remained in this area of research for the next 6 years, and in this time completed a Masters followed by a PhD. The focus of his research was on the development of diagnostic assays for detecting HIV, and genetically engineered vaccines for other viral infections. From 1989–1991, he was a molecular neurobiology research fellow at the Friedrich Miescher Institute in Basel, Switzerland. In 1995 he joined F Hoffmann-La Roche in the Pharmaceuticals Divisions’ Biotechnology Business group. From 1997–1999 he was the Global Business Unit Head for HIV/AIDS and is currently responsible for the Roche Disease Area Strategy for HIV. He is the leader for the Roche-Trimeris fusion-inhibitor development programme, and dedicates a significant proportion of his time to addressing the challenges of HIV in the developing world.
TLID: You are the Global Franchise Leader and Disease Area Strategy Head for HIV/AIDS at F Hoffmann-La Roche Ltd. Could you describe this role and your responsibilities? DR: What it means is that I take the lead in the HIV area, in co-ordinating the overall strategy for the company in the HIV disease area that impacts across the research, development, and business fronts. I also lead the HIV fusion-inhibitor programme for Roche. TLID: How easy was it to make the transition from pure science into the business sector? DR: I think in this role it has been a great benefit to understand the science, the basics of virology, because so much of this position is trying to define what are the key unmet scientific and medical needs, and then to define the strategy the company needs to take to address those needs in the future. This position is geared towards looking to the future. So working with viruses was a great advantage, and with the right support within Roche, it wasn’t a massive transition for me. It is something I have grown into over the years while working with the company. TLID: There has been a great deal of excitement surrounding enfuvirtide, (Fuzeon, T-20)—the firstborn of a new generation of fusion inhibitors to treat HIV. Where do you see this drug in future treatment options?
110
DR: This is a drug that is different to the currently available drugs, because it is from a new class. It is a fusion inhibitor, it actually stops HIV from fusing with the human cell and entering it, while the other existing drugs act once the virus has entered the cell. Because T-20 has a different mechanism of action, it means that the drug has got good activity against HIV that has become resistant to the currently available classes of drugs. Therefore, we see that this drug really has its key role to play in pretreated patients—ie, those who have had experience with one or more members of each of the currently available classes of drugs, and who really do need a new treatment option to be able to suppress their virus. TLID: The manufacturing process for Fuzeon is very complex. Could you tell us why and the challenges that you still need to overcome to produce the large quantities required to meet the likely demand? DR: Fuzeon is a 36-aminoacid peptide and we are piecing it together chemically, and on top of that it is being done at the ton scale. In terms of pharmaceutical manufacturing this is probably the greatest challenge ever undertaken. There are 106 separate chemical synthesis steps required to build this molecule, whereas a typical drug usually has within the region of four to five steps. T-20 requires quite a lot of specialised raw materials, in fact to make 1000 kg of the drug requires 45 000 kg of raw materials. So it was a massive challenge to undertake but we needed to do that,
THE LANCET Infectious Diseases Vol 3 February 2003
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview and at the same time keep the pace with very fast drug development and regulatory review timelines. What I mean by regulatory review timelines is that HIV drugs are now approved based upon surrogate markers for clinical efficacy—changes in viral load and the patient’s immune status. Previously, clinical endpoint studies in HIV required several years to show a difference in terms of reducing mortality or delaying progression to new AIDSdefining illnesses. But we now know that the changes in surrogate markets seen after only 16–24 weeks of therapy are highly predictive of improvements in terms of survival, or delaying time to disease progression. The ability to approve drugs based upon these surrogate markers makes the drug development process for HIV drugs faster. So taking the complex production challenge posed by Fuzeon, compressing it into an even shorter timeframe than normal, and then to be able to reproducibly manufacture the drug at a commercial scale, this has really been quite an achievement for us. TLID: As a result of the expenses incurred in the manufacturing process, what are the cost implications to industry and to the patient? Are there plans to use this drug in Africa? DR: I think that is a very fair question. Clearly, considering the very high costs for raw materials and the complex manufacturing process, this drug will be priced higher than any of the current available HIV medications. And we have been very clear about that from the start. However, there is a very clearly defined role for this drug, and there are no other HIV compounds on the horizon for the next couple of years that will be available to large numbers of patients that really do have a different mechanism of action. So it was critically important to bring this drug ahead. In answer to the second part of your question, there are really two key fronts in the battle against HIV. The first is in Africa where the greatest burden of the disease exists. Here, getting people access to first-line and second-line regimens is the absolute priority. But the second front is here in the developed world, where we are facing the beginnings of a new epidemic, and that is drug-resistant HIV. You need to address the virus on both fronts. So Fuzeon responds to today’s problem in the developed world, but it is highly likely that in the developing world we are also going to have the same issues in the future. As a result we have got an active drug discovery programme in place, which is looking for the new and less complex drugs that will be active against the drug-resistant virus of tomorrow. TLID: Could you tell us about Roche’s work in Africa? DR: The way we are looking at Africa and the UN’s least developed countries, and that includes most of the hardest hit countries, is that within these regions we have pledged that we won’t make a profit from sales of our HIV medications. What this means is that, we are a company
THE LANCET Infectious Diseases Vol 3 February 2003
that has our strength in the HIV protease inhibitor area. We are making one adult drug formulation and one paediatric formulation available at a no-profit price. We have also said that we will not file patents on our new HIV drugs in these countries. In those places in sub-Saharan Africa and the UN least-developed country list where we do hold patents on our currently marketed HIV drugs, we will not enforce our patents against any generic versions of these drugs. So what we are doing in effect, is ensuring that we minimise as much as possible any barriers to access on both fronts, both on the price and on the patent front. Now having said that, making drugs available at a reduced price, or even providing them free, doesn’t address the issue of access, and I think that is one of the problems that we are seeing now. So you can’t really reduce a price, or provide free drugs, and expect the problem of access to be solved. At the 6th International Congress on drug therapy in HIV infection in Glasgow back in November 2002, a leading African physician was part of the panel discussion on the developing world. He was from Botswana, which is perhaps one of the more affluent countries in Africa, but still very hard hit by HIV. Although there has been a lot of investment and aid, he said that even if you were to drop the drug from a helicopter it just wouldn’t do any good without addressing the other issues. So Roche have put in place pilot programmes in Kenya, Uganda, the Ivory Coast, and Senegal. Within these programmes we are providing free HIV medication, free treatment for opportunistic infections, and HIV viral load testing, and, we are providing funding for infrastructure, salaries for healthcare workers, and for training of healthcare professionals. So we are tackling everything to address HIV care. We are doing that in partnership with a not for profit group, PharmAccess International, comprised mainly of Dutch physicians. And those programmes are now enrolling patients and running. So what we have shown is, yes you can make it happen, but you have to address everything, you can’t just do it with the drug alone. One of the lessons for us was that even with all our good intentions and the tremendous expertise of PharmAccess International, it took a year before we got our first patient on medication. So for us there are a couple of messages. One, it is not simple, you have to address everything, but on the other side it is doable, and personally, I believe that if you start things it becomes a catalyst, and it can’t be ignored, and that really is the seed and things grow from there. Second, it is also critical that programmes are developed that are sustainable—we are trying to address this issue too. TLID: At the XIV International AIDS conference in Barcelona (July 7–12, 2002), the issue of testing was discussed, and that many individuals are unaware that they carry the virus. Some experts have said that in part, it is the knowledge of new effective treatment options that are making people less worrisome about the disease, and therefore less likely to be tested. What are your views on this issue?
http://infection.thelancet.com
111
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview
F Hoffmann-La Roche Ltd.
are several points I would like to make on this subject. The first point is that generic drugs alone are not the be all and end all. In India where there are a good many generic HIV drug producers, I think we are seeing that the epidemic is raging and there is still extremely limited access to therapy. The second point is that one of our drugs that is reduced in price actually costs significantly less than the generic drugs that are available. In view of the fact that overall, most HIV medications from the research-based companies are priced close to, or lower than generic equivalents I would ask the question—is that money really going to have its optimal effect in producing drugs that will have little, or no cost advantage A Roche sponsored mobile clinic—the Phelophepa health train in rural South Africa. over the drugs being made available by the research-based companies today? Or DR: In the developed world in the mid 1990s, there was so could that money be better used to provide infrastructure much optimism about HIV therapy. The simple message or healthcare professional training, basically the other sent out was that there was treatment for HIV and it was barriers to care that aren’t being adequately addressed? no longer a worry and, as a result of that, I think you saw some pulling back on prevention and education. I think a TLID: In a recent editorial in The Lancet, the lot of people, probably a lot of younger people, saw less pharmaceutical industry were accused of spending too need to practice safe sex. They are just not so worried much money on recruiting the best talent for their legal anymore, and that is a real problem. What we are seeing departments and not enough on recruiting talent for now is in some groups new infection rates are starting to drug discovery. Would you care to comment on that? really increase again, and the saddest thing is a lot of those new infections are caused by the drug-resistant virus. That DR: I work for a European-based pharmaceutical company is casting us back into an era we thought we had left and I think that in Europe perhaps our views concerning behind, and would rather have left behind. We have got a lawyers may be somewhat different to a US-based lot of work to do on all fronts now to make sure we company. I can say that all companies, be they maintain progress against the virus. pharmaceuticals or not, have their lawyers, but I know In the developing world the challenge is different, and that Roche’s recruitment drive and our focus, is on that is that testing in the absence of treatment is really bringing in and retaining the best research scientists and frustrating and raises the personal question of “why be physicians we can find. We have got a large group of tested?” Place on top of that the fact that in many places if research and clinical scientists. What I can say is that you find you are positive and your positive status becomes I am very proud that a good number of those people known, there is so much stigma that you are ostracised have been working on HIV drugs since the late 1980s, and from your community, from your family, and you can are still part of our team and are now developing, in even lose your job. So you know, it is not a case of some cases, their fourth HIV medication, the fusion ignorance is bliss, but ignorance until the last possible inhibitors. One of our clinical leaders, Miklos Salgo, moment is bliss for those people who have no hope of actually worked on the reverse transcriptase inhibitors access to therapy, and where being HIV positive is back in the late 1980s, then the protease inhibitor associated with so much negative stigma. The unfortunate saquinavir in the early and mid 1990s, and he is now thing is that people that are infected and don’t know can leading our programme for the fusion inhibitors on the go on to transmit the virus, and the vicious cycle clinical side. continues. TLID: What are the next steps for Fuzeon and other TLID: What are your views on some parts of the drugs in the pipeline? developing world taking the situation into their own hands, wanting to ignore drug patents, and produce their DR: Fuzeon has now been filed for regulatory approval in own generic HIV medicines? both the USA and the European Union, and the dossier is currently under evaluation. The phase 3 studies have been DR: Well I have told you what Roche’s stance is on this. provided to the regulatory authorities for evaluation as We leave open the option to use generic copies of our HIV part of those filings, and the data very clearly shows a medications on which we hold patents in sub-Saharan statistically significant benefit in terms of reducing HIVAfrica and the least developed countries. However, there RNA, and improving CD4 cell counts for treatment-
112
THE LANCET Infectious Diseases Vol 3 February 2003
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview experienced patients. We are hoping that the regulatory process proceeds well, and that we may be hearing positive news during the first half of 2003. Behind that, we and Trimeris have another drug which is similar to Fuzeon, called T-1249, another synthetic peptide inhibitor of HIV fusion. It is very closely related to Fuzeon, but at least in the laboratory what we have seen so far is it has potent activity against the majority of the Fuzeon-resistant HIV
strains, and may have an advantage in terms of convenience, in that it is administered only once-daily based on the data that we recently presented. Also in our drug development pipeline we have a novel HIV protease inhibitor, and a non-nucleoside transcriptase inhibitor. We have a healthy pipeline, our activities in HIV are continuing, and we have got very experienced teams of scientists to push these programmes ahead.
Clinical picture Ecthyma gangrenosum and chronic lymphocytic leukaemia A 66-year-old man with a history of chronic lymphocytic leukaemia (CLL) was admitted for evaluation of fever that started 2 weeks earlier and was associated with a skin lesion on the left thigh/buttock area. The patient was taking prednisone 100mg/day for treatment of autoimmune haemolytic anaemia associated with chronic lymphocytic leukaemia. Physical examination was unremarkable except for the skin lesion that was about 2 inches (5 cm) in diameter with surrounding redness, swelling, and tenderness. There was epidermal sloughing with central necrosis suggestive of ecthyma gangrenosum (figure). The patient’s white blood cell count was 34 000 cells/mmoL with only 3% neutrophils, 1% bands and 96% lymphocytes. Aspirate from the lesion and blood cultures obtained on admission grew Pseudomonas aeruginosa. The patient responded well to a 14-day course of intravenous piperacillin/tazobactam and tobramycin. Ecthyma gangrenosum is a characteristic skin sign of life-threatening infection commonly caused by P aeruginosa, although other organisms have been reported to cause ecthyma-like lesions. Ecthyma gangrenosum is usually seen in immunocompromised patients, and hypogammaglobulinaemia is also a predisposing factor for ecthyma gangrenosum; nonetheless, the lesion is rare in patients with CLL.
THE LANCET Infectious Diseases Vol 3 February 2003
Kannan Ramar, Kannan Ramar, Darko Hauer, Anil Potti, and Tze Shien Lo Department of Internal Medicine, University of North Dakota, Fargo, ND, USA. Correspondence: Dr Kannan Ramar, Department of Medicine, University of North Dakota School of Medicine, 1919 Elm St N, Fargo, ND 58102, USA. Fax +1 701 2372486; email [email protected].
http://infection.thelancet.com
113
For personal use. Only reproduce with permission from The Lancet Publishing Group.
David Reddy graduated in cellular and molecular biology from the University of Auckland, New Zealand, in 1983. He remained in this area of research for the next 6 years, and in this time completed a Masters followed by a PhD. The focus of his research was on the development of diagnostic assays for detecting HIV, and genetically engineered vaccines for other viral infections. From 1989–1991, he was a molecular neurobiology research fellow at the Friedrich Miescher Institute in Basel, Switzerland. In 1995 he joined F Hoffmann-La Roche in the Pharmaceuticals Divisions’ Biotechnology Business group. From 1997–1999 he was the Global Business Unit Head for HIV/AIDS and is currently responsible for the Roche Disease Area Strategy for HIV. He is the leader for the Roche-Trimeris fusion-inhibitor development programme, and dedicates a significant proportion of his time to addressing the challenges of HIV in the developing world.
TLID: You are the Global Franchise Leader and Disease Area Strategy Head for HIV/AIDS at F Hoffmann-La Roche Ltd. Could you describe this role and your responsibilities? DR: What it means is that I take the lead in the HIV area, in co-ordinating the overall strategy for the company in the HIV disease area that impacts across the research, development, and business fronts. I also lead the HIV fusion-inhibitor programme for Roche. TLID: How easy was it to make the transition from pure science into the business sector? DR: I think in this role it has been a great benefit to understand the science, the basics of virology, because so much of this position is trying to define what are the key unmet scientific and medical needs, and then to define the strategy the company needs to take to address those needs in the future. This position is geared towards looking to the future. So working with viruses was a great advantage, and with the right support within Roche, it wasn’t a massive transition for me. It is something I have grown into over the years while working with the company. TLID: There has been a great deal of excitement surrounding enfuvirtide, (Fuzeon, T-20)—the firstborn of a new generation of fusion inhibitors to treat HIV. Where do you see this drug in future treatment options?
110
DR: This is a drug that is different to the currently available drugs, because it is from a new class. It is a fusion inhibitor, it actually stops HIV from fusing with the human cell and entering it, while the other existing drugs act once the virus has entered the cell. Because T-20 has a different mechanism of action, it means that the drug has got good activity against HIV that has become resistant to the currently available classes of drugs. Therefore, we see that this drug really has its key role to play in pretreated patients—ie, those who have had experience with one or more members of each of the currently available classes of drugs, and who really do need a new treatment option to be able to suppress their virus. TLID: The manufacturing process for Fuzeon is very complex. Could you tell us why and the challenges that you still need to overcome to produce the large quantities required to meet the likely demand? DR: Fuzeon is a 36-aminoacid peptide and we are piecing it together chemically, and on top of that it is being done at the ton scale. In terms of pharmaceutical manufacturing this is probably the greatest challenge ever undertaken. There are 106 separate chemical synthesis steps required to build this molecule, whereas a typical drug usually has within the region of four to five steps. T-20 requires quite a lot of specialised raw materials, in fact to make 1000 kg of the drug requires 45 000 kg of raw materials. So it was a massive challenge to undertake but we needed to do that,
THE LANCET Infectious Diseases Vol 3 February 2003
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview and at the same time keep the pace with very fast drug development and regulatory review timelines. What I mean by regulatory review timelines is that HIV drugs are now approved based upon surrogate markers for clinical efficacy—changes in viral load and the patient’s immune status. Previously, clinical endpoint studies in HIV required several years to show a difference in terms of reducing mortality or delaying progression to new AIDSdefining illnesses. But we now know that the changes in surrogate markets seen after only 16–24 weeks of therapy are highly predictive of improvements in terms of survival, or delaying time to disease progression. The ability to approve drugs based upon these surrogate markers makes the drug development process for HIV drugs faster. So taking the complex production challenge posed by Fuzeon, compressing it into an even shorter timeframe than normal, and then to be able to reproducibly manufacture the drug at a commercial scale, this has really been quite an achievement for us. TLID: As a result of the expenses incurred in the manufacturing process, what are the cost implications to industry and to the patient? Are there plans to use this drug in Africa? DR: I think that is a very fair question. Clearly, considering the very high costs for raw materials and the complex manufacturing process, this drug will be priced higher than any of the current available HIV medications. And we have been very clear about that from the start. However, there is a very clearly defined role for this drug, and there are no other HIV compounds on the horizon for the next couple of years that will be available to large numbers of patients that really do have a different mechanism of action. So it was critically important to bring this drug ahead. In answer to the second part of your question, there are really two key fronts in the battle against HIV. The first is in Africa where the greatest burden of the disease exists. Here, getting people access to first-line and second-line regimens is the absolute priority. But the second front is here in the developed world, where we are facing the beginnings of a new epidemic, and that is drug-resistant HIV. You need to address the virus on both fronts. So Fuzeon responds to today’s problem in the developed world, but it is highly likely that in the developing world we are also going to have the same issues in the future. As a result we have got an active drug discovery programme in place, which is looking for the new and less complex drugs that will be active against the drug-resistant virus of tomorrow. TLID: Could you tell us about Roche’s work in Africa? DR: The way we are looking at Africa and the UN’s least developed countries, and that includes most of the hardest hit countries, is that within these regions we have pledged that we won’t make a profit from sales of our HIV medications. What this means is that, we are a company
THE LANCET Infectious Diseases Vol 3 February 2003
that has our strength in the HIV protease inhibitor area. We are making one adult drug formulation and one paediatric formulation available at a no-profit price. We have also said that we will not file patents on our new HIV drugs in these countries. In those places in sub-Saharan Africa and the UN least-developed country list where we do hold patents on our currently marketed HIV drugs, we will not enforce our patents against any generic versions of these drugs. So what we are doing in effect, is ensuring that we minimise as much as possible any barriers to access on both fronts, both on the price and on the patent front. Now having said that, making drugs available at a reduced price, or even providing them free, doesn’t address the issue of access, and I think that is one of the problems that we are seeing now. So you can’t really reduce a price, or provide free drugs, and expect the problem of access to be solved. At the 6th International Congress on drug therapy in HIV infection in Glasgow back in November 2002, a leading African physician was part of the panel discussion on the developing world. He was from Botswana, which is perhaps one of the more affluent countries in Africa, but still very hard hit by HIV. Although there has been a lot of investment and aid, he said that even if you were to drop the drug from a helicopter it just wouldn’t do any good without addressing the other issues. So Roche have put in place pilot programmes in Kenya, Uganda, the Ivory Coast, and Senegal. Within these programmes we are providing free HIV medication, free treatment for opportunistic infections, and HIV viral load testing, and, we are providing funding for infrastructure, salaries for healthcare workers, and for training of healthcare professionals. So we are tackling everything to address HIV care. We are doing that in partnership with a not for profit group, PharmAccess International, comprised mainly of Dutch physicians. And those programmes are now enrolling patients and running. So what we have shown is, yes you can make it happen, but you have to address everything, you can’t just do it with the drug alone. One of the lessons for us was that even with all our good intentions and the tremendous expertise of PharmAccess International, it took a year before we got our first patient on medication. So for us there are a couple of messages. One, it is not simple, you have to address everything, but on the other side it is doable, and personally, I believe that if you start things it becomes a catalyst, and it can’t be ignored, and that really is the seed and things grow from there. Second, it is also critical that programmes are developed that are sustainable—we are trying to address this issue too. TLID: At the XIV International AIDS conference in Barcelona (July 7–12, 2002), the issue of testing was discussed, and that many individuals are unaware that they carry the virus. Some experts have said that in part, it is the knowledge of new effective treatment options that are making people less worrisome about the disease, and therefore less likely to be tested. What are your views on this issue?
http://infection.thelancet.com
111
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview
F Hoffmann-La Roche Ltd.
are several points I would like to make on this subject. The first point is that generic drugs alone are not the be all and end all. In India where there are a good many generic HIV drug producers, I think we are seeing that the epidemic is raging and there is still extremely limited access to therapy. The second point is that one of our drugs that is reduced in price actually costs significantly less than the generic drugs that are available. In view of the fact that overall, most HIV medications from the research-based companies are priced close to, or lower than generic equivalents I would ask the question—is that money really going to have its optimal effect in producing drugs that will have little, or no cost advantage A Roche sponsored mobile clinic—the Phelophepa health train in rural South Africa. over the drugs being made available by the research-based companies today? Or DR: In the developed world in the mid 1990s, there was so could that money be better used to provide infrastructure much optimism about HIV therapy. The simple message or healthcare professional training, basically the other sent out was that there was treatment for HIV and it was barriers to care that aren’t being adequately addressed? no longer a worry and, as a result of that, I think you saw some pulling back on prevention and education. I think a TLID: In a recent editorial in The Lancet, the lot of people, probably a lot of younger people, saw less pharmaceutical industry were accused of spending too need to practice safe sex. They are just not so worried much money on recruiting the best talent for their legal anymore, and that is a real problem. What we are seeing departments and not enough on recruiting talent for now is in some groups new infection rates are starting to drug discovery. Would you care to comment on that? really increase again, and the saddest thing is a lot of those new infections are caused by the drug-resistant virus. That DR: I work for a European-based pharmaceutical company is casting us back into an era we thought we had left and I think that in Europe perhaps our views concerning behind, and would rather have left behind. We have got a lawyers may be somewhat different to a US-based lot of work to do on all fronts now to make sure we company. I can say that all companies, be they maintain progress against the virus. pharmaceuticals or not, have their lawyers, but I know In the developing world the challenge is different, and that Roche’s recruitment drive and our focus, is on that is that testing in the absence of treatment is really bringing in and retaining the best research scientists and frustrating and raises the personal question of “why be physicians we can find. We have got a large group of tested?” Place on top of that the fact that in many places if research and clinical scientists. What I can say is that you find you are positive and your positive status becomes I am very proud that a good number of those people known, there is so much stigma that you are ostracised have been working on HIV drugs since the late 1980s, and from your community, from your family, and you can are still part of our team and are now developing, in even lose your job. So you know, it is not a case of some cases, their fourth HIV medication, the fusion ignorance is bliss, but ignorance until the last possible inhibitors. One of our clinical leaders, Miklos Salgo, moment is bliss for those people who have no hope of actually worked on the reverse transcriptase inhibitors access to therapy, and where being HIV positive is back in the late 1980s, then the protease inhibitor associated with so much negative stigma. The unfortunate saquinavir in the early and mid 1990s, and he is now thing is that people that are infected and don’t know can leading our programme for the fusion inhibitors on the go on to transmit the virus, and the vicious cycle clinical side. continues. TLID: What are the next steps for Fuzeon and other TLID: What are your views on some parts of the drugs in the pipeline? developing world taking the situation into their own hands, wanting to ignore drug patents, and produce their DR: Fuzeon has now been filed for regulatory approval in own generic HIV medicines? both the USA and the European Union, and the dossier is currently under evaluation. The phase 3 studies have been DR: Well I have told you what Roche’s stance is on this. provided to the regulatory authorities for evaluation as We leave open the option to use generic copies of our HIV part of those filings, and the data very clearly shows a medications on which we hold patents in sub-Saharan statistically significant benefit in terms of reducing HIVAfrica and the least developed countries. However, there RNA, and improving CD4 cell counts for treatment-
112
THE LANCET Infectious Diseases Vol 3 February 2003
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Interview experienced patients. We are hoping that the regulatory process proceeds well, and that we may be hearing positive news during the first half of 2003. Behind that, we and Trimeris have another drug which is similar to Fuzeon, called T-1249, another synthetic peptide inhibitor of HIV fusion. It is very closely related to Fuzeon, but at least in the laboratory what we have seen so far is it has potent activity against the majority of the Fuzeon-resistant HIV
strains, and may have an advantage in terms of convenience, in that it is administered only once-daily based on the data that we recently presented. Also in our drug development pipeline we have a novel HIV protease inhibitor, and a non-nucleoside transcriptase inhibitor. We have a healthy pipeline, our activities in HIV are continuing, and we have got very experienced teams of scientists to push these programmes ahead.
Clinical picture Ecthyma gangrenosum and chronic lymphocytic leukaemia A 66-year-old man with a history of chronic lymphocytic leukaemia (CLL) was admitted for evaluation of fever that started 2 weeks earlier and was associated with a skin lesion on the left thigh/buttock area. The patient was taking prednisone 100mg/day for treatment of autoimmune haemolytic anaemia associated with chronic lymphocytic leukaemia. Physical examination was unremarkable except for the skin lesion that was about 2 inches (5 cm) in diameter with surrounding redness, swelling, and tenderness. There was epidermal sloughing with central necrosis suggestive of ecthyma gangrenosum (figure). The patient’s white blood cell count was 34 000 cells/mmoL with only 3% neutrophils, 1% bands and 96% lymphocytes. Aspirate from the lesion and blood cultures obtained on admission grew Pseudomonas aeruginosa. The patient responded well to a 14-day course of intravenous piperacillin/tazobactam and tobramycin. Ecthyma gangrenosum is a characteristic skin sign of life-threatening infection commonly caused by P aeruginosa, although other organisms have been reported to cause ecthyma-like lesions. Ecthyma gangrenosum is usually seen in immunocompromised patients, and hypogammaglobulinaemia is also a predisposing factor for ecthyma gangrenosum; nonetheless, the lesion is rare in patients with CLL.
THE LANCET Infectious Diseases Vol 3 February 2003
Kannan Ramar, Kannan Ramar, Darko Hauer, Anil Potti, and Tze Shien Lo Department of Internal Medicine, University of North Dakota, Fargo, ND, USA. Correspondence: Dr Kannan Ramar, Department of Medicine, University of North Dakota School of Medicine, 1919 Elm St N, Fargo, ND 58102, USA. Fax +1 701 2372486; email [email protected].
http://infection.thelancet.com
113
For personal use. Only reproduce with permission from The Lancet Publishing Group.