1060
HCV RNA. This HCV infection rate in spouses is higher than previous estimates,1-4 perhaps because we used both clOO and core antibodies and because our index patients had more advanced liver diseases. 51 spouses were available for liver function tests and the 8 who were seropositive for both clOO and core antibodies were also positive for HCV RNA and had abnormal transaminases. Most spouses who were positive for anti-core only were RNA negative and had normal liver-function tests. HCV RNA from 6 patient-spouse pairs was genotyped. HCV type II (the most abundant genotype in Japan) was identified in both patient and spouse in 4; type III wasidentified in both in 1; and in 1 couple both patient and spouse had mixed II/III (since double infection is rare this probably indicates transmission from one to the other). The genotype was thus identical within the pair, supporting intra-spouse transmission. We thank Dr
Lacy R. Overby for reading the text.
First Department of Internal Medicine, Yamanashi Medical College
YOSHIHIRO AKAHANE
Aikawa Internal Hospital
TATSUYA AIKAWA
Department of Internal Medicine, Iwaki Kyoritsu General Hospital
YOSHIKI SUGAI
Immunology Section, Kitasato Institute, Tokyo
FUMIO TSUDA
Immunology Division,
HIROAKI OKAMOTO
Jichi Medical School Institute of
Immunology,
Koraku 1-1-10,
SHUNJI MISHIRO
Bunkyo-ku, Tokyo 112, Japan 1. Esteban
JI, Lopez-Talavera JC, Genesca J, et al High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med 1991; 115: 443-49. 2 Everhart JE, DiBisceglie AM, Murray LM, et al. Risk for non-A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 1990; 112: 544-45. 3. Wang J-T, Wang T-H, Sheu J-C, et al. Hepatitis C virus RNA in saliva of patients with posttransfusion hepatitis and low efficiency of transmission among spouses. J Med Virol 1992, 36: 28-31 4. Kiyosawa K, Sodeyama T, Tanaka E, et al. Intrafamilial transmission of hepatitis C
virus in Japan. J Med Virol 1991; 33: 114-16 Tajima K, Shimotohno K, Oki S. Natural horizontal transmission of HCV in microepidemic town in Japan. Lancet 1991; 337: 1410 6. Okamoto H, Munekata E, Tsuda F, et al. Enzyme-linked immunosorbent assay for antibodies against the capsid protein of hepatitis C virus with a synthetic oligopeptide. Jpn J Exp Med 1990; 60: 223-33. 7. Okamoto H, Tsuda F, Machida M, et al. Antibodies against synthetic oligopeptides deduced from the putative core gene for the diagnosis of hepatitis C virus infection. Hepatology 1992; 15: 180-86. 8 Okamoto H, Okada S, Sugiyama Y, et al. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5’-noncoding region. Jpn J Exp Med 1990; 60: 215-22. 9. Okamoto H, Sugiyama Y, Okada S, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing 5.
Virol 1992, 73: 673-79. infectious sources. Gen J
HIV false
positivity after hepatitis
B
vaccination SIR,-Next month the World Health Assembly will consider a recommendation that hepatitis B (HB) vaccination be included in the routine vaccination schedule for infants in all countries by 1997.’ The American Academy of Pediatrics has made a similar recommendation.2HB vaccination is now compulsory in Italy and some 35 countries already have a national policy on HB immunisation. This drive for universal immunisation is highly commendable in view of the human and social costs of viral hepatitis but it may unwittingly increase the number of false positives in the screening of blood for HIV antibodies. This prediction is based on a recent observation. A blood donor had consistently tested ELISA negative for anti-HIV since 1985. In 1989, after the second injection of an HB surface antigen recombinant vaccine (Recombivax-HB; Merck, Sharp and Dohme) he tested HIV-false positive, being ELISA positive but negative by western blot and indirect immunofluorescence assay. In the summer of 1990 he still tested false positive. At this time, to show that the false positivity was vaccine dependent, he was given a booster injection with another
recombinant vaccine (Engerix-B; SmithKline Biologicals) that is interchangeable with Recombivax-HB.’ Serum was monitored over 3 weeks by AUSRIA (Abbott Laboratories) for anti-HBs and by Vironostika ELISA (Organon Teknika) for anti-HIV. Both titres rose in parallel (p = 0 003). The "HIV titre" was low, as expected for cross-reactive antibodies, but it was more than 3SD above the negative controls. Neither titre was boosted by an influenza/pneumococcus vaccine given in August, 1991, indicating that the HIV false positivity was HB vaccine specific. This positivity could not be due to DR antibodies,4since he was not exposed to allogeneic blood as a patient nor is he an intravenous drug user. Moreover, he was tested by an ELISA that was free of contaminating MHC class II antigens. This apparent crossreactivity may have gone unnoticed hitherto because false-positive individuals form a small percentage of the immunised population and are not adversely affected by the false positivity. Moreover, in the past false-positive results were not recorded and the individuals were not routinely notified. Since HBV is much more prevalent than HIV, HBV-positive individuals with HIV crossreacting antibodies could outnumber true HIV positives. In current ELI SA screenings for HIV, false positives are much more frequent than true positives in the general population. Higher HIV false-positive rates would be expected in subpopulations at risk; notably, very high false-positive rates for HIV, not associated with DR antibodies, have been reported in subpopulations with endemic HBV or HBV exposure.5-7 Even if the frequency of HIV false positives in HBV-vaccinated individuals is no greater than that in the general population (0-5%8), the doubling of their number could greatly increase the cost of screening since confirmatory tests are more expensive than ELISA. Much greater would be the human cost-that is, the psychological impact associated with the notification of HIV false positivity. Despite these potential drawbacks to universal HBV vaccination, the WHO goal of eradicating HBV hepatitis must outweigh the extra costs of HIV screening. Departments of Microbiology, Pathology, and Pediatrics, Loma Linda University, Loma Linda, California 92350, USA
DEAN A. LEE WILLIAM C. EBY GIUSEPPE A. MOLINARO
1 Anon Hepatitis B in WHO’s EPI. Lancet 1992; 339: 610. 2. American Academy of Pediatrics, Committee on Infectious Diseases. Univesal hepatitis B immunization, policy statement. AAP News 1992; 8(2): 13-22. 3. SmithKline Beckman Corp. Engerix-B hepatitis B vaccine (recombinant) fact sheet, 1989. 4 Kuhnl P, Seidl S, Holzberger G HLA DR4 antibodies cause positive HTLV-III antibody ELISA results. Lancet 1985; i: 1222. 5. Smith DM, Dewhurst S, Shepherd S, Volsky DJ, Goldsmith JC. False-positive enzyme-linked immunosorbent assay reactions for antibody to human immunodeficiency virus in a population of midwestem patients with congenital bleeding disorders. Transfusion 1987; 27: 112. 6. Ujhelyi E, Fust G, Illei E. Different types of false positive anti-HIV reactions in patients on haemodialysis. Immunol Lett 1989; 22: 35-40. 7. Ujhelyi E, Gal G, Mako J, et al. False positive results of HIV virus tests in patients undergoing chronic hemodialysis. Orv Hetil 1989; 130: 67-70. 8. Menitove JE, Richards WA, Bauer P. False-positive anti-HIV tests and blood donation. Lancet 1987; ii. 1213.
HIV among south London heroin 1991
users
in
SIR,—To what extent do drug injecting and sexual behaviour determine HIV risk among heroin users? Injecting drug users are now the fastest-growing group in which HIV is spreading in Europe.1 They are exposed to infection by two routes-injections and sexual activity. Early reports2 mistakenly predicted an imminent epidemic amongst heroin addicts in London. Studies done in cities with established HIV epidemics3,4have examined only injecting heroin users, thus making separate consideration of sexual and injecting risks of HIV transmission difficult. We have interviewed 407 heroin users in south London, and have obtained saliva samples for anonymous HIV testing from 219 for whom we have linked, anonymous data on drug taking and sociodemographic characteristics. 129 (59%) were regular injectors, another 35 (16%) had at some time injected, and 55 (25%) had never injected (most taking their heroin by "chasing the dragon"-ie, heating heroin in a piece of tinfoil and inhaling the vapours5) . Duration of heroin use ranged from less than 1 year to 37 years: 70% had started drug misuse after 1980.
1061
12% (n = 15) of the 129 subjects who usually injected heroin and 3% (3) of the 86 who usually or always took heroin by chasing the dragon were HIV positive; 10% (16) of 164 subjects who had
injected at some time and 4% (2) of 55 who had never injected were HIV positive. Of the 164 subjects who had injected at some time, 38 reported that they had never shared injecting equipment. Seroprevalence was much the same among those who reported never sharing (11 %) and those who had shared (10%). Seropositive subjects were mostly male (15 of 143 men, 3 of 76 women). Rates of HIV infection among our non-injecting heroin users are higher than expected. Might this derive from sexual contact with other drug injectors? Preoccupation of health workers with epidemics in cities with a high number of injecting heroin users may have obscured the amount of sexual transmission among these drug misusers. Whether the increased HIV infection is an indication of new infection or of geographical drift after the Edinburgh epidemic of the mid-1980s3 is unclear: 17 of the 219 subjects were from Scotland, of whom 6 were HIV positive-a third of our seropositives. High rates of HIV infection were also associated with injecting. However, seroprevalence did not differ between those who had ever shared injecting equipment and those who had not. This finding could have implications for both policy and practice. Policy makers and clinicians should be cautious in assigning low HIV risk status to the so-called safe injector. JOHN STRANG
Drug Transitions Study,
MICHAEL GOSSOP PAUL GRIFFITHS BEVERLY POWIS
National Addiction Centre,
Maudsley Hospital, London SE5 8AF, UK
1. World Health Organisation. AIDS surveillance in Europe. Geneva. WHO.
Quart Rep 1990; no 20. 2 Webb G, Wells B, Morgan JR, McManus TJ. Epidemic of AIDS-related virus among intravenous drug abusers. Lancet 1986, i: 1202 3.Brettle R, Bisset K, Burns S, et al. Human immunodeficiency virus and drug misuse—the Edinburgh expenence. Br Med J 1987; 295: 421-24. 4. Des
Jarlais D, Friedman SR. The epidemic of HIV infection among injecting drug New York City the first decade and possible future directions. In: Strang J, Stimson G, eds. Aids and drug misuse: the challenge for policy and practice in the 1990s. London: Routledge, 1990: 86-94. 5. Gossop M, Griffiths P, Strang J. ’Chasing the dragon’: characteristics of heroin chasers. Br J Addict 1988; 83: 1159-62. users in
Cytokines and infection
in
cancer
patients
SIR,—We agree with Dr Jones and colleagues (Jan 18, p 181) that subcutaneous (sc) low-dose recombinant interleukin-2 (rIL-2) deserves special attention because of its use in highly resistant forms of metastatic cancer and that treatment can be given in an outpatient setting and over a long time. Infectious complications have been reported with intravenous (iv) rIL-2’ with dosages 1 0-fold to 30-fold higher than sc regimens.2 Catheter-related infections, bacteraemia, and sepsis requiring iv antibiotics developed with high-dose therapy via iv bolus3,4and constant infusion5,6 in 20-40% of patients, and occasionally in more than 40% on additional lymphokine-activated killer-cell administrationIn these patients, the high incidence of infections might be caused by central venous catheters, intravesicular catheters, or severe dermatological toxicity, or because they received in-vitro cell preparations. Moreover, transient granulocytopenia, neutropenia, or the release of immature granulocytes, and occasional neutropnilia have been reported with high-dose rIL-2 alone. High-dose rIL-2 also induces defective Fe receptor expressionand decreased neutrophil chemotaxis.11 In the absence of high-affinity IL-2 receptors on neutrophils, impairment of neutrophil chemotaxis might be mediated via secondary cytokines.11 In the 7 (sic) patients treated by Jones et al with low-dose sc rIL-2 and recombinant interferon-a (rIFN-&agr;), the 43% incidence of infectious complications seems to be very high. In view of the very low sensitivity of blood cultures,9 the true infection rate may be even higher. Yet, in most of Jones and colleagues’ infected patients, Staphylococcus epidermidis was identified as the aetiological agenta bacterium frequently responsible for false-positive blood cultures due to contamination.9 Furthermore, the 95% confidence limits based on the reported infection rate were very wide, being 9.9%-81.6%.
We report our experience in 109 patients treated with low-dose rIL-2 (Cetus) and rIFN-&agr;2b (Schering-Plough) via sc injection. rIL-2 was given at 48 x 106 IU/m2 thrice daily on day 1, twice daily on day 2, and at 2-4 x 106 IU/m2 twice daily on days 3-5, 8-12, and 15-19; rIFN-a was given at 3 x 106 U/m2 on days 3 and 5, and 6 x 106 U/m2 thrice weekly during weeks 2 and 3.2 A total of 888 treatment weeks were administered. We excluded patients with clinical evidence of severe infection before therapy. In our cohort, severe infection developed in only 1 patient (95% CI, 003-49%), resulting in enduring fever and septicaemia. This patient was admitted and, in the absence of positive blood cultures, was treated with iv antibiotics. In 3 additional patients (95% CI, 0-55-7-6%), local infection occurred, but was always at sc injection sites with no evidence of systemic complications. No antibiotics were necessary in these and all other patients. It should be noted that sc injections were always prepared under sterile conditions in a laminar flow cabinet. In our patients, neutropenia was mild to moderate and did not exceed World Health Organisation grade II. On treatment, peripheral granulocyte counts decreased from 4-7/nl (1-6) (mean [SD] before therapy) and reached a mean nadir of 2-3/nl (1-0) (p < 00005, Wilcoxon’s signed rank test) in most patients during the fourth week of treatment. Conversely, because of treatmentinduced expansion of circulating lymphocytes, total peripheral leucocyte counts increased from 7-5 (2-1) to 11.3/nl (3-8) (p < 0-0005). In all patients, circulating granulocyte counts returned to normal no later than 2 weeks after cessation of therapy. In view of the known efficacy, simple application, and tolerance of low-dose outpatient sc rIL-2 and rIFN-a combination therapy, our experience suggests that infectious complications play no major part in the clinical use of this new and promising method of
palliative cancer immunotherapy. Department of Hematology and Oncology, MHH University Medical Centre, D-3000 Hannover 61, Germany
AXEL G. SCHOMBURG HARTMUT H. KIRCHNER JENS ATZPODIEN
Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889-97. 2. Atzpodien K, Korfer A, Franks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-&agr;2b in advanced human malignancies. Lancet 1990; 335: 1509-12. 3. Saxon RR, Klein JS, Bar MH, et al Pathogenesis of pulmonary edema during interleukin-2 therapy Am JRoentgenol 1991; 156: 281-85. 4. Clark JW, Smith JW, Steis RG, et al. Interleukin-2 and lymphokine-activated killer cell therapy; analysis of a bolus interleukin-2 and a continuous infusion interleukin-2 regimen. Cancer Res 1990; 50: 7343-50. 5. Creekmore SP, Harris JE, Ellis TM, et al. A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. J Clin Oncol 1989; 7: 1.
276-84. 6 Dutcher JP, Gaynor ER, Boldt DH, et al. A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated cells in patients with metastatic melanoma. J Clin Oncol 1991; 9: 641-48. 7. Jablons D, Bolton E, Martins S, et al. Interleukin-2 based immunotherapy alters circulating neutrophils Fc receptor expression and chemotaxis. J Immunol 1990; 144: 3630-36 8. Klempner MS, Noring R, Mier JW, Atkins MB. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med
1990; 322: 959-65. JJ. The diagnosis of infectious disease. In: Wilson JD, et al, eds Harrison’s principles of internal medicine, 12th ed. New York: McGraw-Hill, 1991.
9. Plorde
SIR,-Dr Jones and colleagues report that infection is a complication of treatment of cancer patients with interleukin-2 (IL-2) or IL-2 plus interferon-alpha. They conclude that the infections were probably related to IL-2 administration, secondary to an induced defect in cellular immunity. We agree that IL-2 may produce a defect in neutrophil function1.2 and thereby in nonspecific cellular immunity. However, we suggest an additional possible mechanism for this—direct stimulation of bacterial growth by IL-2. Our studies with virulent and non-virulent strains of Escherichia coli showed that IL-2 preferentially stimulated growth of the virulent strainFurther, this effect was not limited to IL-2 since
ecogramostim (granulocyte-macrophage colony stimulating factor) also enhanced its growth. We have also shown that interleukm-6,4 interleukin-3, and macrophage colony stimulating factor’
HCV RNA. This HCV infection rate in spouses is higher than previous estimates,1-4 perhaps because we used both clOO and core antibodies and because our index patients had more advanced liver diseases. 51 spouses were available for liver function tests and the 8 who were seropositive for both clOO and core antibodies were also positive for HCV RNA and had abnormal transaminases. Most spouses who were positive for anti-core only were RNA negative and had normal liver-function tests. HCV RNA from 6 patient-spouse pairs was genotyped. HCV type II (the most abundant genotype in Japan) was identified in both patient and spouse in 4; type III wasidentified in both in 1; and in 1 couple both patient and spouse had mixed II/III (since double infection is rare this probably indicates transmission from one to the other). The genotype was thus identical within the pair, supporting intra-spouse transmission. We thank Dr
Lacy R. Overby for reading the text.
First Department of Internal Medicine, Yamanashi Medical College
YOSHIHIRO AKAHANE
Aikawa Internal Hospital
TATSUYA AIKAWA
Department of Internal Medicine, Iwaki Kyoritsu General Hospital
YOSHIKI SUGAI
Immunology Section, Kitasato Institute, Tokyo
FUMIO TSUDA
Immunology Division,
HIROAKI OKAMOTO
Jichi Medical School Institute of
Immunology,
Koraku 1-1-10,
SHUNJI MISHIRO
Bunkyo-ku, Tokyo 112, Japan 1. Esteban
JI, Lopez-Talavera JC, Genesca J, et al High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med 1991; 115: 443-49. 2 Everhart JE, DiBisceglie AM, Murray LM, et al. Risk for non-A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 1990; 112: 544-45. 3. Wang J-T, Wang T-H, Sheu J-C, et al. Hepatitis C virus RNA in saliva of patients with posttransfusion hepatitis and low efficiency of transmission among spouses. J Med Virol 1992, 36: 28-31 4. Kiyosawa K, Sodeyama T, Tanaka E, et al. Intrafamilial transmission of hepatitis C
virus in Japan. J Med Virol 1991; 33: 114-16 Tajima K, Shimotohno K, Oki S. Natural horizontal transmission of HCV in microepidemic town in Japan. Lancet 1991; 337: 1410 6. Okamoto H, Munekata E, Tsuda F, et al. Enzyme-linked immunosorbent assay for antibodies against the capsid protein of hepatitis C virus with a synthetic oligopeptide. Jpn J Exp Med 1990; 60: 223-33. 7. Okamoto H, Tsuda F, Machida M, et al. Antibodies against synthetic oligopeptides deduced from the putative core gene for the diagnosis of hepatitis C virus infection. Hepatology 1992; 15: 180-86. 8 Okamoto H, Okada S, Sugiyama Y, et al. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5’-noncoding region. Jpn J Exp Med 1990; 60: 215-22. 9. Okamoto H, Sugiyama Y, Okada S, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing 5.
Virol 1992, 73: 673-79. infectious sources. Gen J
HIV false
positivity after hepatitis
B
vaccination SIR,-Next month the World Health Assembly will consider a recommendation that hepatitis B (HB) vaccination be included in the routine vaccination schedule for infants in all countries by 1997.’ The American Academy of Pediatrics has made a similar recommendation.2HB vaccination is now compulsory in Italy and some 35 countries already have a national policy on HB immunisation. This drive for universal immunisation is highly commendable in view of the human and social costs of viral hepatitis but it may unwittingly increase the number of false positives in the screening of blood for HIV antibodies. This prediction is based on a recent observation. A blood donor had consistently tested ELISA negative for anti-HIV since 1985. In 1989, after the second injection of an HB surface antigen recombinant vaccine (Recombivax-HB; Merck, Sharp and Dohme) he tested HIV-false positive, being ELISA positive but negative by western blot and indirect immunofluorescence assay. In the summer of 1990 he still tested false positive. At this time, to show that the false positivity was vaccine dependent, he was given a booster injection with another
recombinant vaccine (Engerix-B; SmithKline Biologicals) that is interchangeable with Recombivax-HB.’ Serum was monitored over 3 weeks by AUSRIA (Abbott Laboratories) for anti-HBs and by Vironostika ELISA (Organon Teknika) for anti-HIV. Both titres rose in parallel (p = 0 003). The "HIV titre" was low, as expected for cross-reactive antibodies, but it was more than 3SD above the negative controls. Neither titre was boosted by an influenza/pneumococcus vaccine given in August, 1991, indicating that the HIV false positivity was HB vaccine specific. This positivity could not be due to DR antibodies,4since he was not exposed to allogeneic blood as a patient nor is he an intravenous drug user. Moreover, he was tested by an ELISA that was free of contaminating MHC class II antigens. This apparent crossreactivity may have gone unnoticed hitherto because false-positive individuals form a small percentage of the immunised population and are not adversely affected by the false positivity. Moreover, in the past false-positive results were not recorded and the individuals were not routinely notified. Since HBV is much more prevalent than HIV, HBV-positive individuals with HIV crossreacting antibodies could outnumber true HIV positives. In current ELI SA screenings for HIV, false positives are much more frequent than true positives in the general population. Higher HIV false-positive rates would be expected in subpopulations at risk; notably, very high false-positive rates for HIV, not associated with DR antibodies, have been reported in subpopulations with endemic HBV or HBV exposure.5-7 Even if the frequency of HIV false positives in HBV-vaccinated individuals is no greater than that in the general population (0-5%8), the doubling of their number could greatly increase the cost of screening since confirmatory tests are more expensive than ELISA. Much greater would be the human cost-that is, the psychological impact associated with the notification of HIV false positivity. Despite these potential drawbacks to universal HBV vaccination, the WHO goal of eradicating HBV hepatitis must outweigh the extra costs of HIV screening. Departments of Microbiology, Pathology, and Pediatrics, Loma Linda University, Loma Linda, California 92350, USA
DEAN A. LEE WILLIAM C. EBY GIUSEPPE A. MOLINARO
1 Anon Hepatitis B in WHO’s EPI. Lancet 1992; 339: 610. 2. American Academy of Pediatrics, Committee on Infectious Diseases. Univesal hepatitis B immunization, policy statement. AAP News 1992; 8(2): 13-22. 3. SmithKline Beckman Corp. Engerix-B hepatitis B vaccine (recombinant) fact sheet, 1989. 4 Kuhnl P, Seidl S, Holzberger G HLA DR4 antibodies cause positive HTLV-III antibody ELISA results. Lancet 1985; i: 1222. 5. Smith DM, Dewhurst S, Shepherd S, Volsky DJ, Goldsmith JC. False-positive enzyme-linked immunosorbent assay reactions for antibody to human immunodeficiency virus in a population of midwestem patients with congenital bleeding disorders. Transfusion 1987; 27: 112. 6. Ujhelyi E, Fust G, Illei E. Different types of false positive anti-HIV reactions in patients on haemodialysis. Immunol Lett 1989; 22: 35-40. 7. Ujhelyi E, Gal G, Mako J, et al. False positive results of HIV virus tests in patients undergoing chronic hemodialysis. Orv Hetil 1989; 130: 67-70. 8. Menitove JE, Richards WA, Bauer P. False-positive anti-HIV tests and blood donation. Lancet 1987; ii. 1213.
HIV among south London heroin 1991
users
in
SIR,—To what extent do drug injecting and sexual behaviour determine HIV risk among heroin users? Injecting drug users are now the fastest-growing group in which HIV is spreading in Europe.1 They are exposed to infection by two routes-injections and sexual activity. Early reports2 mistakenly predicted an imminent epidemic amongst heroin addicts in London. Studies done in cities with established HIV epidemics3,4have examined only injecting heroin users, thus making separate consideration of sexual and injecting risks of HIV transmission difficult. We have interviewed 407 heroin users in south London, and have obtained saliva samples for anonymous HIV testing from 219 for whom we have linked, anonymous data on drug taking and sociodemographic characteristics. 129 (59%) were regular injectors, another 35 (16%) had at some time injected, and 55 (25%) had never injected (most taking their heroin by "chasing the dragon"-ie, heating heroin in a piece of tinfoil and inhaling the vapours5) . Duration of heroin use ranged from less than 1 year to 37 years: 70% had started drug misuse after 1980.
1061
12% (n = 15) of the 129 subjects who usually injected heroin and 3% (3) of the 86 who usually or always took heroin by chasing the dragon were HIV positive; 10% (16) of 164 subjects who had
injected at some time and 4% (2) of 55 who had never injected were HIV positive. Of the 164 subjects who had injected at some time, 38 reported that they had never shared injecting equipment. Seroprevalence was much the same among those who reported never sharing (11 %) and those who had shared (10%). Seropositive subjects were mostly male (15 of 143 men, 3 of 76 women). Rates of HIV infection among our non-injecting heroin users are higher than expected. Might this derive from sexual contact with other drug injectors? Preoccupation of health workers with epidemics in cities with a high number of injecting heroin users may have obscured the amount of sexual transmission among these drug misusers. Whether the increased HIV infection is an indication of new infection or of geographical drift after the Edinburgh epidemic of the mid-1980s3 is unclear: 17 of the 219 subjects were from Scotland, of whom 6 were HIV positive-a third of our seropositives. High rates of HIV infection were also associated with injecting. However, seroprevalence did not differ between those who had ever shared injecting equipment and those who had not. This finding could have implications for both policy and practice. Policy makers and clinicians should be cautious in assigning low HIV risk status to the so-called safe injector. JOHN STRANG
Drug Transitions Study,
MICHAEL GOSSOP PAUL GRIFFITHS BEVERLY POWIS
National Addiction Centre,
Maudsley Hospital, London SE5 8AF, UK
1. World Health Organisation. AIDS surveillance in Europe. Geneva. WHO.
Quart Rep 1990; no 20. 2 Webb G, Wells B, Morgan JR, McManus TJ. Epidemic of AIDS-related virus among intravenous drug abusers. Lancet 1986, i: 1202 3.Brettle R, Bisset K, Burns S, et al. Human immunodeficiency virus and drug misuse—the Edinburgh expenence. Br Med J 1987; 295: 421-24. 4. Des
Jarlais D, Friedman SR. The epidemic of HIV infection among injecting drug New York City the first decade and possible future directions. In: Strang J, Stimson G, eds. Aids and drug misuse: the challenge for policy and practice in the 1990s. London: Routledge, 1990: 86-94. 5. Gossop M, Griffiths P, Strang J. ’Chasing the dragon’: characteristics of heroin chasers. Br J Addict 1988; 83: 1159-62. users in
Cytokines and infection
in
cancer
patients
SIR,—We agree with Dr Jones and colleagues (Jan 18, p 181) that subcutaneous (sc) low-dose recombinant interleukin-2 (rIL-2) deserves special attention because of its use in highly resistant forms of metastatic cancer and that treatment can be given in an outpatient setting and over a long time. Infectious complications have been reported with intravenous (iv) rIL-2’ with dosages 1 0-fold to 30-fold higher than sc regimens.2 Catheter-related infections, bacteraemia, and sepsis requiring iv antibiotics developed with high-dose therapy via iv bolus3,4and constant infusion5,6 in 20-40% of patients, and occasionally in more than 40% on additional lymphokine-activated killer-cell administrationIn these patients, the high incidence of infections might be caused by central venous catheters, intravesicular catheters, or severe dermatological toxicity, or because they received in-vitro cell preparations. Moreover, transient granulocytopenia, neutropenia, or the release of immature granulocytes, and occasional neutropnilia have been reported with high-dose rIL-2 alone. High-dose rIL-2 also induces defective Fe receptor expressionand decreased neutrophil chemotaxis.11 In the absence of high-affinity IL-2 receptors on neutrophils, impairment of neutrophil chemotaxis might be mediated via secondary cytokines.11 In the 7 (sic) patients treated by Jones et al with low-dose sc rIL-2 and recombinant interferon-a (rIFN-&agr;), the 43% incidence of infectious complications seems to be very high. In view of the very low sensitivity of blood cultures,9 the true infection rate may be even higher. Yet, in most of Jones and colleagues’ infected patients, Staphylococcus epidermidis was identified as the aetiological agenta bacterium frequently responsible for false-positive blood cultures due to contamination.9 Furthermore, the 95% confidence limits based on the reported infection rate were very wide, being 9.9%-81.6%.
We report our experience in 109 patients treated with low-dose rIL-2 (Cetus) and rIFN-&agr;2b (Schering-Plough) via sc injection. rIL-2 was given at 48 x 106 IU/m2 thrice daily on day 1, twice daily on day 2, and at 2-4 x 106 IU/m2 twice daily on days 3-5, 8-12, and 15-19; rIFN-a was given at 3 x 106 U/m2 on days 3 and 5, and 6 x 106 U/m2 thrice weekly during weeks 2 and 3.2 A total of 888 treatment weeks were administered. We excluded patients with clinical evidence of severe infection before therapy. In our cohort, severe infection developed in only 1 patient (95% CI, 003-49%), resulting in enduring fever and septicaemia. This patient was admitted and, in the absence of positive blood cultures, was treated with iv antibiotics. In 3 additional patients (95% CI, 0-55-7-6%), local infection occurred, but was always at sc injection sites with no evidence of systemic complications. No antibiotics were necessary in these and all other patients. It should be noted that sc injections were always prepared under sterile conditions in a laminar flow cabinet. In our patients, neutropenia was mild to moderate and did not exceed World Health Organisation grade II. On treatment, peripheral granulocyte counts decreased from 4-7/nl (1-6) (mean [SD] before therapy) and reached a mean nadir of 2-3/nl (1-0) (p < 00005, Wilcoxon’s signed rank test) in most patients during the fourth week of treatment. Conversely, because of treatmentinduced expansion of circulating lymphocytes, total peripheral leucocyte counts increased from 7-5 (2-1) to 11.3/nl (3-8) (p < 0-0005). In all patients, circulating granulocyte counts returned to normal no later than 2 weeks after cessation of therapy. In view of the known efficacy, simple application, and tolerance of low-dose outpatient sc rIL-2 and rIFN-a combination therapy, our experience suggests that infectious complications play no major part in the clinical use of this new and promising method of
palliative cancer immunotherapy. Department of Hematology and Oncology, MHH University Medical Centre, D-3000 Hannover 61, Germany
AXEL G. SCHOMBURG HARTMUT H. KIRCHNER JENS ATZPODIEN
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276-84. 6 Dutcher JP, Gaynor ER, Boldt DH, et al. A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated cells in patients with metastatic melanoma. J Clin Oncol 1991; 9: 641-48. 7. Jablons D, Bolton E, Martins S, et al. Interleukin-2 based immunotherapy alters circulating neutrophils Fc receptor expression and chemotaxis. J Immunol 1990; 144: 3630-36 8. Klempner MS, Noring R, Mier JW, Atkins MB. An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med
1990; 322: 959-65. JJ. The diagnosis of infectious disease. In: Wilson JD, et al, eds Harrison’s principles of internal medicine, 12th ed. New York: McGraw-Hill, 1991.
9. Plorde
SIR,-Dr Jones and colleagues report that infection is a complication of treatment of cancer patients with interleukin-2 (IL-2) or IL-2 plus interferon-alpha. They conclude that the infections were probably related to IL-2 administration, secondary to an induced defect in cellular immunity. We agree that IL-2 may produce a defect in neutrophil function1.2 and thereby in nonspecific cellular immunity. However, we suggest an additional possible mechanism for this—direct stimulation of bacterial growth by IL-2. Our studies with virulent and non-virulent strains of Escherichia coli showed that IL-2 preferentially stimulated growth of the virulent strainFurther, this effect was not limited to IL-2 since
ecogramostim (granulocyte-macrophage colony stimulating factor) also enhanced its growth. We have also shown that interleukm-6,4 interleukin-3, and macrophage colony stimulating factor’
