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What does HIV teach us about cancer?
Clinical Oncology (1997) 9:355-356 © 1997 The Royal College of Radiologists
Clinical Oncology
Editorial W h a t D o e s H I V T e a c h us A b o u t C a n c e r ? B. S. Peters Senior Lecturer & Head of Academic Unit of Genitourinary Medicine, United Medical & Dental Schools of Guy's & St Thomas' Hospitals, London, UK
No other infectious disease has such a strong link to malignancy as HIV infection. The causal association of HIV with 3 malignancies is proven without doubt. Two of these malignancies, non-Hodgkin's lymphoma (NHL) and Kaposi's sarcoma (KS), appear so much more commonly in AIDS than in the general population, that it is not uncommon for the majority of inpatients on an AIDS unit to have one of these tumours. Cottrill, Bottomley and Phillips have picked a fascinating area to review - the epidemiological, aetiological, pathological, and clinical aspects of AIDS-associated malignancies are all unique and revealing. The lessons to be learnt from this experiment of nature are plentiful. Cottrill and colleagues have, however, chosen a moving target [1]. AIDS itself is a changing disease as a result of our therapeutic interventions [2-4]. The mid-1980's saw the introduction of antibiotic prophylaxis against Pneumocystis carinii pneumonia and 1987 saw the widespread introduction of the first effective antiretroviral compound, a nucleoside reverse transcriptase inhibitor, zidovudine. This was followed at the beginning of the 1990's by dual combination therapy for HIV. Now the optimum response is seen with triple combination antiretroviral therapy, especially when one of the potent new HIV proteinase inhibitors is included. These combinations will usually reduce the serum quantitative HIV viral load down to very low, or undetectable, levels, and produce a Sustained rise in CD4 counts. The advantages that these new combinations bring from the patients are considerable. There iS the potential for an improved quality of life, with a reduction in intercurrent disease and hospitalization, and prolonged survival. But there are also disadvantages associated with these new therapeutic options. These combinations are not a cure for HIV and it is uncertain how long the 'reprieve' will last for. Furthermore, the continued effectiveness of the medication is dependant on strict adherence to the prescribed regimens. Failure to do so will quickly lead to drug resistance and treatment failure. An understanding of the factors leading to an increase in malignancy in HIV may help us improve our management of these conditions, including their Correspondence and offprint requests to: Dr B. S. Peters, United Medical and Dental Schools of Guy's & St. Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK.
prevention. As Cottrill and colleagues point out, there is no strong evidence to suggest that HIV is directly implicated in the development of NHL; HIV is not a transforming virus [5], and HIV DNA, RNA or protein products are rarely found in lymphoma tissue from AIDS patients [6]. EBV is strongly associated with AIDS-associated lymphomas, although the exact role of this virus in the pathogenesis of this tumour remains to be elucidated. The role of cellular genetic events have been touched on in the review, and there is an ever growing body of literature on the possible role of oncogene activation and turnout suppressor gene inactivation in the pathogenesis of AIDSassociated lymphomas. It is important that we define as closely as we can the role of immune suppression in tumourogenesis, as this might indicate the optimum time to introduce antiretroviral therapy to an individual with HIV disease. We need to know a safe level of CD4 count, if one exists, above which NHL and KS are unlikely to develop. Cottrill and colleagues state that NHL can develop at any stage of HIV infection, which, although strictly true, is misleading. NHL, has been reported in patients with CD4 counts in the normal range, but is still comparatively rare in these circumstances. Conversely, the risk of developing NHL increases considerably3 as the CD4 count falls, particularly below 50/ram [7,8]. The degree of immunosuppression is also an important risk factor for the development of KS, along with the presence of HHV-8 and HIV infection. KS does occur in people w i t h normal immune function without HIV infectionl and there are several reports of KS in HIV negative homosexual men [9]. As with NHL, though, the rarity of these reports only emphasizes the importance of immunosuppression. We must remain cautious when interpreting historic data, however. As Pluda and colleagues predicted as early as 1990, the prolonged survival of patients with HIV infection (and immunosuppression) has meant that such individuals are increasingly likely to develop HIV associated malignancies, especially NHL [7]. Observations made on a cohort of patients in London [10], and similar findings from the States [8,11], have confirmed that these predictions are now becoming reality. The message, therefore, appears simple: if you wish to reduce the risk of an HIV positive person developing lymphoma or KS, then maintain a normal
356
immune system for as long as possible. Conversely, a manoeuvre which would increase the risk of malignancy in HIV would be to keep an immunosuppressed patient alive as long as possible. Maintaining the integrity of the immune system may, therefore, be the most important aspect in reducing morbidity and mortality from tumours in HIV. This is not discussed in the review article; it is important to redress the balance as it might prove central to individual patient management. At the very least it should be one factor that we consider when deciding when to start antiretroviral therapy. In their review, the authors gave many possible explanations for the falling incidence in KS. In their desire to give comprehensive coverage they are in danger of losing sight of the most important explanation - the reduction in number of sexual partners among homosexual males. The dramatic reduction of MDS patients developing KS among homosexual males in San Francisco, from 60% in 1981 to 20% in 1987, mirrored a major drop in sexual partner change in the homosexual community [12]. This is of more than theoretical interest. It is rare to develop KS without prior infection with HHV8. It seems likely that the major route of transmission of this virus is sexual. If, as seems likely, HHV8 is so critical to the development of KS, we have the beginning of a management strategy to reduce the incidence of this tumour. Ideally one would like to have a prophylactic vaccine for HHV8 or a treatment for this virus that is effective in preventing tumourogenesis. At present, however, we must not neglect other strategies. If individuals in at risk groups for HIV infection (even if they are HIV negative), adopt safer sex practises, then they will reduce their probability of acquiring or transmitting HHV8. In summary, we are entering a period of cautious optimism in our ability to treat HIV infection, but the very result of this treatment is to increase morbidity in other areas. The AIDS patients of today are presenting with different patterns of disease compared to their counterparts of ten years ago; the AIDS patients of 10 years time are likely to present a different pattern of disease yet again. During these next 10 years it is possible that malignant disease will contribute an even greater proportion of the morbidity and mortality occurring in HIV infection than they do today. This is despite the advances in our understanding of the pathogenesis of HIV disease and the giant strides we have made recently with producing effective antiretroviral combinations. Our goal over the next decade should be to develop drugs which will indefinitely maintain the integrity of the immune system, so that tumours are unlikely to occur. It is improbable that current drugs will fulfill that role for many patients in the developed world, let alone the
B.S. Peters
third world. Other treatments, or treatment modalities, including immunotherapy, are going to be needed. An even greater degree of progress is attendant on our development of an effective prophylactic HIV vaccine. The following words are as apt today in our fight against AIDS, as they were in their original context 50 years ago: 'This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning' [131. In order to reach the endgame, cancer biologists, cellular immunologists, and virologists all have to maintain their collaborative research effort in this area. We will then have, not just an improved management strategy for HIV infection, but a better understanding of malignancy and all manner of other disorders under immunoregulatory and cellular control.
References
1. Cottrill CP, Bottomley DM, Phillips RH. Cancer and HIV Infection. Clin Oncol 1997;7:365-80. 2. Peters BS, Beck E, Coleman DG. Changing Disease Patterns in Patients with AIDS in a Referral Centre in the United Kindgom: The Changing Face of AIDS. BMJ 1991;302:2037. 3. Peters BS, Coleman D, Beck EJ. Changing disease patterns in AIDS. BMJ 1991;302:726. 4. Coleman DG, Beck EJ, Peters BS, Harris JRW, Pinching AJ. Changing disease patterns in AIDS. BMJ 1992;304:839. 5. Wong-Staal F, Gallo RC. Human T-lymphotropic viruses. Nature 1985;317:395-403. 6. Subar M, Neri A, Inghirami. Frequent c-myc oncogene activation and infrequent presence of Eptein-Barr virus genome in AIDS-associated lymphoma. Blood 1988;72:66771. 7. Pluda JM, Yarchoan R, Jaffe ES. Developments of nonHodgkin's lymphoma in a cohort of patients with severe immunodeficiency virus (HIV) infection on longterm antiretroviral therapy. Ann Intern Med 1990;113:276-82. 8. Pluda JM, Venzon DJ, Tosata G. Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. J Clin Oncol 1993;11:1099-107. 9. Friedman-Kein AE, Saltzman BR, Cao Y. Kaposi's sarcoma in homosexual men. Lancet 1990;i:168-9. 10. Peters BS, Tomlinson D, Stuart S, Weber JN. Incidence and disease trends for AIDS-associated lymphomas. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, March 1994. 11. Moore RD, Kessler H, Richman DD. Non-Hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 1991;265:2208-11. 12. Rutherford GW, Schwarz SK, Lemp GF. The epidemiology of AIDS-related Kaposi's Sarcoma in San Francisco. J Infect Dis 1989;159:569-72. 13. Churchill WLS. Mansion House, 10th Nov 1942; speech on the Battle of Egypt.
Clinical Oncology
Editorial W h a t D o e s H I V T e a c h us A b o u t C a n c e r ? B. S. Peters Senior Lecturer & Head of Academic Unit of Genitourinary Medicine, United Medical & Dental Schools of Guy's & St Thomas' Hospitals, London, UK
No other infectious disease has such a strong link to malignancy as HIV infection. The causal association of HIV with 3 malignancies is proven without doubt. Two of these malignancies, non-Hodgkin's lymphoma (NHL) and Kaposi's sarcoma (KS), appear so much more commonly in AIDS than in the general population, that it is not uncommon for the majority of inpatients on an AIDS unit to have one of these tumours. Cottrill, Bottomley and Phillips have picked a fascinating area to review - the epidemiological, aetiological, pathological, and clinical aspects of AIDS-associated malignancies are all unique and revealing. The lessons to be learnt from this experiment of nature are plentiful. Cottrill and colleagues have, however, chosen a moving target [1]. AIDS itself is a changing disease as a result of our therapeutic interventions [2-4]. The mid-1980's saw the introduction of antibiotic prophylaxis against Pneumocystis carinii pneumonia and 1987 saw the widespread introduction of the first effective antiretroviral compound, a nucleoside reverse transcriptase inhibitor, zidovudine. This was followed at the beginning of the 1990's by dual combination therapy for HIV. Now the optimum response is seen with triple combination antiretroviral therapy, especially when one of the potent new HIV proteinase inhibitors is included. These combinations will usually reduce the serum quantitative HIV viral load down to very low, or undetectable, levels, and produce a Sustained rise in CD4 counts. The advantages that these new combinations bring from the patients are considerable. There iS the potential for an improved quality of life, with a reduction in intercurrent disease and hospitalization, and prolonged survival. But there are also disadvantages associated with these new therapeutic options. These combinations are not a cure for HIV and it is uncertain how long the 'reprieve' will last for. Furthermore, the continued effectiveness of the medication is dependant on strict adherence to the prescribed regimens. Failure to do so will quickly lead to drug resistance and treatment failure. An understanding of the factors leading to an increase in malignancy in HIV may help us improve our management of these conditions, including their Correspondence and offprint requests to: Dr B. S. Peters, United Medical and Dental Schools of Guy's & St. Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK.
prevention. As Cottrill and colleagues point out, there is no strong evidence to suggest that HIV is directly implicated in the development of NHL; HIV is not a transforming virus [5], and HIV DNA, RNA or protein products are rarely found in lymphoma tissue from AIDS patients [6]. EBV is strongly associated with AIDS-associated lymphomas, although the exact role of this virus in the pathogenesis of this tumour remains to be elucidated. The role of cellular genetic events have been touched on in the review, and there is an ever growing body of literature on the possible role of oncogene activation and turnout suppressor gene inactivation in the pathogenesis of AIDSassociated lymphomas. It is important that we define as closely as we can the role of immune suppression in tumourogenesis, as this might indicate the optimum time to introduce antiretroviral therapy to an individual with HIV disease. We need to know a safe level of CD4 count, if one exists, above which NHL and KS are unlikely to develop. Cottrill and colleagues state that NHL can develop at any stage of HIV infection, which, although strictly true, is misleading. NHL, has been reported in patients with CD4 counts in the normal range, but is still comparatively rare in these circumstances. Conversely, the risk of developing NHL increases considerably3 as the CD4 count falls, particularly below 50/ram [7,8]. The degree of immunosuppression is also an important risk factor for the development of KS, along with the presence of HHV-8 and HIV infection. KS does occur in people w i t h normal immune function without HIV infectionl and there are several reports of KS in HIV negative homosexual men [9]. As with NHL, though, the rarity of these reports only emphasizes the importance of immunosuppression. We must remain cautious when interpreting historic data, however. As Pluda and colleagues predicted as early as 1990, the prolonged survival of patients with HIV infection (and immunosuppression) has meant that such individuals are increasingly likely to develop HIV associated malignancies, especially NHL [7]. Observations made on a cohort of patients in London [10], and similar findings from the States [8,11], have confirmed that these predictions are now becoming reality. The message, therefore, appears simple: if you wish to reduce the risk of an HIV positive person developing lymphoma or KS, then maintain a normal
356
immune system for as long as possible. Conversely, a manoeuvre which would increase the risk of malignancy in HIV would be to keep an immunosuppressed patient alive as long as possible. Maintaining the integrity of the immune system may, therefore, be the most important aspect in reducing morbidity and mortality from tumours in HIV. This is not discussed in the review article; it is important to redress the balance as it might prove central to individual patient management. At the very least it should be one factor that we consider when deciding when to start antiretroviral therapy. In their review, the authors gave many possible explanations for the falling incidence in KS. In their desire to give comprehensive coverage they are in danger of losing sight of the most important explanation - the reduction in number of sexual partners among homosexual males. The dramatic reduction of MDS patients developing KS among homosexual males in San Francisco, from 60% in 1981 to 20% in 1987, mirrored a major drop in sexual partner change in the homosexual community [12]. This is of more than theoretical interest. It is rare to develop KS without prior infection with HHV8. It seems likely that the major route of transmission of this virus is sexual. If, as seems likely, HHV8 is so critical to the development of KS, we have the beginning of a management strategy to reduce the incidence of this tumour. Ideally one would like to have a prophylactic vaccine for HHV8 or a treatment for this virus that is effective in preventing tumourogenesis. At present, however, we must not neglect other strategies. If individuals in at risk groups for HIV infection (even if they are HIV negative), adopt safer sex practises, then they will reduce their probability of acquiring or transmitting HHV8. In summary, we are entering a period of cautious optimism in our ability to treat HIV infection, but the very result of this treatment is to increase morbidity in other areas. The AIDS patients of today are presenting with different patterns of disease compared to their counterparts of ten years ago; the AIDS patients of 10 years time are likely to present a different pattern of disease yet again. During these next 10 years it is possible that malignant disease will contribute an even greater proportion of the morbidity and mortality occurring in HIV infection than they do today. This is despite the advances in our understanding of the pathogenesis of HIV disease and the giant strides we have made recently with producing effective antiretroviral combinations. Our goal over the next decade should be to develop drugs which will indefinitely maintain the integrity of the immune system, so that tumours are unlikely to occur. It is improbable that current drugs will fulfill that role for many patients in the developed world, let alone the
B.S. Peters
third world. Other treatments, or treatment modalities, including immunotherapy, are going to be needed. An even greater degree of progress is attendant on our development of an effective prophylactic HIV vaccine. The following words are as apt today in our fight against AIDS, as they were in their original context 50 years ago: 'This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning' [131. In order to reach the endgame, cancer biologists, cellular immunologists, and virologists all have to maintain their collaborative research effort in this area. We will then have, not just an improved management strategy for HIV infection, but a better understanding of malignancy and all manner of other disorders under immunoregulatory and cellular control.
References
1. Cottrill CP, Bottomley DM, Phillips RH. Cancer and HIV Infection. Clin Oncol 1997;7:365-80. 2. Peters BS, Beck E, Coleman DG. Changing Disease Patterns in Patients with AIDS in a Referral Centre in the United Kindgom: The Changing Face of AIDS. BMJ 1991;302:2037. 3. Peters BS, Coleman D, Beck EJ. Changing disease patterns in AIDS. BMJ 1991;302:726. 4. Coleman DG, Beck EJ, Peters BS, Harris JRW, Pinching AJ. Changing disease patterns in AIDS. BMJ 1992;304:839. 5. Wong-Staal F, Gallo RC. Human T-lymphotropic viruses. Nature 1985;317:395-403. 6. Subar M, Neri A, Inghirami. Frequent c-myc oncogene activation and infrequent presence of Eptein-Barr virus genome in AIDS-associated lymphoma. Blood 1988;72:66771. 7. Pluda JM, Yarchoan R, Jaffe ES. Developments of nonHodgkin's lymphoma in a cohort of patients with severe immunodeficiency virus (HIV) infection on longterm antiretroviral therapy. Ann Intern Med 1990;113:276-82. 8. Pluda JM, Venzon DJ, Tosata G. Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. J Clin Oncol 1993;11:1099-107. 9. Friedman-Kein AE, Saltzman BR, Cao Y. Kaposi's sarcoma in homosexual men. Lancet 1990;i:168-9. 10. Peters BS, Tomlinson D, Stuart S, Weber JN. Incidence and disease trends for AIDS-associated lymphomas. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, March 1994. 11. Moore RD, Kessler H, Richman DD. Non-Hodgkin's lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 1991;265:2208-11. 12. Rutherford GW, Schwarz SK, Lemp GF. The epidemiology of AIDS-related Kaposi's Sarcoma in San Francisco. J Infect Dis 1989;159:569-72. 13. Churchill WLS. Mansion House, 10th Nov 1942; speech on the Battle of Egypt.