805
LETTERS to EDITOR
HIV, AIDS, and zidovudine SiR,—The central dogma behind Professor Duesberg’s letter (Feb 29, p 551) remains that HIV-1 does not cause AIDS. This view ignores so vast a body of information that it is difficult to know how to refute it. Duesberg’s understanding of the host-parasite relation in human HIV-1infection is flawed, and this is an area in which we feel qualified to correct him. HIV-1genetic information, carried as proviral DNA sequences, is detectable in peripheral blood leucocytes in virtually all individuals whose sera contain antibody to HIV-1. This in itself is pathognomonic for HIV-1 infection but does not imply viral replication. More importantly, advances in cell biology have enabled scientists to show that viable virus is present in the plasma from infected individuals (defmed as antibody positive). We have used such techniques (to be described elsewhere) to detect and quantify HIV-1 RNA in antibody-containing plasma or serum of HIV-1-infected patients. Our method detects intact virions by immunoadhesion and then measurement of HIV-1 RNA. Since viral RNA alone could not survive cell-free in plasma unless protected by protein, this method is most probably measuring HIV-1 recently shed into the blood from infected cells in which the virus is replicating.
with a narrow therapeutic index, the usual dose is not sufficiently ablative of normal lymphocyte populations, using Duesberg’s concept of its "antiviral" effects, to account for a hundred-fold or more reduction in HIV-1. Our data show that zidovudine must be selective in its inhibition of viral replication and can therefore be regarded as an antiretroviral agent, albeit not the panacea that some demand. Division of Virology, Department of Medical Microbiology,
University College and Middlesex School of London W1P 6DB, UK
Medicine,
R. S. TEDDER M. G. SEMPLE M. TENANT-FLOWERS C. LOVEDAY
1. Ho DD,
Moudgil T, Alam M. Quantitation of human immunodeficiency virus type 1 the blood of infected persons. N Engl J Med 1989; 321: 1621-25. 2. Coombs RW, Collier AC, Allain J-P, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626-31 3. Semple M, Loveday C, Weller I, Tedder RS. Direct measurement of viremia in patients infected with HIV-1 and its relationship to disease progression and zidovudine therapy. J Med Virol 1991; 35: 38-45. m
** This letter has been shown to Dr Duesberg whose reply to it and to an
Changes
in
plasma HIV-1 RNA in patient starting zidovudine
therapy. Two things become self evident when quantitative assays for cell-free HIV-1 RNA begin to be used routinely.3 First, viraemia (defmed as HIV-1RNA, wrapped in protein, cell-free in plasma) is ubiquitous among seropositive patients. The levels of plasma viraemia are related to the disease stage of the patient, implying that there is indeed immune modulation of viral replication. Second, when this assay is used to study the early response of viraemia in patients starting zidovudine treatment, viral inhibition confirms that this drug has a profound effect on viral turnover. The reduction is sometimes dramatic; falls of cell-free HIV-1 RNA by a hundred-fold or more are not unusual (figure). The mechanisms for such a rapid reduction of viraemia are not defmed and possibly reflect the selective inhibition of replication and infection in a small subset of provirus-bearing cells. Although zidovudine is cytotoxic
earlier one follows.-ED. L.
SIR,-In response to my argument that inhibition of HIV with zidovudine (azidothymidine, AZT) is not a rational AIDS therapy, Professor Tedder and his colleagues suggest that my "understanding of the host-parasite relation in human HIV-1 infection is flawed". On the basis of their technique to detect "viraemia defined as HIV-1 RNA, wrapped in protein", they conclude that HIV is actively replicating in AIDS patients and is thus a target for AZT inhibition. However, the HIV viraemia detected by Tedder et al is apparently not infectious since, on average, only 1 in 8000 leucocytes of HIV-positive AIDS patients are infected by HIV.’ The probable reason is that the "HIV-1RNA wrapped in protein" is HIV neutralised by antibodies of the "seropositive" patients rather than infectious HIV. Since viruses can only kill cells they infect, HIV cannot be responsible for the loss of T-cells, the hallmark of AIDS. Further, Tedder and colleagues’ observation of an increase in viraemia in relation to disease stage (implying "immune modulation of viral replication") does not support their view that HIV viraemia causes AID S. Instead, it is a classic example of "immune modulation" in "host-parasite relation": the lower the host’s immunity, the more previously suppressed parasites are activated (eg, candida, pneumocystis, cytomegalovirus, herpesvirus, and sometimes even HIV2). The activities of these microbes in AIDS are consequences, not causes, of immunodeficiency. Indeed, many retroviruses were discovered in animals only after immune suppression by radiation, chemicals, or leukaemia or by growing cells in culture.3 Tedder et al would have helped my "flawed" understanding of HIV infection if they had identified which data from the "vast body of information" prove that HIV causes AIDS. In the meantime, I still fail to understand the rationale for AZT. For example, since HIV is said to cause AIDS by killing T-cells, why is it necessary to kill an infected cell twice? What is the basis of Tedder’s hypothesis a small subset of provirus-bearing of "selective inhibition of cells"? Since AZT cannot distinguish provirus-bearing from uninfected leucocytes, a "dramatic" decrease in viraemia is not likely to reflect selective inhibition of HIV-infected cells by AZT. ...
806
Instead it may reflect inhibition of all growing cells, which produce retroviruses much more effectively than resting cells." In another response to my Lancet letter and to Meditel’s programme broadcast in the UK on Channel 4 on Feb 12, Dr Freestone (March 7, p 626) defends the Wellcome product AZT against our challenges. We had pointed out that AZT, as a chain terminator of DNA synthesis originally developed for chemotherapy, is inevitably toxic. Further we argued that it cannot be a rational antiviral drug because only 1 in 8000 leucocytes are infected in AIDS and AZT cannot distinguish between infected and uninfected cells. Freestone cites results of the Wellcomesponsored studys on which the US licence is based. He notes that the primary end-point was death (Iin 145 AZT, 19 in 137 placebo), an end-point "little subject to observer error or bias". However, 30 of the AZT recipients (but only 5 of the placebo recipients) were kept alive only by blood transfusions to compensate for severe bone marrow toxicity. Thus the number of AZT recipients who would have died from anaemia if untreated was 30, which is more than the AIDS deaths and anaemias in the placebo group (19 + 5). Moreover, in 34% of AZT recipients but in only 6% of controls, the lymphocyte count fell by over 50%. 66 AZT recipients (25 controls) had severe nausea. Muscle atrophy, due to termination of mitochondrial DNA by AZT,6was seen in 11and 3, respectively. Indeed, one could argue that any drug (AZT)-sharing in this trial explains the AZT-specific diseases in the placebo group, rather than randomising the benefits of AZT, as Freestone surmises. Independent studies of AZT in AIDS report much higher death rates than 1 in 145. A French study of 365 AIDS patients revealed no benefit 6 months after the start of AZT but identified new AIDS diseases and leucopenia in about 50% and death in 20% within 9 months. That study7 is the largest of its kind. An Australian AZT study in 308 AIDS patients reported 30% mortality within 1-1 ’5 years, and one or more new AIDS diseases, including pneumonia and candidosis, in 172 (56%) within less than 1 year.8 The 1992 US paper9 that Freestone cites showed that on treatment with AZT the mortality of 170 people with early AIDS symptoms was about the same as that of 168 with late AIDS (12-14% in 1-1-5 years). This indicates that AZT is toxic for early AIDS patients because it equalised the death rates in early and late AIDS. The authors concluded, in contrast to the claim in the 1987 paper,s that AZT does not extend life. Leucopenia (80%), anaemia (20%), and nausea (30%) were noted in both AZT treatment groups. It seems that AZT causes potentially fatal diseases, such as anaemia, leucopenia, and muscle atrophy, in healthy HIV carriers and AIDS patients; that it causes these diseases in symptom-free carriers within a year, whereas HIV is said to cause AIDS diseases on average only 10 years after infection; that AZT must kill 8000 leucocytes to destroy just one HIV-infected cell; and that there is no proof for the virus/AIDS hypothesis. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA
PETER H. DUESBERG
JD, Hartigan PM, Simberkoff MS, et al, and the Veterans Affairs Cooperative Study Group on AIDS Treatment. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. N Engl J Med 1992; 326: 437-43. 10. Duesberg PH. AIDS epidemiology: inconsistencies with human immunodeficiency virus and with infectious disease. Proc Natl Acad Sa USA 1991; 88: 1575-79. 9. Hamilton
SiR,—Dr Freestone states that Wellcome refused to take part in television programme because of my refusal to accept criticism from the Broadcasting Complaints Commission (BCC) about our previous programme that had included a short section about zidovudine. BCC did in part uphold complaints by Wellcome and others but the programme was passed by the Independent Broadcasting Authority, and that body’s successor, the Independent Television Commission, stands by the programme and its methods. Furthermore, Channel Four, on which the programme was put out, declared that the BCC had "strayed beyond its normal area of competence into one in which it is extremely difficult for it to be seen to adjudicate fairly". In the programme now under discussion’ we stated that both the US Food and Drug Administrationand trial investigators knew that two trials3,4 that had led to the licensing of zidovudine had become unblinded. Freestone plays down the effects of unblinding. Whether the effects were large or small, the trials should not be called blind when they were not, yet that is the claim consistently made by Wellcome about these trials. These trials, planned for 24 weeks, were terminated after an average of only 17 weeks. In the 21 weeks after the trial ended and the drug became available to all participants, 10% of patients on zidovudine died. Furthermore, when zidovudine became available on a compassionate plea basis survival statistics were kept on 4805 patients. David Barry of Burroughs Wellcome commented to journalist John Lauritsen (May 24, 1988) that somewhere between 8% and 12% of AIDS patients treated with zidovudine died during four months (17 weeks) of treatment. If ina similar period of 17 weeks less than 1% died during the phase II trials yet 8-12% died following release of the drug, then the most likely explanation is that the figure is unreliable. We never suggested that the wording of the US Physicians’ Desk Reference and the UK Data Sheet Compendium should be identical, only that prescribers and patients in the UK should be told that "... the drug has been studied for limited periods of time and long term safety and efficacy are not known". Wellcome attempts to distance its Positive Benefits promotional leaflet, which we consider contains false and misleading claims, from its other literature, but a false or misleading claim about a drug, if successfully prosecuted, is a criminal offence no matter where it is our
printed. Meditel, Bedford Chambers, London WC2 8HA, UK 1.
Dispatches. AZT—Cause for Concern, Channel Four Television, UK. Transmitted
Feb 12, 1992 2 FDA documents obtained through Freedom of Information procedure. Medical Officer Review of NDA 19-655, March 19, 1987. in 3. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 4.
1. Simmonds P, Balfe P, Peutherer JF, Ludlam CA, Bishop JO, Leigh Brown AJ. Human immunodeficiency virus-infected individuals contain provirus in small numbers of peripheral mononuclear cells and at low copy numbers. J Virol 1990; 64: 864-72. 2. Duesberg PH. Quantification of human immunodeficiency virus m the blood. N Engl J Med 1990; 322: 1466. 3. Duesberg PH. Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res 1987; 47: 1199-220. 4. Weiss R, Teich N, Varmus H, Coffin J. Molecular biology of RNA tumor viruses. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1985. 5. Richman DD, Fischl MA, Greico MH, et al, and the AZT Collaborative Working Group. The toxicity of azidothymidme (AZT) m the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317: 192-97. 6. Yarchoan R, Pluda JM, Pemo C-F, Mitsuya H, Broder S. Anti-retroviral therapy of human immunodeficiency virus infection current strategies and challenges for the future Blood 1991; 78: 859-84. 7. Dournon E, Rozenbaum W, Michon C, et al, and the Claude Bernard Hospital AZT Study Group Effects of zidovudine m 365 consecutive patients with AIDS or AIDS-related complex. Lancet 1988; ii. 1297-302. 8. Swanson CE, Cooper DA, and the Australian Zidovudine Study Group Factors influencing outcome of treatment with zidovudine of patients with AIDS in Australia. AIDS 1990; 4: 749-57
JOAN SHENTON
1987; 317: 185-91. Richman DD, Fischl MA, Gneco MD, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317: 192-97.
Didanosine and heart failure SIR,-Dr Willocks and her colleagues (Jan 18, p 190) suggest a relation between the considerable salt content of the current preparation of didanosine (2,3-dideoxyinosine, ddI) and the development of cardiac failure in patients with reduced ventricular function. Cardiac involvement, including myocarditis, endocarditis, pericarditis, and pericardial effusion, sometimes with tamponade,is reported frequently in HIV disease.1-3 Although clinically evident disease is uncommon, symptomless myocardial dysfunction may occur in up to 70% of AIDS patients. With prolonged survival as a result of developments in antiretroviral chemotherapy and management of opportunistic diseases, the incidence of cardiac disease in HIV-infected individuals may increase.
LETTERS to EDITOR
HIV, AIDS, and zidovudine SiR,—The central dogma behind Professor Duesberg’s letter (Feb 29, p 551) remains that HIV-1 does not cause AIDS. This view ignores so vast a body of information that it is difficult to know how to refute it. Duesberg’s understanding of the host-parasite relation in human HIV-1infection is flawed, and this is an area in which we feel qualified to correct him. HIV-1genetic information, carried as proviral DNA sequences, is detectable in peripheral blood leucocytes in virtually all individuals whose sera contain antibody to HIV-1. This in itself is pathognomonic for HIV-1 infection but does not imply viral replication. More importantly, advances in cell biology have enabled scientists to show that viable virus is present in the plasma from infected individuals (defmed as antibody positive). We have used such techniques (to be described elsewhere) to detect and quantify HIV-1 RNA in antibody-containing plasma or serum of HIV-1-infected patients. Our method detects intact virions by immunoadhesion and then measurement of HIV-1 RNA. Since viral RNA alone could not survive cell-free in plasma unless protected by protein, this method is most probably measuring HIV-1 recently shed into the blood from infected cells in which the virus is replicating.
with a narrow therapeutic index, the usual dose is not sufficiently ablative of normal lymphocyte populations, using Duesberg’s concept of its "antiviral" effects, to account for a hundred-fold or more reduction in HIV-1. Our data show that zidovudine must be selective in its inhibition of viral replication and can therefore be regarded as an antiretroviral agent, albeit not the panacea that some demand. Division of Virology, Department of Medical Microbiology,
University College and Middlesex School of London W1P 6DB, UK
Medicine,
R. S. TEDDER M. G. SEMPLE M. TENANT-FLOWERS C. LOVEDAY
1. Ho DD,
Moudgil T, Alam M. Quantitation of human immunodeficiency virus type 1 the blood of infected persons. N Engl J Med 1989; 321: 1621-25. 2. Coombs RW, Collier AC, Allain J-P, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626-31 3. Semple M, Loveday C, Weller I, Tedder RS. Direct measurement of viremia in patients infected with HIV-1 and its relationship to disease progression and zidovudine therapy. J Med Virol 1991; 35: 38-45. m
** This letter has been shown to Dr Duesberg whose reply to it and to an
Changes
in
plasma HIV-1 RNA in patient starting zidovudine
therapy. Two things become self evident when quantitative assays for cell-free HIV-1 RNA begin to be used routinely.3 First, viraemia (defmed as HIV-1RNA, wrapped in protein, cell-free in plasma) is ubiquitous among seropositive patients. The levels of plasma viraemia are related to the disease stage of the patient, implying that there is indeed immune modulation of viral replication. Second, when this assay is used to study the early response of viraemia in patients starting zidovudine treatment, viral inhibition confirms that this drug has a profound effect on viral turnover. The reduction is sometimes dramatic; falls of cell-free HIV-1 RNA by a hundred-fold or more are not unusual (figure). The mechanisms for such a rapid reduction of viraemia are not defmed and possibly reflect the selective inhibition of replication and infection in a small subset of provirus-bearing cells. Although zidovudine is cytotoxic
earlier one follows.-ED. L.
SIR,-In response to my argument that inhibition of HIV with zidovudine (azidothymidine, AZT) is not a rational AIDS therapy, Professor Tedder and his colleagues suggest that my "understanding of the host-parasite relation in human HIV-1 infection is flawed". On the basis of their technique to detect "viraemia defined as HIV-1 RNA, wrapped in protein", they conclude that HIV is actively replicating in AIDS patients and is thus a target for AZT inhibition. However, the HIV viraemia detected by Tedder et al is apparently not infectious since, on average, only 1 in 8000 leucocytes of HIV-positive AIDS patients are infected by HIV.’ The probable reason is that the "HIV-1RNA wrapped in protein" is HIV neutralised by antibodies of the "seropositive" patients rather than infectious HIV. Since viruses can only kill cells they infect, HIV cannot be responsible for the loss of T-cells, the hallmark of AIDS. Further, Tedder and colleagues’ observation of an increase in viraemia in relation to disease stage (implying "immune modulation of viral replication") does not support their view that HIV viraemia causes AID S. Instead, it is a classic example of "immune modulation" in "host-parasite relation": the lower the host’s immunity, the more previously suppressed parasites are activated (eg, candida, pneumocystis, cytomegalovirus, herpesvirus, and sometimes even HIV2). The activities of these microbes in AIDS are consequences, not causes, of immunodeficiency. Indeed, many retroviruses were discovered in animals only after immune suppression by radiation, chemicals, or leukaemia or by growing cells in culture.3 Tedder et al would have helped my "flawed" understanding of HIV infection if they had identified which data from the "vast body of information" prove that HIV causes AIDS. In the meantime, I still fail to understand the rationale for AZT. For example, since HIV is said to cause AIDS by killing T-cells, why is it necessary to kill an infected cell twice? What is the basis of Tedder’s hypothesis a small subset of provirus-bearing of "selective inhibition of cells"? Since AZT cannot distinguish provirus-bearing from uninfected leucocytes, a "dramatic" decrease in viraemia is not likely to reflect selective inhibition of HIV-infected cells by AZT. ...
806
Instead it may reflect inhibition of all growing cells, which produce retroviruses much more effectively than resting cells." In another response to my Lancet letter and to Meditel’s programme broadcast in the UK on Channel 4 on Feb 12, Dr Freestone (March 7, p 626) defends the Wellcome product AZT against our challenges. We had pointed out that AZT, as a chain terminator of DNA synthesis originally developed for chemotherapy, is inevitably toxic. Further we argued that it cannot be a rational antiviral drug because only 1 in 8000 leucocytes are infected in AIDS and AZT cannot distinguish between infected and uninfected cells. Freestone cites results of the Wellcomesponsored studys on which the US licence is based. He notes that the primary end-point was death (Iin 145 AZT, 19 in 137 placebo), an end-point "little subject to observer error or bias". However, 30 of the AZT recipients (but only 5 of the placebo recipients) were kept alive only by blood transfusions to compensate for severe bone marrow toxicity. Thus the number of AZT recipients who would have died from anaemia if untreated was 30, which is more than the AIDS deaths and anaemias in the placebo group (19 + 5). Moreover, in 34% of AZT recipients but in only 6% of controls, the lymphocyte count fell by over 50%. 66 AZT recipients (25 controls) had severe nausea. Muscle atrophy, due to termination of mitochondrial DNA by AZT,6was seen in 11and 3, respectively. Indeed, one could argue that any drug (AZT)-sharing in this trial explains the AZT-specific diseases in the placebo group, rather than randomising the benefits of AZT, as Freestone surmises. Independent studies of AZT in AIDS report much higher death rates than 1 in 145. A French study of 365 AIDS patients revealed no benefit 6 months after the start of AZT but identified new AIDS diseases and leucopenia in about 50% and death in 20% within 9 months. That study7 is the largest of its kind. An Australian AZT study in 308 AIDS patients reported 30% mortality within 1-1 ’5 years, and one or more new AIDS diseases, including pneumonia and candidosis, in 172 (56%) within less than 1 year.8 The 1992 US paper9 that Freestone cites showed that on treatment with AZT the mortality of 170 people with early AIDS symptoms was about the same as that of 168 with late AIDS (12-14% in 1-1-5 years). This indicates that AZT is toxic for early AIDS patients because it equalised the death rates in early and late AIDS. The authors concluded, in contrast to the claim in the 1987 paper,s that AZT does not extend life. Leucopenia (80%), anaemia (20%), and nausea (30%) were noted in both AZT treatment groups. It seems that AZT causes potentially fatal diseases, such as anaemia, leucopenia, and muscle atrophy, in healthy HIV carriers and AIDS patients; that it causes these diseases in symptom-free carriers within a year, whereas HIV is said to cause AIDS diseases on average only 10 years after infection; that AZT must kill 8000 leucocytes to destroy just one HIV-infected cell; and that there is no proof for the virus/AIDS hypothesis. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA
PETER H. DUESBERG
JD, Hartigan PM, Simberkoff MS, et al, and the Veterans Affairs Cooperative Study Group on AIDS Treatment. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. N Engl J Med 1992; 326: 437-43. 10. Duesberg PH. AIDS epidemiology: inconsistencies with human immunodeficiency virus and with infectious disease. Proc Natl Acad Sa USA 1991; 88: 1575-79. 9. Hamilton
SiR,—Dr Freestone states that Wellcome refused to take part in television programme because of my refusal to accept criticism from the Broadcasting Complaints Commission (BCC) about our previous programme that had included a short section about zidovudine. BCC did in part uphold complaints by Wellcome and others but the programme was passed by the Independent Broadcasting Authority, and that body’s successor, the Independent Television Commission, stands by the programme and its methods. Furthermore, Channel Four, on which the programme was put out, declared that the BCC had "strayed beyond its normal area of competence into one in which it is extremely difficult for it to be seen to adjudicate fairly". In the programme now under discussion’ we stated that both the US Food and Drug Administrationand trial investigators knew that two trials3,4 that had led to the licensing of zidovudine had become unblinded. Freestone plays down the effects of unblinding. Whether the effects were large or small, the trials should not be called blind when they were not, yet that is the claim consistently made by Wellcome about these trials. These trials, planned for 24 weeks, were terminated after an average of only 17 weeks. In the 21 weeks after the trial ended and the drug became available to all participants, 10% of patients on zidovudine died. Furthermore, when zidovudine became available on a compassionate plea basis survival statistics were kept on 4805 patients. David Barry of Burroughs Wellcome commented to journalist John Lauritsen (May 24, 1988) that somewhere between 8% and 12% of AIDS patients treated with zidovudine died during four months (17 weeks) of treatment. If ina similar period of 17 weeks less than 1% died during the phase II trials yet 8-12% died following release of the drug, then the most likely explanation is that the figure is unreliable. We never suggested that the wording of the US Physicians’ Desk Reference and the UK Data Sheet Compendium should be identical, only that prescribers and patients in the UK should be told that "... the drug has been studied for limited periods of time and long term safety and efficacy are not known". Wellcome attempts to distance its Positive Benefits promotional leaflet, which we consider contains false and misleading claims, from its other literature, but a false or misleading claim about a drug, if successfully prosecuted, is a criminal offence no matter where it is our
printed. Meditel, Bedford Chambers, London WC2 8HA, UK 1.
Dispatches. AZT—Cause for Concern, Channel Four Television, UK. Transmitted
Feb 12, 1992 2 FDA documents obtained through Freedom of Information procedure. Medical Officer Review of NDA 19-655, March 19, 1987. in 3. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 4.
1. Simmonds P, Balfe P, Peutherer JF, Ludlam CA, Bishop JO, Leigh Brown AJ. Human immunodeficiency virus-infected individuals contain provirus in small numbers of peripheral mononuclear cells and at low copy numbers. J Virol 1990; 64: 864-72. 2. Duesberg PH. Quantification of human immunodeficiency virus m the blood. N Engl J Med 1990; 322: 1466. 3. Duesberg PH. Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res 1987; 47: 1199-220. 4. Weiss R, Teich N, Varmus H, Coffin J. Molecular biology of RNA tumor viruses. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1985. 5. Richman DD, Fischl MA, Greico MH, et al, and the AZT Collaborative Working Group. The toxicity of azidothymidme (AZT) m the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317: 192-97. 6. Yarchoan R, Pluda JM, Pemo C-F, Mitsuya H, Broder S. Anti-retroviral therapy of human immunodeficiency virus infection current strategies and challenges for the future Blood 1991; 78: 859-84. 7. Dournon E, Rozenbaum W, Michon C, et al, and the Claude Bernard Hospital AZT Study Group Effects of zidovudine m 365 consecutive patients with AIDS or AIDS-related complex. Lancet 1988; ii. 1297-302. 8. Swanson CE, Cooper DA, and the Australian Zidovudine Study Group Factors influencing outcome of treatment with zidovudine of patients with AIDS in Australia. AIDS 1990; 4: 749-57
JOAN SHENTON
1987; 317: 185-91. Richman DD, Fischl MA, Gneco MD, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317: 192-97.
Didanosine and heart failure SIR,-Dr Willocks and her colleagues (Jan 18, p 190) suggest a relation between the considerable salt content of the current preparation of didanosine (2,3-dideoxyinosine, ddI) and the development of cardiac failure in patients with reduced ventricular function. Cardiac involvement, including myocarditis, endocarditis, pericarditis, and pericardial effusion, sometimes with tamponade,is reported frequently in HIV disease.1-3 Although clinically evident disease is uncommon, symptomless myocardial dysfunction may occur in up to 70% of AIDS patients. With prolonged survival as a result of developments in antiretroviral chemotherapy and management of opportunistic diseases, the incidence of cardiac disease in HIV-infected individuals may increase.
