Screening for human immunodeficiency virus: a survey of

Transcription

1 Br J clin Pharmac 1993; 36: Screening for human immunodeficiency virus: a survey of British clinical pharmacology units MARGARET THOMSON, WILLIAM G. HAYNES & DAVID J. WEBB University of Edinburgh, Department of Medicine, Western General Hospital, Edinburgh EH4 2XU 1 A survey of screening practices used to detect infection with the human immunodeficiency virus (HIV), covering the 12 months from June 1990 to May 1991, was carried out in 74 clinical pharmacology units performing phase I and II studies. Fortyfive units were identified from the Technomark commercial register, and 29 units were identified from the clinical academic membership of the British Pharmacological Society. 2 An overall response rate of 92% was obtained: 41 replies from commercial units; 27 replies from academic units. Seventeen commercial units and 26 academic units reported involvement with healthy volunteer studies; these were the 43 questionnaires analysed. 3 The majority of clinical pharmacology units did not believe that it was necessary to perform HIV screening by HIV antibody testing. Six commercial units (35%) and three academic units (12%) did perform HIV antibody testing in healthy volunteers. 4 Reasons frequently given for testing were protection of clinical and laboratory staff, and the advantages to the volunteer of prophylaxis and treatment at an early stage of HIV infection. Reasons for not testing included the perceived low risk of a positive test, a lack of benefit from treatment, and the adverse implications in relation to health insurance. Advice from an Ethics Review Committee was not generally a reason for testing. 5 In future, screening patterns may change, depending on prevalence of HIV positivity in the community, the benefits of diagnosis and treatment, and the perceived or real disadvantages of having an HIV antibody test. For the present, we believe that indirect methods, such as an HIV risks questionnaire, are more appropriate than direct antibody testing. Keywords HIV ethics clinical trials volunteers Introduction Over recent years, there has been a marked increase in prevalence of infection with human immunodeficiency virus (HIV) in the UK, and this has been particularly evident in the Edinburgh area, which accounts for 60% of all positive HIV antibody reports in Scotland [1, 2]. It is estimated that 50-60% of current cases in Edinburgh are among young heterosexuals, largely due to a high incidence of HIV seropositivity amongst intravenous drug users, so the potential for heterosexual transmission of HIV infection may be greater in Lothian than many other parts of the UK [3, 4]. As an Edinburgh research unit carrying out early phase clinical trials, generally in healthy male volunteers, we felt compelled to consider screening to prevent subjects with HIV infection entering clinical trials. Proponents of HIV testing under these circumstances suggest several reasons; including that HIV positive individuals may respond differently from the healthy population, that they may be more prone to adverse drug effects, and that exposure to a novel chemical entity might adversely affect their long term prognosis. However, possible disadvantages to HIV testing include the intrusiveness of screening, the impact of a positive HIV result on a low risk subject, difficulties that volunteers may subsequently encounter when trying to obtain life insurance [5, 6], the need for counselling before a test, and the associated commitment from research staff in terms of time and training. Correspondence: Dr David J Webb, University of Edinburgh, Department of Medicine, Western General Hospital, Edinburgh EH4 2XU 293

2 294 M. Thomson, W. G. Haynes & D. J. Webb In order to evaluate UK screening practices in relation to HIV testing, we sent questionnaires to commercial and academic clinical pharmacology units carrying out phase I and II studies in the UK and Eire. Methods A standardised questionnaire was sent to all commercial units listed in the Technomark Register as performing phase I and II clincial trials, and all academic units identified from the clinical section of the British Pharmacological Society. Questionnaires were not sent to units within the pharmaceutical industry, since it was less easy to identify specific units and their director. The questionnaire contained some general questions, and some related specifically to HIV screening in healthy volunteers (see Appendix I). This study had the approval of our local Ethics Committee, and of the clinical section of the British Pharmacological Society. Questionnaires were addressed to the named director in the case of commercial units, and the Head of Department in the case of academic units. Questionnaires, along with a covering letter and a stamped addressed envelope for their return, were sent by post to a total of 45 commercial and 29 academic units. If no reply was forthcoming, a second questionnaire was sent. Following this a single telephone call was made requesting completion of the questionnaire. All replies were made with the understanding that anonymity and confidentiality would be maintained. All returned forms were entered onto a database generated within the Filemaker programme for the Macintosh microcomputer, from which summary data were obtained. Results A total of 74 questionnaires were sent: 45 to commercial and 29 to academic units. Sixty-eight were completed and returned, 41 from commercial units and 27 from academic units, giving an overall response rate of 92%. Of the replies received, 17 from commercial units and 26 from academic units indicated involvement in healthy volunteer studies, and these were the replies analysed. In general, commercial units were larger, and used more volunteers than academic units, but a similar number of units were sited in hospitals and there was little difference in age and sex of volunteers studied (Table 1). The majority of commercial (76%) and academic units (92%) found word of mouth the most successful method of recruitment, although many, particularly the commercial units, advertised locally, either in public places, such as shops and colleges, on the radio, or in the newspapers. Methods used to obtain medical history were also similar in both groups, including a medical practitioner in 70% of commercial and 71% of academic units (Table 2). Medical examination was carried out by an independent practitioner in 47% of commercial units and 58% of academic units. Investigations carried out at the time of medical examination were similar in both groups. Only Table 1 Unit characteristics Number of units: Number of beds: >20 No reply Site: Hospital University Independent site Age: <18 years years years >60 years Number of subjects: mean range Table 2 Commercial Academic Medical history and examination Commercial Academic (n = 17) (n = 26) History obtained by: Nurse only 2 2 Doctor only Doctor and nurse 0 4 Direct questioning only 7 15 Questionnaire only 0 2 Direct questioning and questionnaire 7 9 No reply 3 0 Medical examination by: Volunteer's GP 0 0 Independent GP 2 2 Consultant 3 3 Junior doctor 2 9 In-house doctor 9 11 six units (21%) made specific attempts to exclude volunteers at risk of HIV infection with a screening questionnaire rather than perform testing for HIV antibodies; in three commercial and three academic units. Nine units (21%) routinely tested for HIV seropositivity; six (35%) of these were commercial units and three (12%) academic. Means of counselling before an HIV test varied (Table 3). In four of the commercial, and two of the academic, units counselling was performed by in-house medical staff. A range of reasons were given in favour of, and against, HIV testing, as were reasons for not testing (Table 4). Two of the commercial, but none of the academic, units would consider studying volunteers who refused a test. In the case of a positive HIV test, four of the commercial, and two of the academic units, would refer the volunteers to their GP or to a specialist clinic. In those units performing HIV testing, a positive result had been obtained in one academic unit and one commercial unit in the 12

3 HIV screening in volunteer research 295 Table 4 Table 3 HIV screening Commercial Academic (n = 6) (n = 3) HIV-1 antibody test 6 3 HIV-2 antibody test 3 2 Counselling: Information leaflet 2 0 Group interview 1 0 One-to-one interview 2 3 No reply 1 0 Reasons for and against HIV testing Commercial Academic Reasons for HIV testing: (n = 6) (n = 3) Volunteer safety 3 0 Clinical staff safety 3 2 Laboratory staff safety 4 1 Ethics Committee requirement 1 0 Sponsor requirement 2 1 Reasons against HIV testing: (n = 11) (n = 23) Implications to volunteers 5 11 Opposition from volunteers 1 3 Opposition from staff 1 0 Risk of losing volunteers 0 0 Low risk of positive result 5 13 Lack of proven benefit 6 8 Time involved in counselling 1 5 Overall cost 0 1 months before the survey. Based on the annual number of volunteers recruited in the units testing for HIV, the instance of seropositivity can be estimated at 0.04% for commercial units and 0.15% for academic units, giving a combined positive rate of 0.10%. Units were asked to comment on their present arrangements regarding HIV testing. Comments varied from '... specific guidelines from the Royal College of Nursing warning that to take an HIV sample without full consent constitutes assault...' and '... HIV carriers are most infectious before HIV antibody test converts to positive...' to '... in principle, expect HIV testing to become the norm...'. Interestingly, despite the wide range of different practices, only two units were unsatisfied with their present arrangements for HIV testing. Discussion This survey was distributed to all commercial units in the Technomark register listed as performing Phase I and II clinical trials and all of the academic clinical pharmacology units, identified from the British Pharmacological Society, within the UK and had an overall response rate of more than 90%. Although inhouse pharmaceutical company units were not studied, it is likely that commercial units broadly reflect the needs of industry. Hence, this survey should provide a representative view of practices with regard to HIV antibody testing in early phase clinical trials in the UK. It is apparent from the results of the survey that in mid few units performing healthy volunteer studies believed that it was of benefit, for either volunteers or staff, to perform HIV testing. The results of our survey show that the majority of clinical pharmacology units, both academic and commercial, do not screen volunteers for the presence of HIV antibodies. This may be for a number of legal and ethical reasons. First, before an HIV test is performed, there is a compelling argument that informed consent should be obtained from the volunteer [7, 8]. Before touching a patient the doctor is ordinarily under a legal duty to obtain the consent of the patient. However under normal circumstances, consent is implied as the patient has approached the physician for treatment. This may not be the case in the circumstances of screening of volunteers for clinical trials. Second, the implications to a volunteer who has consented to HIV testing should also be considered, because difficulties may subsequently arise when seeking life insurance. It has been reported that policy applications have been rejected or premiums loaded where subjects have admitted to a negative HIV test, regardless of the reason for testing [6]. A minority of clinical pharmacology units do perform HIV testing and these units give a number of different reasons for such a policy. One of the common reasons put forward was safety of clinical and laboratory staff. Nevertheless, the risk of passage of HIV infection from patients to clinical staff is negligible [9] and it has been suggested that universal precautions for blood and body fluids remove the need for HIV antibody testing of either health care workers or their patients for the purpose of infection control [10]. It would, therefore, seem unlikely that staff who follow guidelines for the safe handling of blood samples should be at risk from any volunteer, whether HIV positive or not. Furthermore not all units were testing for antibodies to the HIV-2 virus, and the HIV-1 and HIV-2 viruses cannot be assumed to be the only infectious agents causing acquired immunodeficiency. Therefore, HIV testing may provide a false sense of security, and lead to complacency when handling biological fluids. Another reason for testing is the risk that novel chemical entities may adversely affect the prognosis of an HIV positive subject. This seems unlikely for most drugs, but might be relevant for agents with immunomodulatory properties. Interestingly, two of the commercial units would consider studying volunteers who refuse an HIV test. Unfortunately, we did not specifically request reasons for this position, so we cannot be sure whether this reflects varying requirements between different pharmaceutical companies, or an uncertainty about the validity of HIV testing. A more compelling reason for HIV testing is that there are benefits in terms of outcome to be gained from early detection and intervention in HIV positive subjects, though these may not have been as clear at the time of the survey. In view of the potential benefits, one might now argue for more widespread population

4 296 M. Thomson, W. G. Haynes & D. J. Webb screening for HIV infection. However this view remains controversial at present and so there presently appears to be no reason to single out the generally low risk subjects taking part in clinical trials, particularly if one accepts the benefits of screening by questionnaire, correspondence with the volunteer's General Practitioner and hepatitis B surface antigen screening. In our personal experience using this screening process in Edinburgh only one volunteer out of 500 has tested positive for Hepatitis B in the past 2 years. It is our personal view that there is presently no place for HIV testing in the majority of studies performed in healthy volunteers; an HIV risks questionnaire should suffice. Since only 6 of the 43 units surveyed presently use an HIV risks questionnaire, we would encourage the others to consider adopting this technique. The survey shows differences in counselling practices before HIV testing. Although the numbers were small, academic units appeared to attach more importance to one-to-one counselling, whereas commercial units dealt with counselling in a variety of different ways, including information leaflets and group interviews. Advice in this area is conflicting. Some state that pretest counselling is of great importance, giving an opportunity to discuss the personal, medical, social, psychological and legal implications of being diagnosed either HIV positive or negative [11]. Others have also argued that pre-test counselling is necessary, but that it risks impairing the process of HIV testing if too detailed or time consuming [12]. However, this argument would not apply in the context of screening for volunteer studies. It appears that more commercial units perform HIV testing than academic units. This may be because many academic units use their own staff as volunteers and do not feel they are at high risk. Alternatively, it may be that some sponsors request HIV testing to allow shipment of samples abroad. If subjects are not HIV tested, there remains a small risk that some volunteers who are HIV positive will enter phase I and II clinical trials. This risk may depend on the extent of other screening procedures. This survey has shown that the majority of clinical pharmacology units in the UK do not carry out routine screening of volunteers for HIV infection. In view of the absence of evidence of benefit from testing to either clinical or laboratory staff, and the extremely low risk that investigational drugs without immunomodulatory actions will influence disease activity, it seems likely that this situation will prevail. This work was presented in poster form at the December 1991 meeting of the British Pharmacological Society at University College, London. We wish to thank all those who contributed to the paper by completing our questionnaire. References 1 Flegg PJ, Brettle RP. AIDS in Edinburgh drug users: observations on the epidemic and implications for its future management. J Infect 1990; 22: France AJ. Heterosexual spread of human immunodeficiency virus in Edinburgh. Br med J 1988; 296: Richardson AM, Gaskill PA. HIV Infection and AIDS in Lothian. Responding to the AIDS Challenge, ed Pye M, Harlow, Longman; 1989: pp Zealley H. Health in Lothian. The Annual Report of the Director of Public Health, Lothian Health Board; 1990: pp Department of Health and Association of British Insurers. AIDS and Life Insurance. HMSO Publications; Barton S, Roth P. Life insurance and HIV antibody testing. Br med J 1992; 305: Kennedy I, Grubb A. Testing for HIV infection: the legal framework. The Law Society's Gazette 1989; 7: Kennedy I, Grubb A. Testing for HIV infection: further examples. The Law Society's Gazette 1989; 9: Jeffries DJ. Doctors, patients and HIV. Br med J 1992; 304: Elford J, Cockcroft A. Surgeons and HIV. Br med J 1991; 402: Bor R, Miller R, Johnson M. A testing time for doctors: counselling patients before an HIV test. Br med J 1991; 303: Miller R, Bor R. Pre-HIV antibody testing: too much fuss? Genitourinary Medicine 1992; 68: (Received 8 March 1993, accepted 11 June 1993)

5 Appendix I HIV screening in volunteer research 297 HIV SCREENING QUESTIONNAIRE Please tick the box, or boxes, as appropriate. 1. Where is your unit sited? a) University/College L b) Hospital L c) Pharmaceutical company site L d) Other (please specify) 2. How many beds does it contain? a) 1-5 L b) 6-10 L c) L d) L e) >30 L 3. Approximately how many healthy volunteers have you studied in the past 12 months? 4. Approximately how many patients have you studied in the past 12 months? 5. Which of the following recruitment methods do you use? a) Word of mouth L b) Newspaper advertisements L c) Radio advertisements L d) Poster advertisements L e) Other (please specify) 6. Which method is most successful? a) Word of mouth L b) Newspaper advertisements Li c) Radio advertisements LI d) Poster advertisements L e) Other (please specify) 7. What age range of volunteers do you study? a) <18 yrs L b) yrs LI c) yrs LI d) >60 yrs LI

6 298 M. Thomson, W. G. Haynes & D. J. Webb 8. What sex are your volunteers? a) Male LI b) Female LI 9. What pre-trial screening do you perform? HISTORY i) Who obtains the history? a) Doctor LI b) Nurse LI c) Other (please specify) ii) How do you obtain the history? a) Questionnaire LI b) Direct questioning LI c) Other (please specify) iii) Do you include a specific HIV risks questionnaire? a) Yes LI b) No LI iv) Do you exclude any of the following ethnic minorities? a) Asian L b) African LI c) Indian LI d) Chinese LI c) Other (please specify) EXAMINATION i) Do you carry out a medical examination? a) Yes L b) No LI ii) If so, who carries out a medical examination? a) Independent GP L b) Volunteer/patients GP LI c) Independent consultant physician L d) Junior hospital doctor LI e) In-house medical staff LI f) Other (please specify)

7 HIV screening in volunteer research 299 iii) Which of the following are used in your screening? YES a) ECG L LI b) Haematology LI LI c) Biochemistry L d) ESR LL e) Urinalysis LI f) Hepatitis B surface antigen L g) Hepatitis C virus antibody LI LI h) HIV-1 antibody LI LI i) HIV-2 antibody LL j) Drug screen (please specify) k) Other (please specify) NO If responses to h) or i) are positive please continue. If not, please go to Q Why do you perform testing for HIV antibody? a) Volunteer safety LI b) Clinical staff safety LI c) Laboratory staff safety LI d) Ethics Committee requirement LI e) Other (please specify) 11. Do you counsel volunteers prior to testing? a) Yes L b) No L If the response to Q.11 is positive, please continue. If not, please go to Q What form does the counselling take? a) Informational leaflet LI b) One to one interview Li c) Group interview L d) Other (please specify) 13. Who performs the counselling? a) Psychiatrist L b) Psychologist L c) Volunteer/patients GP L d) Independent GP LI e) In-house medical staff LI f) In-house nursing staff LI g) Other (please specify)

8 300 M. Thomson, W. G. Haynes & D. J. Webb 14. Do you encounter any opposition to HIV testing from volunteers? a) Yes L b) No LI If Yes, please comment: 15. Do you believe that you lose volunteers as a direct result of suggesting HIV testing? a) Yes LI b) No L] 16. If a volunteer refuses to be HIV tested would you still consider using him/her in a trial? a) Yes Li b) No FL 17. i) Who carries out the HIV testing? a) Hospital laboratory LI b) Own laboratory L c) Private laboratory L d) Other (please specify) ii) Which test is used for: a) HIV-1 b) HIV-2 Other comments: 18. Have you ever had a positive result? a) Yes I b) No L If yes, please state how many: 19. Were any of these within the past 12 months? a) Yes L] b) No L] If yes, please state how many: 20. If you obtain a positive HIV result and confirmatory test, what is,your next course of action? (please tick more than one box if necessary) a) Inform the volunteer LI] b) Inform the volunteer's GP LI] c) Refer to specialist clinic d) No further action LI] e) Other (please specify)

9 HIV screening in volunteer research If you do not include HIV testing in your pre-trial screening, what are your reasons? a) Implications to volunteers (life insurance, etc) I b) Opposition from volunteers LI c) Opposition from staff I d) Risk of losing significant numbers of volunteers L e) Likelyhood of a positive test considered negligible I f) Lack of proven benefit of positive test to volunteers L g) Time involved in counselling L h) Overall cost of testing LI i) Other (please specify) 22. Are you happy with your present arrangements concerning HIV testing? a) Yes LI b) No LI If No, please comment: These responses will be used for research purposes only The practices of individual units will not be identifiable