Uncertain future for anti-HIV therapy

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Medicine and the Law Triazolam licensing in UK Acting on the advice of the Committee on Safety of Medicines (CSM), the UK Department of Health suspended the product licences for triazolam (Halcion) on Sept 30, 1991. On June 12, 1993, despite a hard-fought battle by the manufacturers, Upjohn Ltd-who have now exhausted all the statutory avenues of appeal provided by the Medicines Act 1968-the Licensing Authority announced that the revocation of licences would be permanent. Upjohn appealed to the CSM but its application was unsuccessful. In May, 1992, the company took its case to the Medicines Commission, which advised revocation of licences for 0.25 mg products but thought that problems with 0.125 mg tablets could be dealt with otherwise. The

Licensing Authority, however, proposed on July 17,1992,

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error, is "not implausible, although ... even in 1978, a properly organised company should have operated checks which eliminated such errors". One difficulty those advising the Licensing Authority had to contend with was the "relative lack of data about the efficacy and effects of triazolam at the licensed doses of 0 125 mg and 0.25 mg" and at the beginning of the hearing that problem troubled the panel also."... we find it unfortunate that Upjohn failed to respond at all readily to requests made by the Licensing Authority as early as 1990, that they should carry out a new post-marketing surveillance study". However, the panel was impressed (more so than the Minister) with a UK post-marketing surveillance study. The panel felt that the starting dose for triazolam in the young and middle-aged ought to be 0-125 mg, increasing to 0.250 mg "only if necessary". The same logic suggests that the elderly should be started on 0.0625 mg, but no data are yet available (a US study is expected to be available this year). Shortly before the publication of this report saw the successful appeal against the Legal Aid Board’s refusal to allow potential Halcion claims to be investigated where applications for legal aid were made after the deadline of Oct 20, 1991. This date was imposed by Mr Justice Kennedy, limiting the right of entry by legally aided litigants into the first group action in the multiplaintiff benzodiazepine litigation. Some 580 claimants, many of whom came

that licences for both dosages be revoked. Since that determination went against advice from the Medicines Commission, Upjohn invoked the right, rarely exercised, to present its case to a panel appointed by the Licensing Authority under the 1968 Act. The four-day hearing was in private but the panel’s 37-page report is in the public domain. Its findings were sympathetic to Upjohn’s case-ie, "the data are generally reassuring but rare idiosyncratic episodes of violence in association with triazolam, as with forward after the critical BBC Panorama television other [benzodiazepines], cannot be ruled out". on triazolam in October, 1991, can expect to programme Notwithstanding the best efforts of the distinguished panel, receive limited legal aid to allow for investigation of their the findings were arrived at after a one-sided presentation of claims. The audit of Halcion claims along with some 3000 evidence and argument. Furthermore, much of the evidence Ativan (lorazepam) claims already served, is due to be cannot be independently assessed. For instance, the finding completed shortly. Further judicial directions in the on equivalent doses (which is at odds with the views of the proceedings of the litigation are expected in July. CSM) is handled by reference to oral evidence, to published Upjohn has at all times contended that Halcion is safe and work, and to a transcript. No attempt is made to summarise effective and that any errors in the presentation of its or to quote extensively or to append the reference material to the Licensing Authority were unintended, and it documents. As the panel notes, the statutory procedure is suing the BBC for libel. The company is also suing Prof makes no provision for a balanced argument; only Upjohn Ian Oswald, a psychiatrist expert in the field of sleep and was able to present its case and its witnesses and evidence, hypnotics, and he is counterclaiming for libel. The cases are though the Licensing Authority provided material and the due to be heard together before a judge in London without a panel "followed up leads from this material and from that jury, in January. presented by Upjohn". The panel notes that "it would be Diana Brahams simpler and much more satisfactory if the procedure provided for the ’contrary case’ to be presented". The panel is clearly dissatisified with its remit "only to hear the licence Conference holder" and, after an extensive examination of the evidence, to report to, but not be entitled to make recommendations to, the Licensing Authority. Uncertain future for anti-HIV therapy The panel concludes that overall the benefits outweighed The IXth International Conference on AIDS held in the risks of the drug at doses of 0.25 and 0.125 mg when Berlin last week provided a forum for the luminaries of HIV with One was data sheets. "vital area" provided appropriate research-Luc Montagnier, Robert Gallo, and Anthony that of "equivalent dose". The panel notes difficulty in Fauci-to tantalise an audience of over 12 000 with their making exact comparisons but found the weight of evidence was "in favour of a dose of 0.25 mg triazolam being roughly speculations about future treatment. For those individuals with symptomless HIV infection, equivalent to a dose of 30 mg flurazepam or 20 mg the apparent conflict between the results of the Anglotemazepam (UK formulation). We accept this represents a French Concorde studyl and US data seems to be moving major change from earlier views that the equivalent doses towards a resolution. Zidovudine does consistently provide were triazolam 05 mg to 30 mg flurazepam or 20 mg a time-limited benefit for up to 12-18 months in such temazepam". The Licensing Authority is unconvinced by this finding which is, in effect, that the triazolam doses in patients. The remaining disagreement is whether zidovudine monotherapy should begin early to take comparative trials were not equivalent to those of advantage of this short-lived benefit or whether one should flurazepam. wait until symptoms develop. Arguments over toxicity and Protocol 321 (in prison volunteers) was of "marginal cost-benefit are finely balanced. A consensus meeting value" in assessing the safety of the drug in 1993, the panel between US and European investigators is planned for later felt, and Upjohn’s explanation that the incomplete this month, the aim being to devise more general guidelines information on adverse effects was due to a transcribing

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THE LANCET

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early intervention with zidovudine in symptom-free subjects. One concern must be the risk of generating zidovudineresistant HIV mutants. For instance, a homosexual man recently became infected with a zidovudine-resistant strain of HIV -1,2 although he had not taken zidovudine himself. He had most likely become infected through a partner who had been receiving zidovudine. Early treatment might therefore risk selecting out mutant strains of HIV. Such strains develop rapidly: in one in-vitro study (Larder BA, et al, Beckenham, UK) at time zero, 87-7% of HIV isolates were wild-type with only 6-6% mutants. By 48 weeks in the presence of zidovudine, the proportion of mutants had increased to 53-9%. The clinical importance of this observation is shown by viral resistance studies from ACTG 116B/117, a trial which compared zidovudine with didanosine (ddI). Zidovudine resistance predicted subsequent treatment failure. Data from combination therapy studies are also gradually becoming available. Margaret Fischl (Miami, USA) presented results from ACTG 155 which showed that who had among symptomatic patients (CD4<300/L) taken zidovudine for a median of 18-19 months, the combination of zidovudine and zalcitabine (ddC) was no better than either zidovudine or zalcitabine alone (primary end points, first AIDS-defining event or death; mean

follow-up, 17 months). Convergent combination chemotherapy refers to the use of several antiretroviral drugs-nucleoside and nonnucleoside reverse transcriptase (RT) inhibitors-to damage the virus to such a degree that its replication is permanently impaired. The efficacy of this approach with zidovudine, didanosine, and nevirapine has been reported in vitro and patients have

further discussed in Berlin. Over 400 already been recruited into a trial to test this regimen. Intriguing in-vitro studies also suggest that introduction of resistance mutations to one antiretroviral compound (didanosine) can diminish previously documented resistance to another agent (zidovudine). However, Robert Gallo voiced concern about multidrug cocktails. The more drugs that one gives, the more likely it is that damage to host DNA polymerase will take place. The potential toxicity of these agents should not be underestimated. Much emphasis has been placed on the theoretical value of tat and protease inhibitors. The tat (transactivator) gene of HIV controls the rate of viral DNA replication. In vitro, Ro-24-7429, a benzodiazepine derivative, inhibits RNA replication and viral protein production. In a randomised blinded phase 1/11 trial comparing Ro-24-7429 with nucleoside RT inhibitors in 96 patients (CD4 54-500/µL), Haubrich et al (California, USA) found that although the drug was well tolerated, it was ineffective in producing either a rise in CD4 count or a fall in p24 antigen activity. Inhibition of HIV protease should slow maturation of virion core proteins and retroviral enzymes. Nanomolar concentrations of protease inhibitors show highly specific antiretroviral activity. An Abbot protease inhibitor (A77003) given intravenously produced no beneficial changes in CD4 count or p24 antigen in 22 HIV-positive patients (mean CD4 300/µL). In a few cases, there was a decline in quantitative HIV culture from plasma (but not from peripheral blood mononuclear cells). Roche’s oral protease inhibitor, Ro-31-8959, was tested in three phase 1/11 protocols: advanced disease with (France) and without (Italy) previous zidovudine treatment, and symptom-free or was

minimally symptomatic disease (UK). Although well tolerated, the effects on CD4 count, p24 antigen, and HIV titres from mononuclear cells and plasma were weak and variable. In the Italian study, the effects of Ro-31-8959 were comparable with zidovudine. Clinical trials of antisense oligonucleotides that bind to and inhibit the HIV gag gene sequence will begin later this year with GEM 91 (genetic expression modulation) from Hybridon. For the future, the application of dominant negative viral mutants (which, when mixed with wild-type virus, render it non-infectious), capsid-targeted virus inactivation (a similar process leading to viral degradation rather than inactivation), and virus-specific inhibition (for instance, by targeting the rev response element that is essential for normal rev protein function in virus assembly) was discussed by Max Essex (Harvard AIDS Institute, USA) and F. Wong-Staal (California, USA). Where are the glimmers of hope? Despite Anthony Fauci’s assertion that "the virus is the major factor in HIV disease," it was clear that a shift in emphasis is taking place from direct antiretroviral strategies to immune-directed therapies. HIV infection induces a state of immune activation leading to loss of follicular dendritic cells and normal lymph node architecture.4 Interference with this process by targeting the activated T cell, apoptosis, or cytokine secretion might stabilise the immune system and control the course of infection. Effective cell-mediated immunity is central to limiting viral damage. Gallo noted that virus replicated faster in an activated cell where deoxyribonucleotides are in plentiful supply. Hydroxyurea inhibits the rate-limiting enzyme

supplying deoxyribonucleotides-ribonucleotide

reductase---and substantially diminishes HIV replication. Gallo also quoted some of the latest work of Daniel Zagury’s team which has discovered a pentapeptide motif in gpl20 which is also present in CD4 and which interferes with antigen activation possibly leading to a state of cell anergy and immunodeficiency. The case for autoimmune damage in HIV infection was supported by Wilson et al (London, UK) who have found a 13 aminoacid sequence in gp 120 that mimics human MHC molecules. If autoimmune processes are important, T cell vaccination might be a suitable treatment strategy.5 Jonas Salk’s team in California, USA, reported the first results of phase I/II clinical trials with a gp 120-depleted treatment vaccine. Both humoral and cell-mediated immune responses were generated and HIV copy number fell during the vaccination period compared with controls. The promise of immunotherapeutic strategies to combat HIV infection was one strong and clear message to emerge from Berlin. The next world AIDS conference will take place in Yokohama, Japan, in 1994 and subsequent meetings will be held biennially. Richard Horton 1. Aboulker J-P, Swart AM. Preliminary analysis of the Concorde trial. Lancet 1993; 341: 889-90. 2. Erice A, Mayers DL, Strike DG, et al. Brief report: primary infection with zidovudine-resistant human immunodeficiency virus type 1. N Engl J Med 1993; 328: 1163-65. 3. Chow YK, Hirsch MS, Merrill DP, et al. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature 1993; 361: 650-54. 4. Pantaleo G, Grazziosi G, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362: 355-58. 5. Atlan H, Gerston MJ, Salk PL, Salk J. Can AIDS be prevented by T-cell vaccination? Immunol Today 1993; 14: 200-02.

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1992-97 AIDS projections for England and Wales

Noticeboard WHO and Yugoslavia Dr Nils Rosdahl, former director of public health in Denmark, has taken up a WHO assignment as adviser to the UN High Commissioner for Refugees in former Yugoslavia. Based in Zagreb, he succeeds Sir Donald Acheson, who went there in July last year on what was expected to be a two or three month assignment. WHO now has some fifty staff in the area, half of whom are locally engaged. On return from a ten-day visit to the five republics of former Yugoslavia, Dr Hiroshi Nakajima, WHO Director-General, was visibly appalled by what he had seen in Bosnia-Herzegovina particularly the destruction of some 260 hospitals and the gravity of the wounds caused by the high-velocity bullets. Some children among Sarajevo’s 330 000 inhabitants were showing signs of malnutrition. Diarrhoea and dysentery outbreaks were increasing and tuberculosis and hepatitis were major threats. State dispensaries no longer had even the most common antibiotics. Dr Nakajima, accompanied on his tour by Dr Jo Asvall, head of WHO’s European regional office in Copenhagen, said that he had been asked several times if Yugoslav funds frozen in the US and other countries could not be used for purchase of medical supplies. He promised to pass this idea on.

Alan

McGregor

Financing health service Until recently, most national governments muddled along with health-care systems derived from a mixture of charitable support, private practice, and voluntary or compulsory insurance. Health care was seldom a major political issue, and inequalities in its provision were considered as inevitable as inequalities in wealth. WHO turns its attention to the matter in its latest Technical Report,l which notes the experience of representative nations from Algeria to Zimbabwe. Just how diverse they are is shown by the proportion of health care provided privately. Among the richer nations, in the USA 58% of health care is private, and in the UK, 13%. In developing nations, the extremes are 80% in Uganda and 12% in Lesotho. Within such diversity there is no common standard of achievable health care. WHO suggests there should be, and, if not a common way of paying for it, at least an agreed means of approaching the difficulties involved. In the UK, the tide is turning from all-out provision of health care by central government to a hybrid where private initiatives are encouraged to compete within state funding. A more radical change may be on the way: a report by the UK Institute of Health Services Management2 concludes that "General taxation must be reconsidered as the major funding of the National Health Service if it continues to fail to deliver adequate levels of resources". Coincidentally, the UK Government’s Department of Health launches a "Help us to help you" campaignwherein sick people are advised how not to waste the limited funds available for their treatment ("... remember to cancel appointments if they cannot be kept...") and reminded by the Secretary of State for Health that "Our primary care system is also the source of considerable envy abroad", as I was reminded again during a recent trip to Russia. Russia’s envy is understandable when, under communist government, the state’s doctors were so slightly rewarded as to make illegal private practice inevitable. Whether Russia’s change to a market economy will lead to the concept of free health care being abandoned, remains to be seen. In the UK, this ideal has been eroding for some time and seems unlikely to survive the escalating costs

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of current treatments. John

Bignall

1. Evaluation of recent changes in the financing of health services. Geneva: World Health Organization (WHO Technical Report Series), 1993. Pp 74. SwFr10. ISBN 9241208295. 2. Future Health Care Options. London: Institute of Health Services Management. 1993. Pp 53. £10. ISBN 0901003956. 3. Help us to help you. Available from Department of Health Information Division, 80 London Road, London SE1 6LW, London, UK.

Revised calculations from a working group chaired by Prof N. E. Day suggest that there will be between 1945 and 3215 new AIDS cases in 1997.1 Projected annual incidences for 1997 in each of the main exposure categories are: homosexual males, 1350; injecting drug users, 165; and heterosexuals, 770. Day and colleagues estimated that there were about 23 400 HIV-infected individuals in

England and Wales by the end of 1991. Although a plateau will develop in the overall incidence of AIDS, there are strikingly different predictions for each exposure category. For homesexual males, the annual incidence of AIDS is expected to plateau in 1994 in line with a peak annual incidence of HIV infection in 1983-84. Among injecting drug users, the peak in HIV incidence took place in 1985 and so the number of AIDS cases is still climbing. For heterosexuals up to 1991, the peak of HIV infection had yet to be reached and so one can expect a continued rise in the annual incidence of AIDS cases for some time to come. The pool of those with HIV infection acquired heterosexually via a partner who had also been infected heterosexually is slowly increasing. The UK Department of Health claims that its AIDS prevention policy is responsible both for the reduction in projected new cases among injecting drug users and the greater certainty about heterosexual exposure. According to Baroness Cumberlege, "the UK now has one of the lowest estimated HIV prevalence rates in western Europe". Day attributes the changes to more detailed and reliable data collection, together with better statistical techniques. The report adopts a cautious note, reflecting concern about a possible recent increase in HIV transmission among homosexual males and the difficulty of guessing sexual mixing patterns between subsets of the population. The latest figures replace 1990 estimates that have proved to be reasonably accurate except for an overestimate of the number of heterosexual exposures (355 vs 255) and an underestimate of cases among homosexual males (910 vs

1165). Richard Horton 1. The incidence and prevalence of AIDS and other severe HIV disease in England and Wales for 1992-1997: projections using data to the end of June 1992. CDR 1993; 3

(suppl 1): S1-17)

Gases and glues Data on deaths in the UK from volatile substances abuse (VSA) have been recorded by a team from the Department of Public Health Sciences, St George’s Hospital Medical School, London, since 1971, and these data have been collected in a "stable and systematic" manner since 1983. The latest report from St George’s,l which covers the period up to the end of 1991, shows that there were 122 deaths from VSA in 1991 compared with 151 in 1990 and 113 in 1989. Since 1983, there has been an average annual increase in VSA deaths of 54% per annum. Young people aged 14-18 years are the age group most likely to die from VSA, accounting for 61 5% of all VSA deaths between 1971 and 1991, and the figures for 1991 show no significant change in this pattern. 87% of deaths from VSA in 1991 were in males, and again this percentage did not differ from the overall figure since 1971. Between 1971 and 1991, the most popular substances for abuse were gas fuels (primarily cigarette-lighter refills and bottled domestic gases; 351% of deaths), aerosols (primarily deodorants/

antiperspirants and pain-relief sprays; 20-9%), glues (mostly contact adhesives; 19-2%), and "other" (typewriter correction fluid and anaesthetic gases figure prominently in this group, which also included petrol, plastic remover, and dry-cleaning fluid; 20-7%). With the exception of glue (13-9%), the figures for substances abused in 1991 differ little from the overall figures. In 1991, VSA was most likely to occur in a public place (42%) or at home (39%). Unsurprisingly, most deaths from VSA were in hospital or on the way to hospital (47%), and causes of death were recorded as direct toxic effects (49-2%), inhalation of vomit (148%), trauma-eg, hanging or drowning (11-5%), suffocation inside a plastic bag (7-4%), and "other/not known" (17-2%). From February, 1992, the UK Department of Health sponsored the broadcast of television