HIV HERALD Publication from the National Treatments Project -- Australian Federation of AIDS Organisations PO Box H274, Australia Square, Sydney NSW, 2000 Australia Tel : (+612) 231 2111 Fax : (+612) 231 2092 October 1994 Volume 4 No 9 Contents Bits and Pieces >Possible Floconazole/Atovaquone Drug Interaction >Fluconazole for Candidiasis >L735,524/Merke Protease >GEM 91 >Cimetidine (Tagamet) - New Study Results >Oral Ganciclovir Beneficial for Primary Prohylaxis of CMV Disease >Oral Valciclovir Passes Phase I Trials >Changing Antibodies to Enter Cells >Immuno-C, a New Treatment for Cryptosporidiosis Antiviral News >Individualised therapy >Combination Treatments Womens Issues >Maternal Transmission of HIV News >Management of HIV in Children >Questions Raised about Nitrite Inhalants "Amyl/Poppers" and Kaposi's Sarcoma Opportunistic Illnesses >Liposomal Doxorubicin Submitted to American Authorities for Approval --- Trials in Australia set to Start Clincal Trial News >935U83 - A New Antiviral Drug Trial Now Recruiting in Sydney BITS AND PIECES By Ian McKnight - Smith Possible Fluconazole/Atovaquone drug interaction There has been some confusion regarding drug interactions between atovaquone and fluconazole. After discussions with Burroughs Wellcome, what they have found is that people who take both fluconazole and atovaquone seem to have higher levels of atovaquone in the blood compared to those who take atovaquone alone. Atovaquone or Mepron is used in the treatment of PCP and is also entering studies to determine its effectiveness in preventing the illness in people who are intolerant to sulphur based drugs like co-trimoxazole. [Project Inform Sept 12 1994] Fluconazole for Candidiasis Preliminary analysis of a Community Research Initiative trial studying the effect of fluconazole for the prevention of candidial infections showed that fluconazole was effective in preventing candidiasis, however there were several people that developed resistance to fluconazole. Resistance to fluconazole seemed to develop when the CD4+ count dropped below 50. [Project Inform September 12 1994] L 735,524 / Merck Protease: A meeting with Merck Sharpe and Dohme recently took place to discuss their protease inhibitor L-735,524. No new data were presented and the majority of the meeting was spent discussing how difficult this drug is to manufacture. Merck is planning on conducting two Phase III (wider access) trials at the beginning of next year. (It is noted that as far as we can ascertain MSD does not appear to have any intentions for trial work in Australia.... maybe we are considered to be too small a market?) One of the US trials will be for people who are antiretroviral therapy naive (i.e. that is they have not taken antiretrovirals before.) and the other will be for people who have taken antiretrovirals. Both studies are expected to enrol 900 people. A follow up meeting is scheduled for this month when concept sheets will be presented to Project Inform for further comment. Project inform (San Francisco) has been working with Hoffman La Roche (makers of the protease inhibitor saquinavir) and Merck in starting an expanded access program for their protease inhibitors. While both companies are interested in establishing an expanded access program, drug supply and the difficulty in manufacturing these compounds will limit the size of such a program as well as when they might be available in the US. (Of course this will have an even greater negative impact on the availability in Australia) Hoffman La Roche ran into manufacturing problems with saquinavir and as a result, the compassionate access program will now be delayed until 1995 at the earliest. Merck claims to have difficulty in manufacturing their protease as mentioned previously, and now is looking to get its drug approval in the traditional system (i.e. a full approval rather than an accelerated approval and that way they do not have to instigate an expanded access program). Merck currently manufactures about 30,000 kilos a year of Vasotec, their billion dollar a year drug for treating high blood pressure, but they think that they will need to manufacture as much as a million kilos a year of the L-735,524. In addition they claim that this is the most complex compound that they have ever discovered and the manufacturing is more difficult than that for imipenam which is widely considered to be the most complex commercial drug to synthesis. In a related development, Dr. Kessler, the FDA Commissioner, is committed to enter into dialogue with Merck and Roche and to pressure them to develop an expanded access program for their protease inhibitors. In fact, Dr. Kessler has already spoken to a representative from Roche. In effect, this will push/encourage the companies into increasing the production of the drugs in question (not withstanding their professed inability to do so without a great deal of trouble.) [Project Inform Sept 12 and Oct 3rd 1994] GEM 91 Hybridon the makers of Gem 91, have released plans for an upcoming Phase II study in the United States. Gem 91 is an antisense drug. Viruses insert their genetic material into cellular DNA, once infected, the DNA programs the cell to manufacture the component proteins of the virus (HIV for example). To produce proteins, the DNA transmits it s information to a messenger RNA (mRNA) molecule. This m-RNA is known as the sense strand. Antisense drugs are the opposite or a mirror image of the sense strand. These drugs attach to m-RNA and block production of the particular proteins necessary for viral activity. This is a simplistic description of the antisense process. The new GEM 91 study is designed to detemine the safety and antiviral activity of the drug. The principal sites for the research will be in New York and in Alabama. At the same time the company will be doing another study in France using a 2 hour infusion formulation of 3 different doses of GEM 91 every other day in 30 people. Plans are that all of these studies will start in October or November of this year. In the US the study is also to be by infusion. However they will be looking at people with CD4 counts between 100 and 500 and who are clinically stable . Previous antiretroviral use will be O.K. However a 2 week washout period is required before starting the active treatments. 2/3 will receive active drug (They are looking at two groups since they are looking at two different doses) and 1/3 will be on a placebo. The active drug will be given by a daily continuous infusion for the first two weeks and then every other day infusion for the 2nd 2 weeks. People receiving placebo for the first two weeks will receive active GEM 91 for the second part of the study. All participants will be hospitalised for the duration of receiving study drug. So far no significant toxicities have been seen with GEM 91. Antiviral activity of GEM 91 will be measured by branched DNA (viral load) tests. At this point in time no trials are planned for this drug in Australia, however it is suggested that if these studies provide good responses, that broader phase III type studies should indeed be considered very quickly. [Project Inform September 26 1994] Cimetidine (Tagamet)-New study results A study recently completed by the Community Research Initiative in New England (US) comparing cimetidine (Tagamet- a commonly used drug to treat intestinal ulcers) versus placebo showed that there were no differences in CD4 and CD8 counts / percentages. This study contradicts a German study which found that cimetidine was able to stimulate T-cell counts. [Project Informs September 26 1994] Oral Ganciclovir beneficial for primary prophylaxis of cytomegalovirus (CMV) disease. An independent data safety monitoring board (DSMB) for Syntex ICM study 1654 in the USA, evaluating the potential benefit of oral ganciclovir for prevention of CMV disease has recommended ending the placebo arm due to a highly statistically significant difference in the incidence of and time of development to CMV disease in the treatment arm. All patients in placebo arm have been offered active drug. Approximately one half of the enrollers had completed 10 months of therapy at the interim analysis. The study was designed as a double blind placebo controlled multicentre phase III trial that began enrolment in November 1992. Enrolment of 725 participants was completed in December 1993. The entry criteria included HIV seropositivity, CMV serpositivity and a CD4 lymphocyte count less than 50 /mm3 or less than 100/mm3 and history of an AIDS defining opportunistic illness. Two thirds of enrollers were randomised to receive active drug while the other third received placebo. The treatment arm dosage was 1,000 mg 3 times a day of oral ganciclovir. Follow up has included eye examinations by an opthamologist every 2 months along with CMV cultures and other laboratory measurements. The primary endpoint was a diagnosis of CMV disease, while secondary endpoints included survival and quality of life. The study will continue with a open-label unblinded status to monitor the patients for further efficacy and safety. [Beta September 1994] Oral Valciclovir passes phase I trials Seventeen HIV infected people with a mean CD4 lymphocyte count of 44 /mm3 completed the phase I study of oral valciclovir, 4 times a day with 1000 mg or 2000 mg for a period of one month. Valciclovir is a "prodrug" of acyclovir, that is to say the active ingredient is still acyclovir, but the formulation has been created that the active ingredient is not released until it has been absorbed into the blood stream. This in turn significantly increases serum levels of acyclovir. There are few side effects. With the higher dosage, the serum levels of the active agent in the blood were five times greater than levels achieved with the standard form of acyclovir (800 mg five times a day). Such levels hold promise in the prevention and treatment of HIV- related CMV, varicella zoster virus, herpes simplex, and possibly herpes 6 virus. [Jacobson SFO General Hospital 1994] Changing Antibodies to Enter Cells. By Alan Strum Antibodies are proteins produced by the immune system that recognise and help to eliminate bugs such as viruses from the blood and surrounding tissues. The only problem with antibodies is that they can't enter cells to inhibit viruses that replicate inside of the cells. A new technique has now been developed that changes antibodies so they can enter into cells to stop or reduce viral replication that may be taking place inside of the cells. This technique involves removing antibodies from people with HIV (hyperimmune immunoglobulins - HIVIG) and exposing the antibodies to a chemical called hexamethylenediame. The result of this is that the protein structure of the antibodies changes what is called its iso-electric point and is then called a cationized antibody. This is a different balance of positive and negative electric charges that is made up of the atoms of the antibody. When the antibody has a particular electric charge it is able to attach to the surface of cells and passes through the cell wall to enter to the inside of the cell where it can start to inhibit the replication of HIV. This process is a bit like magnets that have opposite ends. One end of a magnet will repel or reject another end of a magnet that has the same charge, whereas the ends of a magnet that are of opposite charges will attract and attach to each other. In a test tube experiment with HIV infected immune cells the changed antibodies (cationized HIVIG) were able to reduce the production of p24 antigen by 90%, which indicates that HIV replication had been substantially reduced in infected cells. Source: AIDS Weekly, October 3, 1994 Immuno-C, a new treatment for cryptosporidiosis. By Alan Strum Cryptosporidiosis is a parasitic infection of the gut responsible for diarrhoea, malabsorption and wasting. To date, over 70 drugs have been tested against this infection with only limited success. Biommune Systems Inc., have developed a new passive immune (antibody based) treatment which appears to inhibit the development of this bug between the second and fifth days of it's developmental life cycle. The company developed a new cell culture (test tube) technique to test the new treatment. This new test will also aid in testing new drugs against cryptosporidiosis in the future. Immuno-C will enter phase I trials later this year in healthy people to evaluate the safety of the treatment.Source: AIDS Weekly, October 3, 1994 Antivirals News INDIVIDUALISED THERAPY By Ian McKnight-Smith Today, just a handful of physicians are already offering to their patients components of a treatment strategy that has been termed individualised therapy . Within 6-12 months it is estimated that many more community physicians will adopt elements of this approach to therapy for HIV. As access increases to powerful new diagnostic technologies and to more effective treatments regimens the picture of HIV patient management is going to change significantly. By the end of 1995, the majority of people with HIV cared for by the mainstream HIV physicians will likely have access to the primary ingredients of this new treatments strategy. There are five key components of Individualised therapy: I. Wider access to HIV RNA testing, a new technology that provides an accurate measure of HIV load in the blood plasma of the person with HIV or AIDS. II. Tailoring anti retroviral treatments to each individual person, based primarily upon periodic measurement of viral load and the responses seen with the introduction of a particular treatment. III. Accelerated approval of, and a wider access to the new generation of treatments, including protease inhibitors, non nucleoside reverse transcriptase inhibitors, etc that show particular promise when used in combination with the nucleoside analogues. IV. More widespread use of 3 or 4 drug regimens that combine different classes of drugs. This cocktail being specifically designed to the responses that are observed with viral load testing. V. Early initiation of drug treatments, while the immune system is relatively intact and capable of a strong response to HIV infection. Combination treatments By Ian McKnight-Smith Three drug combinations hold the most promise for effective sustained control of viral activity. Historically, 3 or 4 drug combinations have been necessary for the effective treatment of certain chronic infections and other diseases. For example, state of the art treatment of TB calls for early initial treatment with 4 or 5 different drugs. In therapy for various cancers treatment with cocktails of 3 or more chemotherapeutic agents is commonly the standard of care. In HIV disease, laboratory studies of certain 3 drug combinations of AZT+ddI+3TC and AZT+ddC+Nevirapine produce a synergistic effect that resources HIV activity to near zero, according to reports from Wellcome. While in test tube data may not translate into clinical benefit, the fact that these triple antiretroviral combinations can completely suppress viral activity in laboratory cultures suggests that 3 drug combinations hold promise for providing people with a significant clinical advantage over the monotherapy or double drug treatment that is currently being used. It is also important to note that the drugs that constitute these promising combinations are already being used clinically through trials, which should and could be expanded into broad scale combination access evaluations. This would quickly indicate which combinations were most effective in which groups of people etc. In the near future the combinations most likely will be comprised of the following: Nuclesoside analogue reverse transcriptase inhibitors (NARTIs) ...... AZT, ddI , ddC, d4T, and 3TC. Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): ....Nevirapine, BHAPs such as ateviridine and delaviridine, alpha APA, Protease Inhibitors ... Abbott 77003/74704/80987, Merck, 735524, Roche 31-8959, Dupont/Merck q8045 and q8050, Nikko KNI227, KNI272 and many others in earlier stages of development. While three drug combinations using protease inhibitors plus reverse transcriptase inhibitors are currently the best hope for sustained clincial benefits. Over the next 24-36 months people with HIV may have increased access to other types of antiretroviral treatments. These may include immunomodulating therapies such as the therapeutic vaccines and autologous CD8+ cell infusion, passive hyperimmune therapy and interleukin 2, as well as other novel approaches now in the research pipeline. Conclusion Individualised therapy is an emerging new treatment strategy for HIV, that differs from the current cookbook approach which relies almost entirely upon CD4 cell counts and clinical symptoms to dictate the treatment decisions. The essential elements of individualised therapy include the use of powerful tests for (1) measuring HIV viral load to determine disease stage as well as treatment efficacy, (2) evaluating treatment regimens and (3) guiding the timing and choice of changing antiviral treatments. The concept of early antiretroviral treatment in HIV disease, also a component of individualised therapy, is supported by the finding that, after the initial immune response to acute infection, 25% of CD4 T lymphocytes in the lymph node are infected with HIV. Furthermore, it is now well established that HIV is actively replicating in the lymph nodes and other lymphoid tissue throughout the asymptomatic period of the illness. Since monotherapy with AZT in early disease appears to have only limited effect on HIV load in the lymph nodes, earlier treatment with double and triple combination regimens using nucleoside analogue reverse transcriptase inhibitors plus a protease inhibitor potentially offer the possibility of producing prolonged suppression of the viral replication and therefore improved clinical benefits. Before individualised therapy can be put into widespread practice, the following ongoing developments need to be completed: 1) Clinical trials now in progress must be completed and new ones must be designed and implemented to show conclusively that viral load measurement using quantitative PCR and/or branched chain DNA assays (The two systems being developed to measure viral load) correlates with clinical outcomes. 2) Standardised kits of these two assays must be developed and approved by the regulatory authorities to ensure consistent results when the tests are run in different laboratories. 3) New drugs currently in the research pipeline most notably the protease inhibitors, and the NNRTIs must become available as soon as possible for use in widespread 3 and 4 drug combination access studies. 4)ADEC (The Australian Drug Evaluation Committee) must maintain the current standards for rapid evaluation and approval of promising new AIDS drugs namely that these drugs demonstrate reasonable safety and efficacy. Women's Issues Maternal Transmission of HIV. By Alan Strum Caesarean sections may reduce maternal HIV transmission by 4.6% NB : This study may not be applicable to Australian conditions. A study published in the American Journal of Public Health has indicated that there is enough statistically significant evidence to suggest that children can catch HIV during the birthing process and that reducing the risks of exposure to HIV at birth can reduce the numbers of paediatric HIV/AIDS in the United States. Generally approximately 25 - 30% of children born to mothers with HIV will eventually show signs of HIV infection, but these statistics vary between different countries. The study suggests we know that some children are born without HIV being detectable in their blood at birth, by testing directly for HIV genetic material (PCR). Approximately half of the infants with HIV can be detected at this early stage, but half go on to develop detectable levels of HIV over a period of time. This suggests that these children may be exposed to HIV at birth. A further reason to believe that children are exposed to HIV at birth is that the first born of twins often develops HIV infection while the second born twin does not. This suggests that the first born is exposed to higher levels of HIV during the initial birthing process, whereas the second birth is usually a faster birthing process not exposing the child to as much HIV in the birth canal. This particular study looks at the events that took place during the birth of 632 children with HIV/AIDS and compares the events that took place at birth to that of births in children without HIV. The results of this study suggest that there is a less chance of mother to child transmission of HIV if the child is born by caesarean section, followed by natural birth without complications, caesarean section with complications and natural birth with complications respectively. The statistics indicate that a problem free caesarean birth could reduce the rate of HIV births by 4.6%. The down side of this study is that it makes many assumptions based on the lifestyles and health of the mothers of which many may not be applicable to situations in Australia. Firstly, it was noted that there was a high percentage of mothers in this study who were from low socio-economic groups, had limited health care available to them in the USA, a high proportion of mothers were using drugs and there was a much higher incidence of sexually transmitted diseases. All or any of these parameters could effect the results and make it difficult to say that the same statistics would apply to Australian conditions. Not to mention that these statistics do not account for the most recent information about the use of AZT reducing the rates of HIV births by about 70%. However, this information could help to indicate when the most appropriate time might be to use antivirals like AZT to prevent transmission at birth. Source : American Journal of Public Health, July 1994, Vol. 84. No.7 News Management of HIV in Children By Alan Strum The U.S. Department of Health and Human Services has released a clinical guide for evaluating and managing HIV in children in the Unites States. The guide stresses the importance of early detection of HIV in children as they can tend to progress to AIDS quickly. In adults, generally, antibody tests will detect the presence of HIV within 3 months of exposure to the virus. In new born babies of HIV positive mothers, the antibody test is inappropriate as the baby initially carries the mothers antibodies to HIV up until 18 months of age. Thus it is necessary to carry out viral culture tests or tests to detect HIV genetic material (PCR tests) one month after the baby is born. If these tests are not available, p24 antigen tests can be used to determine whether HIV is present. If the tests are negative, they should then be repeated between 3 - 6 months of age. If at 6 months of age the tests are still negative, then they should have antibody tests at 15 and 18 months to further try to determine the HIV status of the child. During this time, CD4 cell counts should be obtained at 1, 3 and 6 months followed by every 3 months until the HIV status of the child is known. If the child does have HIV then a CD4 count should be done every 3 - 6 months. Monitoring the CD4 cell count can bring to the attention of the doctor any problems that might occur due to immune suppression and will also indicate when to consider prophylaxis against PCP (pneumocystis carinii pneumonia) or if antiviral therapy should be considered as shown by the CD4 cell counts for children in table 1. It is a bit confusing to look at this table if comparing CD4 counts of children to those of adults. In general, very young children have a much higher CD4 count than adults. However, opportunistic illnesses occur in children at much higher counts than they do in adults. Table 2 shows conditions that children may develop as a result of HIV disease. A particular issue is a range of neurological disorders that occurs in up to 19% of infants and young children. This figure may be as high as 90% in older children showing neurodevelopmental (eg co-ordination) delays or regression and neuropsycological (eg. intelligence, personality, and brain function) deficits. To monitor for these effects it is necessary to perform age related development assessments every 3 months up until 24 months, and then every 6 months. If HIV is affecting the nervous system/development, measures can be taken to lessen the impact of the virus' effects on the child's development. These measures could include nutritional supplementation, physical therapy, speech therapy, and early intervention programs. A baseline CT scan or MRI scan of the brain may be considered at the time of diagnosis so that a comparison can be made if neurological problems develop later in life. Source: The AIDS Reader, July/August 1994, Vol.4 No.4. Table 2: HIV-Associated Conditions in Children with HIV. * Failure to thrive * Generalised lymphadenopathy - swollen glands * Hepatomegaly - large liver * Spleenomegaly - large spleen * Persistant oral candidiasis - thrush * Parotitis - inflammation around the bones * Recurrent or chronich diarrhoea * Encephalopathy - any disease of the brain * Lymphoid interstitial pneumonitis - inflammation of the lungs * Hepatitis - inflammation of the liver * Cardiomyopathy - disease of the heart * Nephropathy - disease of the kidneys * Recurrent bacterial infections * Opportunistic infections * Malignancies (lymphoma) - cancer of the lymph tissue Questions raised about Nitrite Inhalants "Amyl/Poppers" and KS By Ian McKnight-Smith Over the last twelve to fifteen years that we have been diagnosing people with HIV and AIDS, one of the lingering controversies is the possible effect that using nitrite inhalants (poppers) has on the progress of the disease. In particular many have suggested that there is a direct association between using nitrite inhalants and the development of Kaposi's Sarcoma (KS). In the United States the sale of these substances has been banned since 1989, and it would now appear that similar moves are being considered in the United Kingdom. In May of this year the US National Institute of Drug Abuse convened a meeting to discuss the evidence surrounding the impact of poppers on KS and HIV progression. The result of this conference was that there was no clear result. However, the Scientists all agreed that this is still a very important question and that there should be active research to provide answers once and for all about the product. SOME OF THE ARGUMENTS IN THE DEBATE At the extreme of course is Peter Duesberg who claims that the nitrites are one of the principal causes of AIDS. His suggestions are that HIV is not the principal component in the epidemic and only acts as a co-factor. Many disagree with him, and now he plans to put his theories to the test with animal experiments. He plans to follow groups of mice who have been exposed to nitrites alone, nitrites plus HIV and HIV alone. However the problem with this approach is the inability of HIV to impact on mice in the same way that it does in humans. Some of the studies that have tried to look at the effects of poppers on groups of people with KS, in terms of their sexual and drug use history, have come up with very mixed and inconclusive results. In some cases the only factor which was shared by the people with KS was the use of poppers. Other studies have shown that only rimming (oral-anal contact) or a history of parasitic gut infections have been the only common factor. Research in animals have shown that nitrites can cause mutations, cancer development and deformities in the foetus. However there has been no research to indicate if this is also true in humans. However, there is some evidence to suggest that the use of poppers does have a suppressive effect on both animal and human immune system functions. Further it has been established that poppers can cause the depletion (even though in most cases temporarily) of chemicals that are of key importance to the functioning of the immune system. One such chemical is glutathione. Some researchers have suggested that the effects are directly linked to the frequency of use. This is very much in line with effects seen with cigarette use. So the person who is using poppers heavily and over a long period of time will be at far greater risk of immune damage and the development of KS than the person who uses only occasionally. Many researchers are sceptical of any direct association between poppers and KS. They argue that the evidence suggests that the more plausible data is that KS is caused by an as yet unknown sexually transmitted pathogen.Some of the evidence that supports this idea has been the development of KS by women partners of bisexual men with KS and in some cases with very similar forms of the illness. Further there have also been a number of cases of HIV negative gay men who have developed KS, and only in a very small proportion of these people had they been heavy users of poppers. One theory that has been proposed to support the transmission of a pathogen, is by Prof Don Abrams of San Francisco General Hospital. He suggests that the incidence of KS in HIV could be linked to the epidemic of gay bowel syndrome that was seen to peak between 1978 and 1982 in the larger US cities. San Francisco City Clinic Cohort has shown a history of amoebiasis as the only significant factor that can be linked to KS in their study cohort. A British study was able to demonstrate very similar relationships between the practices of rimming and faecal contact to the incidence of KS in a group of AIDS patients that they investigated. In addition the incidence of KS is not confined to gay men, but is seen extensively in certain communities in Africa. In these communities the incidence is the same in both males and females, and occurs in the complete absence of poppers. While Dr. Robert Gallo argues that the KS we see in people with HIV is very different to that seen in the populations of Africa, the symptoms are not that removed to suggest that it is being caused by a very different causative agent. Further more there is a considerable amount of evidence that has shown KS to occur in people who have never or only on rare occasions used poppers. Arguments have also been made that the incidence of KS would have moved outside of the gay male community into other communities that are affected with AIDS if it is directly related to a sexually transmitted pathogen. (e.g. the hispanic or black populations etc.) This has not largely been the case and therefore they suggest that this weakens the pathogenic theory. However others suggest that the sexual practices are different and indeed the practice of rimming etc. is more likely to be a gay activity. Further other infectious diseases have indeed tended to be confined to specific target populations such as Hepatitis B in gay men. DOES THE INHALATION OF NITRITES SUPPRESS THE IMMUNE SYSTEM ? Several studies have now been conducted to look at the effects of nitrites on the immune system of animals and humans. The first animal study of nitrites was reported in 1983, and dismissed their effects as insignificant. Critics of the study say this result was hardly surprising given the doses used, doses which one would expect to encounter if one left an open bottle of poppers in the room, rather than inhaling them directly from the bottle. Even though the mice were receiving comparatively low doses, they developed a yellowish skin tone and their white blood cell counts (cells in the immune system) went down. Later studies used larger doses and found correspondingly greater impairment of immune function. Researchers at the University of Arkansas found that mice exposed to nitrites for 45 minutes daily for 14 days in a row suffered serious impairment of their T-cell functions and the ability of their macrophages to control the development of potential tumours. Critics of this study point out that the mice were exposed to massive amounts of the nitrites and that it may well be toxic as would be the case with many other substances that we ingest. The only study to have taken place in humans gave normal doses of nitrites to HIV negative men three times a day for one week and then intermittently for a further one and a half weeks. By the end of this period the main defect in the immune function was in the levels of natural killer cells (NK), which recognise and destroy a wide range of infected body cells or tumour (cancer) cells. Levels of T-lymphocytes were not seriously affected and there was no selective effect on any of the sub- groups of T-cells. However researchers concluded that their evidence suggested that "chronic exposure to inhaled nitrites, even at relatively infrequent intervals, is sufficient to produce longer lasting alteration in lymphocyte functions... In humans, inhalation of volatile nitrites causes cycles of modest immunosuppression, particularly in natural killer cell activity, followed by a gradual recovery when the drug is not inhaled over several days...Nitrite induced suppression of natural killer cell may play a role in KS pathogenesis." While these studies can provide suggestive evidence, it is important to remember that they are far from conclusive. We don't know whether such changes in immune cell levels actually have any harmful effects. No studies to date have yet demonstrated that alterations to the NK levels correlate with any of the different patterns of illness, with the possible exception of KS. Even if poppers do cause immune suppression, this would not necessarily automatically result in the development of KS. In the absence of conclusive evidence, most experts feel that it is too early to make any hard and fast recommendations on the use of poppers. RESEARCH IS NEEDED A number of key issues need to be resolved through controlled research.. *To look at the incidence of KS in outlying cases, such as women, drug users and haemophiliacs and other subcommunities where HIV/AIDS is prevalent and to determine if there are any direct relationships between the use of poppers and the development of KS. At the same time it would be important to eliminate as many of the other variables as possible. In particular if there are any direct relationships of the sexual practices of the community and the development of KS. *To further investigate the effects of nitrites on the immune system. Are there different responses in people who are HIV positive etc. *Ongoing research into the other potential factors that may contribute to the development of KS. Is it an infectious agent that is passed on through certain sexual contact. More intensive study of KS occurrence in people who are HIV negative may also shed more light on this question. Our thanks to NAM Publications for allowing us to use some of the text from AIDS Treatment Update. Terms used in this article: Poppers: A slang term for amyl nitrite and related volatile chemicals that are often used as a "dance drug" or to increase the intensity of sexual pleasure. When inhaled it causes a dilation of the blood vessels, increased heart rate and a feeling of being "high". Pathogenesis: The mechanism by which an organism causes illness. Rimming: Oral to anal sexual contact. Natural Killer Cells: Immune cells which can recognise and destroy a wide range of infected blood cells, or tumour cells. Lymphocyte: A kind of white blood cell that is involved in immune function. Volatile: Able to evaporate into a gas or vapour at room temperature. Opportunistic Illnesses LIPOSOMAL DOXORUBICIN SUBMITTED TO AMERICAN AUTHORITIES FOR APPROVAL -- TRIALS IN AUSTRALIA SET TO START By Ian McKnight - Smith The liposomal formulation of doxorubicin (DOX-SL) has been submitted to the regulatory authorities in the US (FDA) for general approval as a treatment for Kaposi's Sarcoma. Liposomal Technology filed a new drug application, as a chemotherapy to treat symptomatic Kaposi's Sarcoma. DOX-SL is a liposome (fat) encapsulated formulation of doxorubicin (Adriamycin). This formulation helps the drug stay in the body longer and is supposed to reach its target, namely KS, in greater concentrations by using less drug and therefore with fewer side effects than the non-liposomal form of the drug. However unlike most conventional liposomes, it is composed of tiny spheres composed of durable and primarily biodegradable lipid (fat) membranes. DOX-SL is a trademark "Stealth" liposome that is surrounded by long chains of a substance called polyethylene glycol (PEG). These coated chains alter the surface of the liposomes and in doing so shield them from engulfment by the "phagocytes" in the human immune system. Thus the "stealth" liposomes are able to travel through the blood stream for longer periods of time and hence deliver their contents directly to the sites of the disease. It is therefore hoped that this form of the drug will deliver active ingredients more effectively. Results from phase I and II trials demonstrate that the drug is relatively safe and yields significantly higher response rates than those reported with standard doxorubicin. Northfelt and others (1993) showed that in their phase I study that DOX-SL has a half life in the blood of over 40 hours compared to free doxorubicin which has a reported half life of about 5 minutes. Further the active ingredient was detected in the KS lesions at a concentration that was between 5 and 11 times greater than the peak levels seen with standard doxorubicin. Side effects appear to be milder but include alopecia (hair falling out), neutropenia (low white blood cell count) and anaemia (low red blood cell counts). G-CSF is often used to avoid the problem of neutropenia. The cardiac (heart) problems that have been associated with the use of high dose doxorubicin have not been reported with the liposomal forms. Most recently, preliminary results on 48 patients on an early study in people with advanced KS showed a 66.7% (2/3) partial response rate (Thommes 1994). The average duration of the response before disease progression seen was in the order of 83 days. It is generally believed that if the drug is introduced earlier in the course of the illness the better the response will be, however this has yet to be seen in a clinical trial. Further many of the US studies with this drug now appear to have closed to recruitment to some of its trials. The only remaining studies are: i) An open access study where people can get DOX-SL if they have undergone a minimum of 2 cycles of systemic chemotherapy and have then progressed or have had to stop therapy due to toxicity. ii) There is also a comparative trial of DOX-SL versus a combination of bleomycin and vincristine. iii) It is also proposed that when DOX-SL is approved that a further study will be conducted to look at the effects of DOX-SL in combination with other drug groups such as vincristine and bleomycin After two years of protracted negotiations with Liposomal technologies International an agreement has been made on the protocol for an open trial to be conducted with DOX-SL in Australia. The study will be for treatment of moderate to severe AIDS related KS. People who will be eligible to enter this study are those who have AIDS related KS of an extent that is measurable and a severity that requires systemic chemotherapy. You will not be able to enter the trial if: *You are pregnant or breast feeding. *Had radiotherapy, electron beam therapy, cytotoxic chemotherapy, or interferon within the preceding three weeks. No previous radiotherapy or intralesional therapy to indicator lesions allowed. *Previous treatment with DOX-SL or other anthracycline drug of greater than 60 mg/m2 cumulative dose. *Have other neoplasms (cancer) treated with extensive chemotherapy. *Have significant cardiac disease, or active opportunistic illnesses. The initial standard dose of DOX-SL will be 20 mg/m2 administered intravenously. The dose will be decreased to 10 mg/m2 according to the toxicity and responses to the treatments. The treatment will be administered every six weeks until six cycles are completed beyond the best response measured in that person. A maximum of 40 cycles or an accumulative dose of 400 mg/m2 has been set as an upper limit of the treatment schedule. We understand that the protocol has now been prepared for submission to the ethics committee and then with this approval will start recruiting shortly there after. It is our estimate that this will be at the earliest in December and more likely in the beginning of the New Year. Refs: Northfelt D.W. et al Proc Am Soc.Clin Oncol 12:51 (8A) 1993. Thommes et.al.Proc Am Soc.Clin Oncol 13:55 (24) 1994. Clinical Trial News 935U83 - A New Antiviral Drug Trial Now Recruiting in Sydney. By Alan Strum 935U83, a Wellcome drug, is a new nucleoside analogue similar to AZT, ddI and ddC but targets a different part of the HIV reverse transcriptase enzyme. The 935U83 is different from the current nucleoside analogues as it is based on a different nucleotide (building block of DNA) called guanine. This means that this drug interferes with a different part of the HIV genetic material as the reverse transcriptase tries to convert the HIV into proviral DNA (the part of HIV that inserts itself into human DNA). As such, it is possible that this drug will have an entirely different side effect and viral resistance profile to the antivirals currently being used against HIV. Thus, if someone has HIV that is already resistant to AZT, ddI or ddC, this drug may still be able to inhibit the replication of these resistant strains. Laboratory tests in test tubes have shown that 935U83 does in fact inhibit HIV that is resistant to AZT or ddI. In the USA and Australia some trial participants have been taking 935U83 for up to 30 weeks with no particular side effects that can be attributed to the use of the drug. There have been 2 isolated incidents, one who has had an elevated liver enzyme result and one who has had an inflammation of the eye, but at this early stage it is difficult to tell if these incidents are related to the use of the new drug. The general feeling of this drug so far is that it does not have any significant side effects (unlike AZT with anaemia or ddI and ddC with neuropathy or pancreatitis), but it is still too early to tell. Early results of p24 antigen and HIV RNA polymerase chain reaction tests, to indicate the amount of virus in the blood, look promising, suggesting that the drug does inhibit HIV in humans, but more time is required to confirm these preliminary indicators. The trial itself is a Phase I safety and efficacy multi- national trial with 40 places available around the world, 10 of which are in Sydney. Of these places, only 5 are now still open for people who are interested in entering the trial in Sydney. The trial will run for an initial period of 12 weeks with an option to continue the trial for and additional 24 weeks (36 weeks all up). The 935U83 is to be taken in combination with ddI during the trial. It is possible that the drug may be made freely available to the trial participants at the end of the trial depending on whether the treatment is considered to be safe and effective. Conditions of entry to the trial are as follows ; - Main Inclusion Criteria *CD4 count between 100 and 500mm3. *No AIDS defining conditions including Kaposi's Sarcoma. *Must have tolerated and be currently using ddI for at least 3 months. Main Exclusion Criteria *Must not have had AZT or ddC for at least 3 months. *Must not be currently taking any other experimental drugs. People entering the trial will be randomised to different dosing regimes. Either ; - 100mg 3 x per day + 400mg ddI 200mg 3 x per day + 400mg ddI 300mg 3 x per day + 400mg ddI 500mg 3 x per day + 400mg ddI After entry to the trial all participant will be expected to attend a full days examination at day 3. A simpler examination and blood tests will be carried out every 2 weeks for the first 12 weeks. This will be followed by a blood test every 2 weeks with an examination every 4 weeks until week 24. After week 24 blood tests and examinations will take place every 4 weeks until week 36. All examinations and blood tests will be at the trial clinic at St. Vincent's hospital so it is not expected that participant will have to wait around for a long period of time ie:- the process is meant to be over and done with very quickly. There is, however, one small catch. There will be a randomisation of the 40 participants world wide for which some people will be expected to attend the clinic for 3 full consecutive days of tests. There is no telling how many, if any, people in Sydney will be randomised into this group. If randomised into this group, the drug company will reimburse the participant for any expected loss in wages over this time. For further information contact the trial investigator, Dr. David Austin - pager # 6807, or the trial nurse, Robyn Beckerleg - pager # 6419 at St. Vincent's Hospital on 339-1111.