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Doubts about zidovudine
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421 Noticeboard Doubts about zidovudine Debate about the efficacy and safety of zidovudine (AZT) is being stifled by a medical and scientific community that continues to display a striking arrogance over those it claims to serve, says a UK television documentary (Dispatches, Channel 4) screened this week. These criticisms have been the subject of intense discussion in the USA, where several AIDS organisations are now campaigning against the more widespread prescription of zidovudine to symptom-free HIV-positive individuals. Help groups have even been established to enable HIV-positive patients gain the confidence to come off their medication. Zidovudine is approved for use in those with symptomatic HIV disease, early symptomatic disease with CD4 counts below 500/al, or symptom-free HIV-positive patients with CD4 counts below 200/pl (or 500/ul and falling rapidly). A 1987 report on the efficacy of zidovudine in patients with AIDS or AIDS-related complex1led to fast-track FDA approval. The UK and French Concorde trial, begun in 1988, on whether zidovudine delays the development of symptoms in healthy people infected with HIV, is still in progress, with a final analysis expected later this year. A Wellcome trial in symptom-free patients with CD4 counts of more than 400/pl has recently been terminated early after analysis revealed a significant reduction of disease progression. What evidence is there to support the change in attitude to a drug whose supposed efficacy led to pressure from these same organisations for its rapid passage through the Food and Drug Administration (FDA) licensing procedures? Dispatches pointed to irregularities in the protocol of the trial that led to fast-track approval. It revealed that an internal FDA report on this Burroughs-Wellcome funded study, says that "treatment groups unblinded themselves early" in the first few weeks, which "could have resulted in bias". The programme also drew attention to theoretical considerations that have led some to suggest that zidovudine may not exert a specifically antiviral action. Dr Peter Duesberg-who is also the main proponent of the belief that HIV is not the cause of AID S-argues that once an individual seroconverts to HIV, viral replication probably ceases, thus removing the target for zidovudine’s action-namely, reverse transcriptase. This view is not consistent with known data on antigenic drift in a single strain of HIV in a given individual. The virus is constantly able to escape, by small changes to its antigenic profile, the neutralising antibodies produced in response to its presence. Viral replication will therefore proceed, albeit at a low level, and zidovudine is likely to continue to act as a DNA chain terminator even after seroconversion. Several other criticisms are made in the programme. For instance, although Wellcome’s product brochure states that "AZT improves both the quality and length of life", no firm data are yet available on either point. Moreover, they claim that "no life threatening toxicities are associated with zidovudine", but Dispatches said that severe cytopenias and its activity as a "potential carcinogen" (from an FDA report based on in-vitro data) might suggest otherwise (but the data sheet does admit to chromosomal damage in in-vitro studies of human lymphocytes as well as evidence of carcinogenicity in rodents) The makers of the Dispatches programme intend to forward their fmdings to the Medicines Control Agency. Irrespective of how one interprets the scientific and clinical trial data, there is clearly a growing concern among the HIV-positive community that more open debate about these issues is needed before further treatment recommendations are given or new trials are planned. The Channel 4 programme sought the views of Wellcome UK and investigators from the Concorde trial about the current place of zidovudine in the management of HIV-positive subjects. However, because the Broadcasting Complaints Commission found a previous programme by the same television production company to be both misleading and confusing (see Lancet Aug 31, p 566), both parties declined the invitation to discuss these concerns further. 1. Fischl MA, Richmann DD, Grieco MH, et al. The efficacy of 3’-azido- 3’deoxythymidine, an inhibitor of HTLV III/LAV replication, in patients with AIDS or AIDS-related complex a double-blind placebo-controlled trial. N Engl J Med 1987; 317: 185-91. Disposal of previable fetuses A stillborn baby must be formally buried or cremated, and unused embryos created in vitro must be disposed of "sensitively". But hospitals have no obligation to make special arrangements for the disposal of the dead fetus between the embryo stage covered by the 1990 Human Fertilisation and Embryology Act (up to 14 days from fertilisation) and the legal gestational age of viability (28 weeks at present but likely to be reduced to 24 in forthcoming legislation). Many parents who have lost a baby before the legal age of stillbirth are distressed to find that their loss is scarcely acknowledged by health professionals. Parents need to know that the dead fetus is disposed of respectfully and to have a choice about the means of disposal. Few, presumably, would opt for the hospital incinerator, yet a quarter of hospitals responding to a postal survey carried out by the Stillbirth and Neonatal Death Society (SANDS) said that they incinerated at least some pre-28-week fetuses along with hospital waste. Last year the NHS Management Executive issued two circulars requesting hospital managers to satisfy themselves that their disposal arrangements are acceptable, and SANDS has now issued recommendations for good practice in the disposal of small babies’ bodies or remains. I The main recommendations are that parents should be offered choices about what is done and that the remains of all previable fetuses should be disposed of in a respectful and dignified way, irrespective of gestational age or how the loss occurred. If there is an identifiable body, burial or cremation, and possibly a religious or non-religious ceremony, should be offered. If there is no identifiable body-for instance, after a miscarriage or termination-the remains should be committed to the hospital incinerator separately from hospital waste and under the supervision of an appointed member of staff. The guidelines urge hospital staff to be imaginative, flexible, and responsive to parents as individuals. Parents should also be given written information about hospital policy and procedures and the choices available. Hospital staff may find disposal the most distressing aspect of dealing with pregnancy loss, and they should be given support and trained to help the bereaved parents. Some health professionals have expressed concern that parents will be hindered rather than helped in their grieving by an "overzealous" approach to pregnancy loss, but in SANDS’ experience parents’ requests "are almost always reasonable, usually very modest, and rarely inappropriate". And resource demands, the organisation says, "are minimal when compared with the distress of parents whose needs go unmet... [and] who realise too late, that the hospital procedures they depended on were far from respectful". 1. A dignified ending: recommendations for good practice in the disposal of the bodies and remains of babies born dead before the legal age of viability. By Nancy Kohner. SANDS, 28 Portland Place, London WIN 4DE. £7.95 + £1 packing and postage. Containment of drug-resistant malaria How to contain drug-resistant falciparum malaria remains a major challenge in tropical countries. An international meeting of World Health Organisation personnel, technical experts, and health workers, held in Bangkok in November, produced three important recommendations on this subject. Firstly, in areas where chloroquine-resistant malaria is seen as a threat serious consideration should be given to exploring combination chemotherapy (eg, quinine and tetracycline; sulphadoxine and pyrimethamine; mefloquine and tetracycline; mefloquine and sulphadoxine and pyrimethamine) in the first instance, rather than after resistance to monotherapy becomes widespread. This approach may improve treatment efficacy for individual patients, could prevent or delay the spread of multiresistant strains of Plasmodiumfakiparum, and seems sensible by analogy with what is known about tuberculosis. A degree of pre-existing resistance to one or other drug may not preclude its usefulness in combination therapy. Secondly, many studies have shown that cure rates can be greatly improved by adding a tetracycline to the drug regimen. There is also evidence, as yet unconfirmed, that the emergence of resistant strains might be curtailed by this means. An evaluation of the use of doxycycline in this context might be especially appropriate;
Transcript of Doubts about zidovudine
421
Noticeboard
Doubts about zidovudineDebate about the efficacy and safety of zidovudine (AZT) is
being stifled by a medical and scientific community that continuesto display a striking arrogance over those it claims to serve, says aUK television documentary (Dispatches, Channel 4) screened thisweek. These criticisms have been the subject of intense discussion inthe USA, where several AIDS organisations are now campaigningagainst the more widespread prescription of zidovudine to
symptom-free HIV-positive individuals. Help groups have evenbeen established to enable HIV-positive patients gain theconfidence to come off their medication.
Zidovudine is approved for use in those with symptomatic HIVdisease, early symptomatic disease with CD4 counts below 500/al,or symptom-free HIV-positive patients with CD4 counts below200/pl (or 500/ul and falling rapidly). A 1987 report on the efficacyof zidovudine in patients with AIDS or AIDS-related complex1ledto fast-track FDA approval. The UK and French Concorde trial,begun in 1988, on whether zidovudine delays the development ofsymptoms in healthy people infected with HIV, is still in progress,with a final analysis expected later this year. A Wellcome trial insymptom-free patients with CD4 counts of more than 400/pl hasrecently been terminated early after analysis revealed a significantreduction of disease progression.What evidence is there to support the change in attitude to a drug
whose supposed efficacy led to pressure from these same
organisations for its rapid passage through the Food and DrugAdministration (FDA) licensing procedures? Dispatches pointed toirregularities in the protocol of the trial that led to fast-track
approval. It revealed that an internal FDA report on this
Burroughs-Wellcome funded study, says that "treatment groupsunblinded themselves early" in the first few weeks, which "couldhave resulted in bias". The programme also drew attention totheoretical considerations that have led some to suggest thatzidovudine may not exert a specifically antiviral action. Dr PeterDuesberg-who is also the main proponent of the belief that HIV isnot the cause of AID S-argues that once an individual seroconvertsto HIV, viral replication probably ceases, thus removing the targetfor zidovudine’s action-namely, reverse transcriptase. This view isnot consistent with known data on antigenic drift in a single strain ofHIV in a given individual. The virus is constantly able to escape, bysmall changes to its antigenic profile, the neutralising antibodiesproduced in response to its presence. Viral replication will thereforeproceed, albeit at a low level, and zidovudine is likely to continue toact as a DNA chain terminator even after seroconversion. Severalother criticisms are made in the programme. For instance, althoughWellcome’s product brochure states that "AZT improves both thequality and length of life", no firm data are yet available on eitherpoint. Moreover, they claim that "no life threatening toxicities areassociated with zidovudine", but Dispatches said that severe
cytopenias and its activity as a "potential carcinogen" (from anFDA report based on in-vitro data) might suggest otherwise (butthe data sheet does admit to chromosomal damage in in-vitrostudies of human lymphocytes as well as evidence of carcinogenicityin rodents) The makers of the Dispatches programme intend toforward their fmdings to the Medicines Control Agency.
Irrespective of how one interprets the scientific and clinical trialdata, there is clearly a growing concern among the HIV-positivecommunity that more open debate about these issues is neededbefore further treatment recommendations are given or new trialsare planned. The Channel 4 programme sought the views ofWellcome UK and investigators from the Concorde trial about thecurrent place of zidovudine in the management of HIV-positivesubjects. However, because the Broadcasting ComplaintsCommission found a previous programme by the same televisionproduction company to be both misleading and confusing (seeLancet Aug 31, p 566), both parties declined the invitation to discussthese concerns further.
1. Fischl MA, Richmann DD, Grieco MH, et al. The efficacy of 3’-azido-3’deoxythymidine, an inhibitor of HTLV III/LAV replication, in patients withAIDS or AIDS-related complex a double-blind placebo-controlled trial. N Engl JMed 1987; 317: 185-91.
Disposal of previable fetuses
A stillborn baby must be formally buried or cremated, andunused embryos created in vitro must be disposed of "sensitively".But hospitals have no obligation to make special arrangements forthe disposal of the dead fetus between the embryo stage covered bythe 1990 Human Fertilisation and Embryology Act (up to 14 daysfrom fertilisation) and the legal gestational age of viability (28 weeksat present but likely to be reduced to 24 in forthcoming legislation).Many parents who have lost a baby before the legal age of stillbirthare distressed to find that their loss is scarcely acknowledged byhealth professionals. Parents need to know that the dead fetus isdisposed of respectfully and to have a choice about the means ofdisposal. Few, presumably, would opt for the hospital incinerator,yet a quarter of hospitals responding to a postal survey carried outby the Stillbirth and Neonatal Death Society (SANDS) said thatthey incinerated at least some pre-28-week fetuses along withhospital waste. Last year the NHS Management Executive issuedtwo circulars requesting hospital managers to satisfy themselvesthat their disposal arrangements are acceptable, and SANDS hasnow issued recommendations for good practice in the disposal ofsmall babies’ bodies or remains. I
The main recommendations are that parents should be offeredchoices about what is done and that the remains of all previablefetuses should be disposed of in a respectful and dignified way,irrespective of gestational age or how the loss occurred. If there is anidentifiable body, burial or cremation, and possibly a religious ornon-religious ceremony, should be offered. If there is no
identifiable body-for instance, after a miscarriage or
termination-the remains should be committed to the hospitalincinerator separately from hospital waste and under the
supervision of an appointed member of staff. The guidelines urgehospital staff to be imaginative, flexible, and responsive to parents asindividuals. Parents should also be given written information abouthospital policy and procedures and the choices available. Hospitalstaff may find disposal the most distressing aspect of dealing withpregnancy loss, and they should be given support and trained tohelp the bereaved parents.Some health professionals have expressed concern that parents
will be hindered rather than helped in their grieving by an"overzealous" approach to pregnancy loss, but in SANDS’
experience parents’ requests "are almost always reasonable, usuallyvery modest, and rarely inappropriate". And resource demands, theorganisation says, "are minimal when compared with the distress ofparents whose needs go unmet... [and] who realise too late, that thehospital procedures they depended on were far from respectful".1. A dignified ending: recommendations for good practice in the disposal of the bodies
and remains of babies born dead before the legal age of viability. By Nancy Kohner.SANDS, 28 Portland Place, London WIN 4DE. £7.95 + £1 packing and postage.
Containment of drug-resistant malaria
How to contain drug-resistant falciparum malaria remains amajor challenge in tropical countries. An international meeting ofWorld Health Organisation personnel, technical experts, and healthworkers, held in Bangkok in November, produced three importantrecommendations on this subject.
Firstly, in areas where chloroquine-resistant malaria isseen as a threat serious consideration should be given to
exploring combination chemotherapy (eg, quinine and tetracycline;sulphadoxine and pyrimethamine; mefloquine and tetracycline;mefloquine and sulphadoxine and pyrimethamine) in the first
instance, rather than after resistance to monotherapy becomeswidespread. This approach may improve treatment efficacy forindividual patients, could prevent or delay the spread ofmultiresistant strains of Plasmodiumfakiparum, and seems sensibleby analogy with what is known about tuberculosis. A degree ofpre-existing resistance to one or other drug may not preclude itsusefulness in combination therapy.
Secondly, many studies have shown that cure rates can be greatlyimproved by adding a tetracycline to the drug regimen. There is alsoevidence, as yet unconfirmed, that the emergence of resistant strainsmight be curtailed by this means. An evaluation of the use ofdoxycycline in this context might be especially appropriate;
