730
RESULTS OF TWO CASE-CONTROL STUDIES
cardiovascular monitoring. We would restrict its use to patients for whom no alternative measures are available, and we also recommend the use of erythropoietin in such patients.1 Blood Transfusion Service,
Kyushu University Hospital, Fukuoka 812, Japan
S. INABA
Department of Anaesthesiology and Critical Care Medicine, Faculty of Medicine,
S. HOKA
Kyushu University
J. YOSHITAKE
1. Maeda H, Hitomi Y, Hirata R, Lancet 1989; ii: 284.
et
al.
Erythropoietin and autologous blood donation. I
*Piroxicam not listed
I
pharmaceutical benefit during study 1 n study 1, tDiclofenac. diflumsal, ibuprofen, indomethacin, naproxen, and sulindac and same drugs with the addition of ketoprofen m study 2
NSAIDs and risk of upper
gastrointestinal
bleeding SIR,-We were surprised by the magnitude of the odds ratios (OR) estimated by Dr Laporte and colleagues (Jan 13, p 85) in their case-control study of non-steroidal anti-inflammatory drugs (NSAIDs) and hospital admission for upper gastrointestinal bleeding. The differences in the estimated OR for individual NSAIDs should be interpreted with caution too. We have done two case-control studies. The first covered patients aged 50 years and over admitted with upper gastrointestinal bleeding or ulcer perforation to two public hospitals in the Newcastle area of New South Wales (population 400 000) between 1985 and 1987. The second recruited consecutive admissions with
haemorrhage or perforation (irrespective of age) to all public hospitals in the area between mid-1988 and mid-1990. The aim of study 1 was to estimate the overall relative risk of ulcer complications associated with any NSAID. The aim of study 2 was to compare the OR with piroxicam to that of the other NSAIDs. By combining data from the two studies we hope to investigate the importance of other factors, such as dose-duration of therapy, co-prescription of aspirin, ulcer site, and history of peptic ulceration. Almost all cases of haemorrhage had a diagnostic endoscopy within 24 hours of admission. Cases were matched with hospital controls (1:in study 1; 1:2 in study 2) for sex and age within 5 years. Controls were new admissions with primary diagnoses not thought to be related to NSAIDs, and they were interviewed within a week of the cases. Information on use of NSAIDs by cases and controls during the week before admission was obtained by one research nurse using a structured interview, with a mixture of open followed by closed questions and prompts in the form of the Australian proprietary names of all marketed NSAIDs. This information was compared with that held in family practitioner prescribing records with simple rules to resolve conflict between these sources. In Australia drugs are little used in the community unless they are listed in the Commonwealth Government’s Schedule of Pharmaceutical Benefits. The NSAIDs listed were diclofenac, diflunisal, ibuprofen, indomethacin, naproxen, and sulindac for study 1, ketoprofen and piroxicam being added in study 2. The results are summarised in the table. OR and 95 % confidence intervals (CI) were calculated by conditional logistic regression with adjustment for social status, smoking, and alcohol consumption. The levels of use of NSAIDS (excluding aspirin) by cases and especially by controls were much higher than those recorded by Laporte et al. We have confirmation of this high use from a concurrent prevalence study of a statistically representative sample (n 2578) of the Newcastle community which established that NSAIDs had been used in the previous 4 days by 15-4% of those aged 55-64 years and by 21-4% of those aged 65 or more (unpublished). In our first study the OR for bleeding or perforation with use of any NSAID in the previous week was 2-9 (95% CI 1-8-4-8), and in the second study it was 3-1 (2-3-4-1). The comparable figures from the study of Laporte et al were 7-4 (2-4-23-0) and 8-0 (3-8-16-6) with and without a previous history of ulceration. In contrast to Laporte et al we found the estimated relative risk with piroxicam to be only slightly higher than that with
as
the other commonly used NSAIDs, and there was substantial overlap of CIs (table). The proportion of our NSAID-using cases who had taken piroxicam (21 %) was identical to that drug’s national market share during the study period (data provided by Pfizer
Australia). The OR for use of any NSAID agrees well with the pooled estimates of risk from Hawkey’s meta-analysis of four other case control studies (pooled OR 3-1, 95% CI 2-3-4-2) and our meta-analysis of eleven case control studies (34, 28-43) 2 Although our relative risk estimates for bleeding or perforation with use of any NSAID are lower than those from the Spanish study, the Australian population attributable risk (aetiological fraction) is higher (24% vs about 15%) because of the higher use of NSAIDs in the Australian community. The low use of NSAIDs by the Spanish controls results in that study having a lower power than our study, and a similar power to some previously published case-control studies despite its large size. We calculate that the minimum OR that the Spanish study could have detected with a power of 0-8 (rJ. 0-05) was 1 8.3 This calculation takes account of matching and assumes a correlation between cases and controls on exposure of 0-2. Under the same assumptions our second study would have detected an odds ratio as low as 1 ’6. The case-control studies of Somerville et all and Griffin et all could have detected OR as low as 1 and 20, respectively. We agree with Laporte et al that NSAIDs are an important cause of serious gastrointestinal bleeding. In our view it is the population risk rather than the individual risk that is most significant. Since the problem in Australia is, in the main, dependent on the prevalence of exposure to the risk factor, rather than the magnitude of the individual’s risk, prevention should in most cases be directed at reducing exposure rather than attempting to lower risk by co-prescription of protective agents. Although we do not rule out the possibility that piroxicam is associated with a significantly higher relative risk than other NSAIDs, we believe that on present evidence apparent differences between individual agents should be interpreted with caution. —
Supported by grants from the National Health and Medical Research Council of Australia and Pfizer Austrialia Pry Ltd. The full results of this study will be published later.
Departments of Clinical Pharmacology, Statistics, and Nursing, University of Newcastle, Newcastle, NSW 2300, Australia
DAVID HENRY ANNETTE DOBSON CATHY TURNER PAMELA HALL CAROLINE FORBES PHILIPPA PATEY
=
1.
Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. Br Med J1990, 300: 278-84.
Henry DA. Gastrointestinal bleeding and non-steroidal anti-inflammatory drugs In Lawson DH, ed. Royal College of Physicians of Edinburgh Current medicine-3 Edinburgh: Churchill Livingstone, (in press). 3. Dupont WD, Plummer WD. Power and sample size calculations, a review and computer program. Controlled Clin Trials 1990; 11: 116-28 4. Somerville K, Faulkner G, Langman M. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet 1986; i: 462-64. 5. Griffin MR, Ray WA, Schaffner W. Non-steroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988; 109: 359-63
2.
731
THE LANCET
infection SiR,—Transmission of HIV is primarily through intimate sexual with an infected individual or contact with infected blood via shared needles among intravenous drug users, occupational exposure to contaminated "sharps", or transfusions with contaminated blood products, for example. We present a case of possible HIV infection via a previously undescribed route. A 49-year-old heterosexual male was referred for evaluation of HIV seropositivity found on screening during a routine application for life insurance. A repeat ELISA and subsequent western blot were both reactive for HIV. The patient had been married for over 25 years and had three children. His wife’s serum was non-reactive for HIV antibody. He denied ever having sex with a man, nor with another woman since marriage, and claimed he had been impotent for about 10 years. He denied ever having received blood products. He had used intravenous drugs once, 3 years previously, but distinctly remembered not sharing needles but using a needle from an unopened package. On repeated questioning he adamantly denied using drugs on any other occasion. This was all independently corroborated by his wife. On a follow-up visit the patient, dissatisfied with the explanation that the alleged one-time exposure to intravenous drugs was his risk factor, inquired if contact with infected blood on cuts of the skin could lead to infection. He said that in 1982-88 he worked as a truck driver, primarily in the New York/New Jersey area. During that time he admitted that he and work colleagues would go out "gay bashing". They sought out places frequented by gay men and systematically beat them. The patient admitted doing this "too many times to count", and would frequently get large amounts of the victim’s blood on himself. He frequently sustained small lacerations on his hands while administering the beatings. On the patient’s first examination we noted several small scabbed lacerations over his proximal interphalangeal joints that had, allegedly, resulted from a recent fight. Mucocutaneous exposure to infected blood has been confirmed as the route of infection in several health-care workers with AIDS.’ One man seroconverted after contact with another’s blood when they both sustained numerous lacerations in a motor vehicle accident.2 Although we cannot prove that contact with blood from infected persons during gay bashing was the mechanism of acquisition in this case, it is certainly plausible. Perhaps this case will serve as a deterrent to the dreadful practice of "bashing" people simply because they belong to a particular minority. contact
Department of Internal Medicine, Medical Center, University of Nebraska, Omaha, Nebraska 68198, USA
PAUL CARSON JONATHAN C. GOLDSMITH
1. CDC.
Update: human immunodeficiency virus infections in health care workers exposed to blood of infected patients. MMWR 1987; 36: 285-89. 2. Hill DW. HIV infection following motor vehicle trauma in central Africa JAMA 1989; 261: 282-83.
Transiently positive HIV antibody test after treatment with tetanus immune globulin SIR,-A 25-year-old nurse injured her hand on the edge of an operating-table. She was given a prophylactic injection of tetanus immune globulin (TIG). The following day a blood sample was taken to test for hepatitis B virus (HBV) markers and HIV antibody, as is routine at this hospital in cases of possible accidental exposure to HBV and HIV. HBV markers were negative but she was anti-HIV positive with both ELISA tests used in our laboratory (Sorin Biomedica, Behring), and the same sample was western blot positive (Sorin Biomedica), showing reactivity against all viral proteins. A careful history excluded
any risk factor for HIV
infection other than hospital employment. A second blood sample, taken 12 days later, was anti-HIV negative by ELISA but showed reactivity for gp 120 and p24 by western blot. A third sample, taken 1 month after the first, was negative by both ELISA and western blot. The passive transfer of HIV antibodies
proteins have been detected in HBIG. The history and serological findings in this case suggest passive transfer of HIV antibodies by TIG given 24 hours before the first blood sample was taken. This could explain the initial reactivity, and the progressive disappearance of reactivity in western blot tests is consistent with this explanation. We could not test the TIG preparation for HIV antibody because neither lot number nor manufacturer were
HIV
"Gay bashing" as possible risk for HIV
known. A. GONNELLI P. ALMI M. RUBINO M. TOTI
Division of Infectious Diseases,
Ospedale S Maria della Scale, 53100 Siena, Italy
1. Schlench WF, Spencer SHS, Cook J, et al. Passive transfer of HIV antibody by hepatitis B immuneglobulin. JAMA 1989; 261: 411-13. 2. Wood CC, Williams AE, McNamara JG, et al. Antibody against the human immunodeficiency virus in commercial intravenous gammaglobulin preparations. Ann Intern Med 1986; 105: 536-38. 3. Lai-Goldman M, McBride JH, Howanitz PJ. Presence of HTLV III antibodies in immune serum globulin preparations. Am J Clin Pathol 1987; 87: 635-39. 4. Steele DR. HTLV III antibodies in human immune gammaglobulin. JAMA 1986; 255: 609.
Potential molecular
competitor for
SiR,—The theory of genotypic selection (ref 1 and unpublished) that a non-pathogenic HIV-1 strain might be identified
predicts
that could compete in vivo with virulent strains and ameliorate the course of disease. The phenotype of a non-pathogenic virus (which may be confused with "long-latency") should result in a symptom-free HIV-positive status. An epidemiological search of one affected population identified an individual who might be harbouring such a strain: he had HIV-1 (DNA-PCR gag, strong western blot, probable infection for longer than 10 years, no antiviral treatment), T4 lymphocyte counts about 1000/pJ, and normal mitogenic and delayed-type hypersensitivity skin test (DTH) responses. History revealed multiple high-risk contacts and intravenous drug abuse, suggesting exposure to numerous wild-type pathogenic strains from partners who subsequently died from AIDS as early as 1983. Viral growth in culture was uncharacteristically slow. This donor was negative for active hepatitis, syphilis, herpes, cytomegalovirus,
Epstein-Barr virus, toxoplasma, cryptococcus, and histoplasma. 11severely immunocompromised patients (T4 mean 66/pi) with immunological deterioration and disease progression despite zidovudine or dideoxyinosine treatment provided informed consent and agreed to discontinue all antiviral treatment. Each patient received two inoculations of blood z2-0 ml) from the putative non-pathogenic donor. Strains from symptomless donors must be characterised for competition and non-pathogenicity before inoculation. Patients have now been followed up weekly for six months and clinically 4 have improved, 3 have shown a mixed response, 3 have regressed, and 1 has died. Apart from transient myalgia, low-grade fever, and diarrhoea, no new symptoms were noted. After a zero to trace DTH response at baseline, all 10 survivors progressed to a moderate to strong response in six months (one responding to all of eight antigens and another to seven of eight), suggesting a gradual return of cell-mediated immunity.* Average total T, T4, and T8 cell numbers and percentages remained stable, fluctuating around baseline mean for six months. The above observations are paradoxical in the absence of antiviral therapy or in the presence of progressive immunological deterioration, but indicate that no harm was caused by the infusions. Importantly, an epitope of p17 (a fragment of gag product), appearing strongly in the donor strain and initially absent or weakly present in the inoculated population, subsequently increased strikingly in all patients who improved. These preliminary findings suggest a variable degree of in vivo colonisation and perhaps competition between a putative nonpathogenic strain and wild-type virulent strains. If the inoculated strain merely had a phenotype of long latency and pathogenicity, we should not have seen clinical improvement and restoration of
by hepatitis B immune
globulin (HBIG) has been demonstratedl-4 but neither HIV
nor
HIV
*Details available from The Lancet or Immuvax.
RESULTS OF TWO CASE-CONTROL STUDIES
cardiovascular monitoring. We would restrict its use to patients for whom no alternative measures are available, and we also recommend the use of erythropoietin in such patients.1 Blood Transfusion Service,
Kyushu University Hospital, Fukuoka 812, Japan
S. INABA
Department of Anaesthesiology and Critical Care Medicine, Faculty of Medicine,
S. HOKA
Kyushu University
J. YOSHITAKE
1. Maeda H, Hitomi Y, Hirata R, Lancet 1989; ii: 284.
et
al.
Erythropoietin and autologous blood donation. I
*Piroxicam not listed
I
pharmaceutical benefit during study 1 n study 1, tDiclofenac. diflumsal, ibuprofen, indomethacin, naproxen, and sulindac and same drugs with the addition of ketoprofen m study 2
NSAIDs and risk of upper
gastrointestinal
bleeding SIR,-We were surprised by the magnitude of the odds ratios (OR) estimated by Dr Laporte and colleagues (Jan 13, p 85) in their case-control study of non-steroidal anti-inflammatory drugs (NSAIDs) and hospital admission for upper gastrointestinal bleeding. The differences in the estimated OR for individual NSAIDs should be interpreted with caution too. We have done two case-control studies. The first covered patients aged 50 years and over admitted with upper gastrointestinal bleeding or ulcer perforation to two public hospitals in the Newcastle area of New South Wales (population 400 000) between 1985 and 1987. The second recruited consecutive admissions with
haemorrhage or perforation (irrespective of age) to all public hospitals in the area between mid-1988 and mid-1990. The aim of study 1 was to estimate the overall relative risk of ulcer complications associated with any NSAID. The aim of study 2 was to compare the OR with piroxicam to that of the other NSAIDs. By combining data from the two studies we hope to investigate the importance of other factors, such as dose-duration of therapy, co-prescription of aspirin, ulcer site, and history of peptic ulceration. Almost all cases of haemorrhage had a diagnostic endoscopy within 24 hours of admission. Cases were matched with hospital controls (1:in study 1; 1:2 in study 2) for sex and age within 5 years. Controls were new admissions with primary diagnoses not thought to be related to NSAIDs, and they were interviewed within a week of the cases. Information on use of NSAIDs by cases and controls during the week before admission was obtained by one research nurse using a structured interview, with a mixture of open followed by closed questions and prompts in the form of the Australian proprietary names of all marketed NSAIDs. This information was compared with that held in family practitioner prescribing records with simple rules to resolve conflict between these sources. In Australia drugs are little used in the community unless they are listed in the Commonwealth Government’s Schedule of Pharmaceutical Benefits. The NSAIDs listed were diclofenac, diflunisal, ibuprofen, indomethacin, naproxen, and sulindac for study 1, ketoprofen and piroxicam being added in study 2. The results are summarised in the table. OR and 95 % confidence intervals (CI) were calculated by conditional logistic regression with adjustment for social status, smoking, and alcohol consumption. The levels of use of NSAIDS (excluding aspirin) by cases and especially by controls were much higher than those recorded by Laporte et al. We have confirmation of this high use from a concurrent prevalence study of a statistically representative sample (n 2578) of the Newcastle community which established that NSAIDs had been used in the previous 4 days by 15-4% of those aged 55-64 years and by 21-4% of those aged 65 or more (unpublished). In our first study the OR for bleeding or perforation with use of any NSAID in the previous week was 2-9 (95% CI 1-8-4-8), and in the second study it was 3-1 (2-3-4-1). The comparable figures from the study of Laporte et al were 7-4 (2-4-23-0) and 8-0 (3-8-16-6) with and without a previous history of ulceration. In contrast to Laporte et al we found the estimated relative risk with piroxicam to be only slightly higher than that with
as
the other commonly used NSAIDs, and there was substantial overlap of CIs (table). The proportion of our NSAID-using cases who had taken piroxicam (21 %) was identical to that drug’s national market share during the study period (data provided by Pfizer
Australia). The OR for use of any NSAID agrees well with the pooled estimates of risk from Hawkey’s meta-analysis of four other case control studies (pooled OR 3-1, 95% CI 2-3-4-2) and our meta-analysis of eleven case control studies (34, 28-43) 2 Although our relative risk estimates for bleeding or perforation with use of any NSAID are lower than those from the Spanish study, the Australian population attributable risk (aetiological fraction) is higher (24% vs about 15%) because of the higher use of NSAIDs in the Australian community. The low use of NSAIDs by the Spanish controls results in that study having a lower power than our study, and a similar power to some previously published case-control studies despite its large size. We calculate that the minimum OR that the Spanish study could have detected with a power of 0-8 (rJ. 0-05) was 1 8.3 This calculation takes account of matching and assumes a correlation between cases and controls on exposure of 0-2. Under the same assumptions our second study would have detected an odds ratio as low as 1 ’6. The case-control studies of Somerville et all and Griffin et all could have detected OR as low as 1 and 20, respectively. We agree with Laporte et al that NSAIDs are an important cause of serious gastrointestinal bleeding. In our view it is the population risk rather than the individual risk that is most significant. Since the problem in Australia is, in the main, dependent on the prevalence of exposure to the risk factor, rather than the magnitude of the individual’s risk, prevention should in most cases be directed at reducing exposure rather than attempting to lower risk by co-prescription of protective agents. Although we do not rule out the possibility that piroxicam is associated with a significantly higher relative risk than other NSAIDs, we believe that on present evidence apparent differences between individual agents should be interpreted with caution. —
Supported by grants from the National Health and Medical Research Council of Australia and Pfizer Austrialia Pry Ltd. The full results of this study will be published later.
Departments of Clinical Pharmacology, Statistics, and Nursing, University of Newcastle, Newcastle, NSW 2300, Australia
DAVID HENRY ANNETTE DOBSON CATHY TURNER PAMELA HALL CAROLINE FORBES PHILIPPA PATEY
=
1.
Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. Br Med J1990, 300: 278-84.
Henry DA. Gastrointestinal bleeding and non-steroidal anti-inflammatory drugs In Lawson DH, ed. Royal College of Physicians of Edinburgh Current medicine-3 Edinburgh: Churchill Livingstone, (in press). 3. Dupont WD, Plummer WD. Power and sample size calculations, a review and computer program. Controlled Clin Trials 1990; 11: 116-28 4. Somerville K, Faulkner G, Langman M. Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet 1986; i: 462-64. 5. Griffin MR, Ray WA, Schaffner W. Non-steroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988; 109: 359-63
2.
731
THE LANCET
infection SiR,—Transmission of HIV is primarily through intimate sexual with an infected individual or contact with infected blood via shared needles among intravenous drug users, occupational exposure to contaminated "sharps", or transfusions with contaminated blood products, for example. We present a case of possible HIV infection via a previously undescribed route. A 49-year-old heterosexual male was referred for evaluation of HIV seropositivity found on screening during a routine application for life insurance. A repeat ELISA and subsequent western blot were both reactive for HIV. The patient had been married for over 25 years and had three children. His wife’s serum was non-reactive for HIV antibody. He denied ever having sex with a man, nor with another woman since marriage, and claimed he had been impotent for about 10 years. He denied ever having received blood products. He had used intravenous drugs once, 3 years previously, but distinctly remembered not sharing needles but using a needle from an unopened package. On repeated questioning he adamantly denied using drugs on any other occasion. This was all independently corroborated by his wife. On a follow-up visit the patient, dissatisfied with the explanation that the alleged one-time exposure to intravenous drugs was his risk factor, inquired if contact with infected blood on cuts of the skin could lead to infection. He said that in 1982-88 he worked as a truck driver, primarily in the New York/New Jersey area. During that time he admitted that he and work colleagues would go out "gay bashing". They sought out places frequented by gay men and systematically beat them. The patient admitted doing this "too many times to count", and would frequently get large amounts of the victim’s blood on himself. He frequently sustained small lacerations on his hands while administering the beatings. On the patient’s first examination we noted several small scabbed lacerations over his proximal interphalangeal joints that had, allegedly, resulted from a recent fight. Mucocutaneous exposure to infected blood has been confirmed as the route of infection in several health-care workers with AIDS.’ One man seroconverted after contact with another’s blood when they both sustained numerous lacerations in a motor vehicle accident.2 Although we cannot prove that contact with blood from infected persons during gay bashing was the mechanism of acquisition in this case, it is certainly plausible. Perhaps this case will serve as a deterrent to the dreadful practice of "bashing" people simply because they belong to a particular minority. contact
Department of Internal Medicine, Medical Center, University of Nebraska, Omaha, Nebraska 68198, USA
PAUL CARSON JONATHAN C. GOLDSMITH
1. CDC.
Update: human immunodeficiency virus infections in health care workers exposed to blood of infected patients. MMWR 1987; 36: 285-89. 2. Hill DW. HIV infection following motor vehicle trauma in central Africa JAMA 1989; 261: 282-83.
Transiently positive HIV antibody test after treatment with tetanus immune globulin SIR,-A 25-year-old nurse injured her hand on the edge of an operating-table. She was given a prophylactic injection of tetanus immune globulin (TIG). The following day a blood sample was taken to test for hepatitis B virus (HBV) markers and HIV antibody, as is routine at this hospital in cases of possible accidental exposure to HBV and HIV. HBV markers were negative but she was anti-HIV positive with both ELISA tests used in our laboratory (Sorin Biomedica, Behring), and the same sample was western blot positive (Sorin Biomedica), showing reactivity against all viral proteins. A careful history excluded
any risk factor for HIV
infection other than hospital employment. A second blood sample, taken 12 days later, was anti-HIV negative by ELISA but showed reactivity for gp 120 and p24 by western blot. A third sample, taken 1 month after the first, was negative by both ELISA and western blot. The passive transfer of HIV antibodies
proteins have been detected in HBIG. The history and serological findings in this case suggest passive transfer of HIV antibodies by TIG given 24 hours before the first blood sample was taken. This could explain the initial reactivity, and the progressive disappearance of reactivity in western blot tests is consistent with this explanation. We could not test the TIG preparation for HIV antibody because neither lot number nor manufacturer were
HIV
"Gay bashing" as possible risk for HIV
known. A. GONNELLI P. ALMI M. RUBINO M. TOTI
Division of Infectious Diseases,
Ospedale S Maria della Scale, 53100 Siena, Italy
1. Schlench WF, Spencer SHS, Cook J, et al. Passive transfer of HIV antibody by hepatitis B immuneglobulin. JAMA 1989; 261: 411-13. 2. Wood CC, Williams AE, McNamara JG, et al. Antibody against the human immunodeficiency virus in commercial intravenous gammaglobulin preparations. Ann Intern Med 1986; 105: 536-38. 3. Lai-Goldman M, McBride JH, Howanitz PJ. Presence of HTLV III antibodies in immune serum globulin preparations. Am J Clin Pathol 1987; 87: 635-39. 4. Steele DR. HTLV III antibodies in human immune gammaglobulin. JAMA 1986; 255: 609.
Potential molecular
competitor for
SiR,—The theory of genotypic selection (ref 1 and unpublished) that a non-pathogenic HIV-1 strain might be identified
predicts
that could compete in vivo with virulent strains and ameliorate the course of disease. The phenotype of a non-pathogenic virus (which may be confused with "long-latency") should result in a symptom-free HIV-positive status. An epidemiological search of one affected population identified an individual who might be harbouring such a strain: he had HIV-1 (DNA-PCR gag, strong western blot, probable infection for longer than 10 years, no antiviral treatment), T4 lymphocyte counts about 1000/pJ, and normal mitogenic and delayed-type hypersensitivity skin test (DTH) responses. History revealed multiple high-risk contacts and intravenous drug abuse, suggesting exposure to numerous wild-type pathogenic strains from partners who subsequently died from AIDS as early as 1983. Viral growth in culture was uncharacteristically slow. This donor was negative for active hepatitis, syphilis, herpes, cytomegalovirus,
Epstein-Barr virus, toxoplasma, cryptococcus, and histoplasma. 11severely immunocompromised patients (T4 mean 66/pi) with immunological deterioration and disease progression despite zidovudine or dideoxyinosine treatment provided informed consent and agreed to discontinue all antiviral treatment. Each patient received two inoculations of blood z2-0 ml) from the putative non-pathogenic donor. Strains from symptomless donors must be characterised for competition and non-pathogenicity before inoculation. Patients have now been followed up weekly for six months and clinically 4 have improved, 3 have shown a mixed response, 3 have regressed, and 1 has died. Apart from transient myalgia, low-grade fever, and diarrhoea, no new symptoms were noted. After a zero to trace DTH response at baseline, all 10 survivors progressed to a moderate to strong response in six months (one responding to all of eight antigens and another to seven of eight), suggesting a gradual return of cell-mediated immunity.* Average total T, T4, and T8 cell numbers and percentages remained stable, fluctuating around baseline mean for six months. The above observations are paradoxical in the absence of antiviral therapy or in the presence of progressive immunological deterioration, but indicate that no harm was caused by the infusions. Importantly, an epitope of p17 (a fragment of gag product), appearing strongly in the donor strain and initially absent or weakly present in the inoculated population, subsequently increased strikingly in all patients who improved. These preliminary findings suggest a variable degree of in vivo colonisation and perhaps competition between a putative nonpathogenic strain and wild-type virulent strains. If the inoculated strain merely had a phenotype of long latency and pathogenicity, we should not have seen clinical improvement and restoration of
by hepatitis B immune
globulin (HBIG) has been demonstratedl-4 but neither HIV
nor
HIV
*Details available from The Lancet or Immuvax.
