Second meeting of the WHO Collaborating Centres on AIDS: Memorandum from a WHO meeting.

Bulletin of the World Health Organization, 64 (1): 37-46 (1986) (© World Health Organization 1986 Second meeting of the WHO Collaborating Centres on AIDS: Memorandum from a WHO Meeting* The second meeting of the WHO Collaborating Centres on AIDS (acquired immunodeficiency syndrome) was held in Geneva from 16 to 18 December 1985. Participants reviewed the progress that had occurred since their previous meeting in September 1985 and delineated a programmefor thefurther development ofcollaborative activities between the Organization, its network of collaborating centres, and Member States. Recommendations were made in several different areas including information/ education/prevention, reference reagents and testing for antibodies against LAV/HTL V- III, epidemiological assessment, and research on vaccines and antiviral agents. INFORMATION/EDUCATION/PREVENTION AIDS is a syndrome of life-threatening illnesses that represent the most serious health outcome of infection with LAV/HTLV-III. This virus can be spread by sexual intercourse, by parenteral exposure to blood, and from an infected mother to her child before, during, or shortly after birth. The general public should be made fully aware of the nature of AIDS and the virus that causes it (LAV/HTLV-III), the modes of transmission, and its importance as a health concern to those at increased risk. In particular, the public should be assured that AIDS is not transmitted by casual contact with infected persons or those at increased risk. Provision of information on transmission of LAV/HTLV-III is particularly important for adolescents and young adults since the highest rates of infection have been observed in the 20-39-year age group. The following recommendations concerning dissemination of information are proposed: (1) Officials in ministries of health, education, and social services should take steps to provide timely and accurate information about AIDS to the general public. (2) Doctors, nurses, and other health care personnel should be encouraged to educate patients and members of the public about AIDS and ways to avoid acquiring LAV/HTLV-III infection. (3) Member States should be encouraged to educate school-age children and young adults about * This Memorandum was drafted by the signatories listed on pages 43-44 during the second meeting of representatives from the WHO Collaborating Centres on AIDS, and other experts in virology and public health, in Geneva, Switzerland, on 16-18 December 1985. A French translation of this article will appear in a later issue of the Bulletin. Requests for reprints should be addressed to Division of Communicable Diseases, World Health Organization, 1211 Geneva 27, Switzerland. the manner in which AIDS is spread and how to avoid risks. Information exchange WHO currently publishes information on AIDS on an ad hoc basis, including special reports, summary data, and legislative information. Information on current legislation on AIDS is available in summary form from the Health and Biomedical Information Programme (Health Legislation), WHO, Geneva, Switzerland. The WHO Collaborating Centres should provide timely information to WHO for global dissemi- nation, particularly where this is relevant to the prevention and control of disease. It is important that countries understand the reasons for, and the impor- tance of, providing up-to-date information on AIDS to WHO. In addition to the recommendations made by the participants at the first meeting ofWHO Col- laborating Centres on AIDS,a the following actions are recommended: (1) The reporting systems for AIDS and LAV/HTLV-III infections should be standardized and the international data summarized by WHO should be regularly provided to Member States. The WHO Collaborating Centre for AIDS at the Hopital Claude Bernard, Paris, in cooperation with other Centres and consultants, should devise a model reporting system with forms for (i) surveillance of AIDS cases, (ii) incidence and prevalence of LAV/HTLV-III antibody or infection, and (iii) pre- vention and control activities. These forms should be prepared taking into account national variations in a AIDS and the WHO Collaborating Centres: Memorandum from a WHO Meeting. Bulletin of the World Health Organization, 63: 1003-1007 (1985). 4633 37- MEMORANDUM the ability to collect and analyse information, and should include information that is most important to the design and evaluation of prevention and control measures. Through the WHO Regional Offices individual Member States should provide all such information to WHO headquarters in Geneva. Member States should send case reports to their WHO Regional Office. If they prefer, however, the reports could be sent to WHO headquarters with a copy to the Regional Office. (2) Reliable information should be obtained on the global incidence and prevalence of LAV/HTLV-III infections and AIDS cases. This can be done only with standardization of serological testing and reporting of available data. Reporting of sero- prevalence to WHO would be of use if sufficient details were included on risk groups (e.g., female prostitute, homosexual/bisexual male), site of test (e.g., blood bank, sexually transmitted disease clinic), and types of tests used (e.g., ELISA, immunoblot). (3) The prevention and control measures that are being used in various countries should be monitored. Guidelines In consultation with the WHO Collaborating Centres on AIDS, guidelines on the prevention and control of LAV/HTLV-III infections should be de- veloped in the following areas: 1. Occupational groups (a) Transmission from patients to health care workers. Health care workers in the present context include nurses, physicians, dentists and other dental workers, optometrists, podiatrists, chiropractors, laboratory and blood bank technologists, phleboto- mists, dialysis personnel, paramedics, emergency medical technicians, medical examiners, morticians, hospital domestic staff, laundry workers, and others whose work involves contact with patients, their blood or other body fluids, or corpses. (b) Transmission from health care workers to patients and other persons. Precautions must be taken to prevent transmission of LAV/HTLV-III infection from health care workers to patients. These precautions apply to all health care personnel. (c) Considerations relevant to other workers (i) Personal-service workers. Individuals whose occupations involve close personal contact with clients (e.g., hairdressers, barbers, beauticians, elec- trologists, cosmeticians, manicurists, pedicurists, massage therapists) and those whose services (tattoo- ing, ear piercing, acupuncture, etc.) require needles or other instruments that penetrate the skin should follow the precautions indicated for health care per- sonnel. Other personal-service workers are not at in- creased risk for transmitting or acquiring LAV/ HTLV-III infection. (ii) Food-service workers. All available epidemio- logical and laboratory evidence indicates that LAV/HTLV-III infection is not transmitted during the preparation or serving of food and beverages. (d) Disinfection procedures (see Annex 1). Recent studies have shown that disinfectants commonly used in laboratories and health care facilities will inactivate LAV/HTLV-III at concentrations much lower than those commonly used. Disinfectants that are mycobactericidal are preferred since these are effective against even the most resistant groups of microorganisms. 2. Prevention and control (a) Sexual transmission. Sexual transmission has been shown to be the main mode of LAV/HTLV-III transmission. Factors to be considered, when known, for development of guidelines in this area include: (i) knowledge of the local epidemiological situ- ation and transmission patterns including the pre- valence and distribution of LAV/HTLV-III infection in heterosexual and homosexual populations; (ii) knowledge about sexual behaviour and atti- tudes in the community. (b) Parenteral exposure. Transmission of LAV/HTLV-III infection through parenteral expos- ure is the second most common method of acquiring infection. This occurs as a result of the use of blood- contaminated needles or equipment by drug abusers, administration of infected blood or blood products, or the use of inadequately sterilized needles or skin- piercing instruments. Where applicable, guidelines should be developed for the prevention of LAV/ HTLV-III infection through the administration of blood and blood products and among those who abuse drugs parenterally. In addition, in some countries, where relevant, information should be provided on the risks associated with the administration of parenteral medications and practices such as acupuncture, tattooing, ear piercing and ritual scarification. These guidelines should incorporate the general principles outlined in Annex II. (c) Perinatal transmission of AIDS. Currently available data from the USA indicate that most 38 AIDS AND THE WHO COLLABORATING CENTRES 39 paediatric LAV/HTLV-III infections and AIDS are acquired perinatally from infected women. In one study of 20 infants born to infected mothers, 13 (65%) had serological and/or clinical evidence of infections with LAV/HTLV-III several months after birth. Though additional studies are needed to better clarify the risk of transmission from an infected preg- nant woman to the fetus or newborn, current infor- mation is sufficient to provide recommendations to prevent perinatal transmission of LAV/HTLV-III and AIDS. (d) Other considerations (i) Education and foster care. In many countries, there has been a great deal of concern about edu- cation and foster care of children with LAV/HTLV- III infection. Current evidence indicates that casual person-to-person contact among schoolchildren poses no risk of transmission of infection. Decisions regarding the type of educational day- and foster-care settings for LAV/HTLV-III-infected children should be based on the condition of the child and the avail- ability of educational facilities. Specific recommen- dations on the education and foster care of children infected with LAV/HTLV-III have been published.b (ii) Guidelines appropriate for prisons and cus- todial-care institutions are needed. (iii) International travel. Certification and testing of international travellers is not warranted as a measure to prevent LAV/HTLV-III transmission. Member States are advised not to request such measures. REAGENTS AND TESTS Reference reagents There is an important need for reference reagents which should be made available through the WHO Collaborating Centres on AIDS. (1) Sera. A well-characterized human serum with antibodies to LAV/HTLV-Ill together with a control serum would be of considerable value: (a) to assist laboratories in Member States in gaining experience in the development, interpretation and standardiz- ation of screening and diagnostic tests, and (b) as a basis for comparative studies in different countries. Such reagents are required for reference purposes, to enable laboratories to establish their own reference and working reagents. These needs are now being met by WHO through the provision of reference sera pre- pared by the WHO Collaborating Centre on AIDS, Centers for Disease Control, Atlanta, GA, USA. b Weekly epidemiological record, 60 (38): 290-293 (1985). A larger, more permanent set of sera for general distribution has been prepared by the German Association against Viral Diseases, at the Institute of Clinical and Experimental Virology, Berlin (West). Characterization of these sera will be coordinated by the WHO Collaborating Centre on AIDS, National Institute for Biological Standards and Control, London, England. Tests for antibodies to different viral antigens will be performed by several WHO Collaborating Centres using a variety of tests. An additional panel of sera representing a spectrum of reactions to individual antigens is to be prepared by the WHO Collaborating Centre on AIDS, Centro Nacional de Microbiologia, Virologia e Inmunologia Sanitarias, Madrid, Spain, and pro- vided to other collaborating centres. (2) LAV/HTL V-III virus, antigen and susceptible cell lines. It is premature to establish reference reagents other than sera. LAV/HTLV-III viruses and well-characterized cell lines of known susceptibility to LAV/HTLV-III virus should be available to national laboratories from existing sources (e.g., the Institut Pasteur, Paris, the National Cancer Institute, Bethesda, Maryland, and the American Tissue Culture Collection, Rockville, Maryland). WHO will not provide large quantities of LAV/HTLV-III antigen at the present time; suf- ficient antigen for use in immunoblot methods is available from a number of commercial organ- izations. However, small quantities of antigen for reference purposes may be available from WHO Col- laborating Centres. Specific LAV/HTLV-III anti- gens of value in diagnosis or screening, prepared by DNA methods or chemical synthesis, may be expected to be available in the future. (3) Reagents for training workshops and pro- ficiency-testing programmes. The WHO Collabor- ating Centres should assist in the provision of materials and reagents appropriate for use in WHO training workshops on laboratory techniques in AIDS diagnosis and screening and proficiency-testing programmes. In addition, WHO will request com- mercial organizations to provide test kits suitable for workshop use. Application of tests The group discussed the applicability of various laboratory tests for enzyme-linked diagnostic pur- poses, screening, and serological surveys on LAV/ HTLV-III infection. The role of various immuno- sorbent assays (e.g., ELISA) for these purposes is now fully established and several versions of ELISA have been extensively evaluated. The need for routine application of a confirmatory test like this will de- pend upon the characteristics of the ELISA method 40 MEMORANDUM being used, the aims of the studies (e.g., screening or diagnosis), the prevalence of infection in the group tested, and the technical sophistication of local laboratories. Several confirmatory tests are currently available, utilizing immunoblot, immunofluores- cence and radioimmunoprecipitation methods. The immunoblot assay is considered satisfactory for detecting antibodies against different viral proteins. The performance and interpretation of immunoblot tests require skill and experience. Immunofluorescence is also a satisfactory method but requires skill and experience in its performance and interpretation. Therefore, either of these con- firmatory tests should be undertaken only where it will be used with sufficient frequency to assure pro- ficiency. All these tests should be performed only in laboratories experienced in utilizing good infection- control techniques. Development and evaluation of tests There is an important need for the development of more reliable and sensitive methods for detecting virus or viral components in clinical materials. Cell cultures with greater susceptibility to virus infection should be sought and, subsequently, an accurate cytopathic assay should be developed. Sensitive methods for detection of LAV/HTLV-III antigen, using monoclonal antibodies, should be sought. Specific DNA probes for hybridization analysis have some research applications. but they are not sufficiently sensitive to be a substitute for current virus isolation methods. The WHO Collaborating Centres and the WHO programme should ultimately provide assistance in monitoring the field performance of serological tests and kits and should disseminate this information. Evaluations should include information on the intrinsic properties of individual tests, the con- sistency among serial product lots, and the stability of the test reagents following transport and storage. Work should be continued to improve screening as well as diagnostic and confirmatory tests and to develop new tests. Particular attention should be given to the development of simple methods appro- priate for use in developing countries. New tests should be technically simple, inexpensive, stable under conditions of storage and transport, and in- dependent of technical services (e.g., power supplies) without greatly sacrificing sensitivity or specificity. Thermostability is of particular importance when tests are to be used in tropical regions and evaluations of the stability characteristics of current test kits under field conditions are needed. Special collaborative studies of existing kits to determine their characteristics during use in tropical countries will be coordinated by the WHO Collabor- ating Centre on AIDS, Centre for Drugs and Bio- logics, Food and Drug Administration, Bethesda, MD, USA. International standards There will be a need for the establishment of inter- national biological standards for LAV/HTLV-III but the precise requirements are not yet clear. Progress in vaccine development would require international standards for measurements of antibody responses to vaccination. In addition, international standard anti- gen preparations may be needed in studies of candidate vaccines. Exchange of laboratory material and personnel This programme should facilitate the exchange of scientific and technical material and personnel between laboratories. TECHNICAL COOPERATION Technical cooperation and epidemiological assess- ment must be individualized, based on differences in the prevalence of LAV/HTLV-III infection between countries and the different epidemiological, clinical and laboratory capacities of countries. Some countries that have recognized cases of AIDS lack the capacity for comprehensively assessing the extent of the problem. Consequently, they require assistance in establishing clinical, epidemiological and laboratory diagnostic capabilities. Countries that have not recognized AIDS should nevertheless assess the prevalence of LAV/HTLV-III infection. Through the WHO programme, recommendations might be made and assistance offered to countries based on their needs, thereby focusing on those countries where LAV/HTLV-III infection is a significant problem and where existing national resources are lacking. Clinical case definition ofAIDS The CDC/WHO definition of AIDSc is applicable only in areas where resources are available to consistently identify opportunistic infections and malignancies in patients suspected of having-AIDS. However in countries where the diagnostic resources are limited, a clinical case definition is necessary. The clinical case definition proposed at the WHO Workshop on AIDS in Bangui, Central African e The definition was developed by the Centers for Disease Control (CDC), USA, and adopted by WHO during the present meeting. See Weekly epidemiological record, 61 (10): 69-73 (1986). AIDS AND THE WHO COLLABORATING CENTRES Republic, in October 1985 (see Annex III) has not yet been formally evaluated and there may be differences in clinical features from one country to another. However, it is believed to be a sensitive definition. To improve the specificity, confirmation by detection of specific antibody to LAV/HTLV-III should initially be performed. For surveillance purposes, cases should be reported as either fulfilling (1) the clinical definition alone; or (2) the clinical definition with LAV/HTLV-III serological confirmation. Initial assessment and technical cooperation Consultations between WHO and Member States should lead to the establishment of surveillance and laboratory capabilities for (1) assessing the preva- lence of AIDS and LAV/HTLV-III infection on a continuing basis, (2) identifying the risk factors for transmission, and (3) assessing prevention activities. Methods to rapidly assess the extent of LAV/HTLV-III infection have been developed and should be further refined. Technical cooperation should be offered to selected countries for this assessment which would include: -assessing the extent of AIDS using the proposed clinical case definition, as well as data available from both passive and active surveillance; -performing serological surveys on populations likely to be at increased risk of exposure to LAV/HTLV-III; -assessing the ability of the health infrastructure to conduct LAV/HTLV-III and AIDS surveillance and to conduct prevention and control activities; -developing standard case-report forms and case- investigation techniques to assist present surveillance and control activities; -performing laboratory testing to support the initial epidemiological investigation. The WHO programme's involvement in im- plementing the above may range from the provision of guidelines and reference laboratory support, to the assignment of individuals or a multidisciplinary team for short-term consultation or a longer implemen- tation project. The team should provide expertise in medical epidemiology, laboratory methods, and the clinical aspects of AIDS. During the assessment, the programme should identify the equipment and training neeeds for con- tinued clinical, laboratory, and epidemiological efforts and for LAV/HTLV-III prevention and control. Subsequent technical cooperation Subsequent technical cooperation activities should be based on the findings of the initial assessment and should lay stress on continued surveillance and laboratory capability. Epidemiological support would include (a) pro- vision of training, equipment, and reference materials to assist in establishing and maintaining surveillance activities; and (b) conduct of epidemiological research to determine risk factors and modes of trans- mission (natural history, etc.). Laboratory support would include (a) provision of training equipment, reference reagents, and other materials for establishing and maintaining laboratory activities; (b) assurance of quality control and pro- ficiency testing; and (c) establishment of appropriate infection control methods. Clinical support would include (a) provision of training and reference materials to assist clinical diagnosis; and (b) case management and infection control techniques. Role of WHO Collaborating Centres It is not anticipated that all national health laboratories will be capable of performing confir- matory tests, but such support is a major function of the WHO Collaborating Centres. EachWHO Region should have at least one such centre. These centres would be expected to have the following terms of reference: - assist in planning and conducting initial studies/surveys; - provide technical expertise for development of national laboratory diagnosis systems; -assist in laboratory training; - perform confirmatory serological tests on selected specimens; -conduct quality control including proficiency testing for national reference laboratories; -provide proficiency testing; -provide reference materials and reagents; -assist in disseminating technical information. Adequate funds must be sought to implement technical cooperation as outlined in this section. RESEARCH: VACCINE AND THERAPY Recognizing the need for research in the epidemio- logical, clinical and behavioural aspects of AIDS, the WHO programme should encourage and coordinate research on the prevention, control and treatment of AIDS and foster the free exchange of research information. General considerations for the development of therapeutic approaches and vaccines Studies on therapy and immunoprophylaxis 41 42 MEMORANDUM against LAV/HTLV-III infection should adhere strictly to accepted principles for drug evaluation or immunization. Studies should be coordinated on an international level.d The WHO programme and network of Collaborating Centres should encourage and monitor collaborative studies and distribute relevant infor- mation within their respective regions. Vaccine research (1) Vaccine development. The vaccine develop- ment efforts were described in detail in an earlier report.d Candidate vaccines produced by extraction from the whole virus, chemical synthesis, DNA recombinant technology, and insertion of gene products into virus vectors have been inoculated into animals. Currently efforts are concentrated on attempts to increase the immunogenicity of the products and on identifying the constant and con- served genetic portions of various isolates. The neutralizing capabilities of the antibody produced are being determined by appropriate in vitro assays. In addition, studies are under way to determine whether the observed genetic heterogeneity of LAV/HTLV- III is an important factor in producing a successful vaccine. (2) Testing of vaccines in animals. Successful experimental inoculation of LAV/HTLV-III into chimpanzees, which has been well documented, showed seroconversion, viraemia and subsequent transmission to other chimpanzees, but no significant disease occurred. Other non-human primate species appear more variable in their susceptibility to experi- mental LAV/HTLV-III infection. However, owing to the small numbers of chimpanzees available for study, other animals, preferably non-primate animal species, should be used in the initial testing of the immunogenicity of vaccine preparations. Therapeutic intervention There is a major research effort under way to iden- tify potentially useful antiviral agents through a programme of in vitro screening. Drugs with in vitro antiviral activity are being tested in small animals to determine their toxicity and appropriate dosage, and are scheduled for a phase I clinical trial. It is desirable to seek agents which can be administered orally and which can pass the blood/brain barrier. Suramin, ribavirin, foscarnet sodium, HPA 23, ansamycin, interferons, and azidothymidine (3-azido-3-deoxy- thymidine, AZT, BW A509U) are currently being evaluated clinically. Extensive studies have been per- d Bulletin of the World Health Organization, 63: 1003-1007 (1985). formed with suramin and antiviral effects have been observed. However, considerable toxicity has been observed with suramin particularly in patients with immune deficiency and liver abnormalities. This emphasizes the need for caution in the testing of potent drugs in immunocompromised patients. Studies are continuing in Europe and have been initiated in the USA with HPA 23, including longer- term treatment (for 3 months) and virus isolation studies. Inhibition of viral replication has been observed in these studies. Phase I clinical studies to evaluate toxicity with azidothymidine and ribavirin have been concluded. These drugs appear relatively safe at the dosage tested, and phase II studies to evaluate efficacy will begin shortly. Studies with foscarnet sodium and ansamycin are being initiated in the USA. Small studies in Europe with foscarnet have also been initiated. Interferon alfa studies are continuing in order to determine its role as an antiviral agent. Interferon gamma as well as interleukin-2, thymic hormones, and other immunomodulators are under investi- gation; future studies of combined treatment with antiviral agents and immunomodulators are antici- pated. Further approaches to combined therapy may involve (a) antivirals acting on different steps of viral replication; as well as (b) antibodies directed to cell receptors, or to viral proteins responsible for the cytopathic effects of the virus. Testing systems Appropriate testing systems in animals, preferably readily available laboratory animals, are urgently needed for both vaccine development and therapeutic intervention. To date, the most appropriate, although not ideal systems, involve non-human primates. T-lymphotropic viruses of non-human primates An exogenous T-lymphotropic retrovirus of primates, closely related to LAV/HTLV-III has been designated STLV-III. STLV-IIImac has been isolated from immunodeficient captive rhesus macaques; all the antibody-positive macaques were ill. Inoculation of STLV-IIImac into 6-month old rhesus macaques resulted uniformly in seroconversion and viraemia, and a substantial number developed immunological abnormalities and died of opportunistic infection. Inoculated animals frequently showed pathological and virological evidence of encephalopathy similar to observations in patients with AIDS. STLV-III in macaques may provide a useful animal model for the testing of antiviral drugs; some of these studies are in progress. AIDS AND THE WHO COLLABORATING CENTRES STLV-III antibody profiles in infected primates indicate that the immune response in infected animals is similar to that observed in persons infected with LAV/HTLV-III. Consequently, it may be possible to gain insight relevant to LAV/HTLV-III by testing various STLV-III vaccines in simians. Recommendations (1) Careful preclinical studies should be performed to assess the potential toxicity prior to initiating clinical studies. Once assured of the safety and possible clinical potential of the drug, human trials should proceed very cautiously to determine the drug's safety and optimal dosage. (2) Clinical studies should follow the accepted principles of drug evaluation with sufficient numbers to demonstrate efficacy, and preferably use double- blind placebo-controlled protocols. International multicentre studies should be encouraged. (3) Clear definition of efficacy is needed for clini- cal studies in patients with AIDS or AIDS-related complex, and in asymptomatic seropositive individuals. (4) The WHO programme, through the National Institutes of Health, USA, should maintain a list of all therapeutic regimens being tested and the status of such studies. (5) Research on the development of a simplified reliable method for LAV/HTLV-III isolation and quantitation should be encouraged. Viral isolation must be included at frequent intervals in clinical studies. (6) Further research is needed to develop suitable animal models for LAV/HTLV-III infection. * * L. K. Altman, New York, NY, USA K. Bart, Agency for International Development, Washington, DC, USA J. B. Brunet, Institut de Medecine et d'Epidemio- logie Tropicales, Hopital Claude Bernard, Paris, France S. H. Chan, Faculty of Medicine, University of Singapore, Republic of Singapore J. C. Chermann, Unite d'Oncologie Virale, Institut Pasteur, Paris, France A. J. Clayton, Laboratory Centre for Disease Control, Ottawa, Ontario, Canada J. W. Curran, Division of Viral Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA, USA F. Deinhardt, Department of Hygiene and Medical Microbiology, Max von Pettenkofer Institute, Munich, Federal Republic of Germany I. Domok, National Institute of Hygiene, Budapest, Hungary W. Dowdle, Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA, USA M. Essex, Cancer Biology, Harvard School of Public Health, Boston, MA, USA G. J. Galasso, National Institutes of Health, Bethesda, MD, USA B. Galvao de Castro, Fundaqlo Oswaldo Cruz, Rio de Janeiro, Brazil A. J. Georges, Institut Pasteur, Bangui, Central African Republic A. A. Glynn, Central Public Health Laboratory, London, England P. Goff, Medical Division, Department of State, Washington, DC, USA K. 0. Habermehl, Institute of Clinical and Experimental Virology, Berlin (West) Y. Hinuma, Institute for Virus Research, Kyoto University, Japan L. 0. Kallings, National Bacteriological Laboratory, Solna (Stockholm), Sweden Ph. Kanki, Cancer Biology, Harvard School of Public Health, Boston, MA, USA S. Lengel, Office of Public Affairs, Office of the Assistant Secretary for Health, Department of Health and Human Services, Washington, DC, USA J. Mann, AIDS Project Zaire, Kinshasa, Zaire B. Maskill, National AIDS Reference Laboratory, Fairfield Hospital, Fairfield, Victoria, Australia J. B. McCormick, Division of Viral Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA, USA H. M. Meyer Jr, Center for Drugs and Biologics, Rockville, MD, USA R. Najera, Centro Nacional de Microbiologia, Virologia e Inmunologia Sanitarias, Majada- honda, Madrid, Spain R. Netter, Laboratoire National de la Sante, Minis- tere des Affaires Sociales et de la Solidarite Nationale, Paris, France M. I. Parfanovich, D. I. Ivanovsky Institute of Virology, Moscow, USSR P. Piot, Institut de Medecine Tropicale "Prince Leopold", Antwerp, Belgium G. Quinnan, Division of Virology, Center for Drugs and Biologics, Food and Drug Administration, Bethesda, MD, USA G. C. Schild, National Institute for Biological Standards and Control, London, England 43 44 MEMORANDUM K. Western, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. A. J. Zuckerman, London School of Hygiene and Tropical Medicine, London, England WHO Secretariat G. M. Antal, Sexually Transmitted Diseases, Division of Communicable Diseases, WHO, Geneva, Switzerland F. Assaad, Division of Communicable Diseases, WHO, Geneva, Switzerland B. Bytchenko, Communicable Diseases, WHO Regional Office for Europe, Copenhagen, Denmark B. Dando, Epidemiologist, Harare, Zimbabwe K. Esteves, Virus Diseases, Division of Communi- cable Diseases, WHO, Geneva, Switzerland I. Geizer, Health Laboratory Services, WHO Regional Office for the Western Pacific, Manila, Philippines L. Houang, Health Laboratory Technology, Division of Diagnostic, Therapeutic and Rehabilitative Technology, WHO, Geneva, Switzerland J. Lau Hansen, Health Legislation, Health and Biomedical Information Programme, WHO, Geneva, Switzerland V. Oviatt, Safety Measures in Microbiology, Division of Communicable Diseases, WHO, Geneva, Switzerland N. Sartorius, Division of Mental Health, WHO, Geneva, Switzerland N. K. Shah, Communicable Diseases, WHO Regional Office for South-East Asia, New Delhi, India T. Umenai, Communicable Diseases, WHO Regional Office for the Western Pacific, Manila, Philippines H. C. A. van Vliet, Epidemiologist, Bamako, Mali M. H. Wahdan, Disease Prevention and Control, WHO Regional Office for the Eastern Mediterranean, Alexandria, Egypt P. R. Yang, Disease Prevention and Control, WHO Regional Office for Africa, Brazzaville, Congo Annex I Disinfection procedures to prevent transmission of LAV/HTLV-III Commonly available effective disinfectants, as mentioned in the WHO Laboratory Biosafety Manual,e are described below. 1. Chlorine-sodium hypochlorite A general all-purpose disinfectant solution should have a concentration of 1 g/litre (1000 ppm) as avail- able chlorine. A stronger solution containing 10 g/ litre (10 000 ppm) of available chlorine is recom- mended for disinfection involving blood spillage and/or presence of gross organic matter. A solution of 5 g/litre (5000 ppm) as available chlorine is recom- mended for use in virus diagnostic and research laboratories. Hypochlorite solutions gradually lose strength and therefore need frequent preparation of fresh solutions. Care is required in preparation of the solution as the amount of available chlorine in stock solutions varies with the country of manufacture, e.g., household bleach in USA and Canada (5.2507o available chlorine), Eau de Javel in France (15% available chlorine), "Chloros" in the United Kingdom (10-15% available chlorine). ' World Health Organization. Laboratory biosafety manual. Geneva, 1983. 2. Formaldehyde Formalin is a solution with a concentration of the gas in water of about 370 g/litre (37%). Formal- dehyde in a concentration of active ingredient of 50 g/litre (5%) is commonly used. 3. Ethanol: 700 g/litre (70%) 4. Glutaraldehyde: 20 g/litre (2010) Ideally, all non-disposable equipment and instru- ments used by or on patients should be sterilized by steam under pressure (autoclaving) or by recognized gaseous sterilization techniques if the equipment is heat labile. The use of ethylene oxide (ETO) in gaseous sterilization is not universally recognized. It thus becomes necessary to subject heat-labile equip- ment and instruments to a high level of disinfection. The technique requires scrupulous cleaning of the materials prior to disinfection. The disinfectant of choice is 2% glutaraldehyde with a 30 minute contact time. Following this, the equipment should be thoroughly rinsed with sterile water. Other disinfec- tants may be used but are not the first choice because of various adverse properties such as corrosion. If they are used, the final rinse with sterile water is most important. AIDS AND THE WHO COLLABORATING CENTRES 45 Annex II General principles for prevention of LAV/HTLV-III transmission through parenteral exposure or through donation of organs, sperm, or other tissues (1) Transfusions Physicians should be educated about the proper medical indications for blood transfusion and dis- couraged from injudicious use, particularly of single- unit transfusions. Generally, all blood used for trans- fusion purposes should be screened for the presence of antibody to LAV/HTLV-III. Irrespective of whether screening for antibody is available, blood collecting agencies should develop and provide infor- mation to donors, which would indicate the reasons for deferral of certain individuals as donors of blood intended for transfusion. The use of sterile disposable equipment for collection and transfusion is highly recommended. If unavailable, adequate sterilization between each use is mandatory. (2) Blood products All plasma used for the manufacture of plasma fractions should be screened for the presence of antibodies to LAV/HTLV-III. Insofar as it is techni- cally possible, the methods used in the manufacture of blood products should be capable of inactivating LAV/HTLV-III. At present this is feasible for all of the plasma fractions except for products containing cellular elements such as platelets, leukocytes, or packed red blood cells. All blood products should have been approved for use in the country of manufacture. (3) Safety of human immunoglobulins for intra- muscular or intravenous inoculation Normal and specific immunoglobulins for intra- muscular use. Normal and specific immunoglobulins, prepared for intramuscular administration by cold- ethanol fractionation according to Cohn-Oncky methods, are safe and without any risk of transmit- ting bloodborne infections, including LAV/HTLV- III. This has been demonstrated by: (a) epidemio- logical studies; (b) testing commercial batches of immunoglobulin for presence of LAV/HTLV-III; and (c) measuring, on an experimental basis, the amount of virus inactivated at each step of the fractionation process. Immunoglobulin preparations intended for intra- venous use. Methods used for manufacturing of immune globulins for intramuscular administration typically involve stepwise precipitations with cold ethanol (methods of Cohn-Oncky). However, these processes are not used in the manufacture of all immune globulins for intravenous administration. All the evidence indicates that the various stepwise cold ethanol precipitation methods result in immune globulin preparations that are safe with respect to potential transmission of LAV/HTLV-III. Vali- dation of individual manufacturing processes is to be encouraged. The complete data base available per- taining to safety of immune globulins and other blood products will be considered at a subsequent meeting on safety of blood and blood products in relation to AIDS in April 1986. (4) Donors of organs, sperm, or other tissues Wherever feasible, serum from donors of sperm, or organs or tissues used for transplantation should be tested for antibody to LAV/HTLV-III. (5) Parenteral drug abusers Drug abuse should be strongly discouraged and all drug abusers informed of the risks of acquiring LAV/HTLV-III from needle sharing or the use of non-sterile needles or other equipment. (6) Administration ofparenteral medications Injectable medication should be limited to circum- stances where this is the most effective therapy. It is necessary to ensure that the needle and syringe and the medication itself are sterile. Appropriate sterile procedures must be employed in the use of multidose vials. Either single-use disposable or sterilized equipment is required. (7) Jet injections The group reaffirmed the statement made at the previous WHO meetingf of Collaborating Centres on AIDS concerning the possible transmission of infectious diseases to humans through the use of jet- injection devices. Limited experimental studies and extensive experience with the use of jet injection through mass inoculation in many millions of indivi- duals for over 20 years have shown that parasitic, f AIDS and the WHO Collaborating Centres: Memorandum from a WHO Meeting. Bulletin of the World Health Organization, 63: 1003-1008 (1985). 46 MEMORANDUM mycotic, bacterial and viral diseases, including hepatitis B and hepatitis non-A, non-B are not trans- mitted with jet-injection guns. It was therefore agreed that there was no confirmed evidence to suggest a risk of transmitting bloodborne diseases with these devices. However, limited laboratory studies evaluating the risk of transmission from different types of jet injectors are at present in progress and more extensive studies in this area should be supported. (8) Other practices Skin-piercing equipment used for medical, cosmetic or ritual purposes should be cleaned and adequately sterilized between each use. Annex III Proposed clinical case-definition of AIDSg A. Adult AIDS in an adult is defined by the existence of at least 2 major signs associated with at least 1 minor sign, in the absence of known causes of immuno- suppression such as cancer or severe malnutrition or other recognized etiologies. 1. Major signs (a) Weight loss > 10 per cent of body weight. (b) Chronic diarrhoea for > 1 month. (c) Prolonged fever for > 1 month (intermittent or constant). 2. Minor signs (a) Persistent cough for > 1 month. (b) Generalized pruritic dermatitis. (c) Recurrent herpes zoster. (d) Oropharyngeal candidiasis. (e) Chronic progressive and disseminated alpha- herpes simplex virus infection. (f ) Generalized lymphadenopathy. The presence of generalized Kaposi's sarcoma or cryptococcal meningitis is alone sufficient for a diagnosis of AIDS. 8 Adopted from the report of the WHO Workshop on AIDS, Bangui, Central African Republic, October 1985. B. Children Paediatric AIDS is suspected in an infant or child presenting with at least 2 of the following major signs associated with at least 2 of the following minor signs, in the absence of known causes of immunosuppression such as cancer or severe malnutrition or other recognized etiologies. 1. Major signs (a) Weight loss or abnormally slow growth. (b) Chronic diarrhoea for > 1 month. (c) Prolonged fever for > 1 month. 2. Minor signs (a) Generalized lymphadenopathy. (b) Oropharyngeal candidiasis. (c) Common repeated infections (otitis, pharyn- gitis, etc.). (d) Persistent cough. (e) Generalized dermatitis. (If) Confirmed maternal LAV/HTLV-III infec- tion.