HIV HERALD From The AFAO NATIONAL TREATMENTS PROJECT P.O. BOX H274 AUSTRALIA SQUARE SYDNEY NSW 2000 AUSTRALIA Ph: (02) 231 2111 Fax:(02) 231 2092 National Treatments Officer: IAN McKNIGHT-SMITH DECEMBER 1994 VOL. 4 No. 11 3TC WITH AZT COULD BE A REAL TREATMENT CHOICE By Ian McKnight-Smith There is growing agreement that the use of the nucleoside analogue 3TC (lamivudine) in combination with AZT can provide some benefits against HIV. It is important to point out, however, that current clinical reports have not demonstrated a clinical benefit in terms of survival or delay to disease progression. Later in this overview article we will report the encouraging results from the recent meeting in Glasgow. First, a review of 3TC (lamivudine) and the experience with it to date. The drug 3TC, now called lamivudine, is a nucleoside analogue. It comes from the same family as ddC, AZT etc. Clinical experience with the member of this family of drugs is quite long, with several studies conducted over several years showing it to be relatively safe with few serious side effects. As a result this drug has been available through expanded access in the United States and in Canada for several months, particularly for people who have CD4 counts of less than 300 and who are unable to take other drugs in this group. In earlier trials where 3TC was used as a single drug therapy against HIV, the results were far from encouraging. It was concluded that when the drug is used alone it has a very weak antiviral activity, although it was clear it was well tolerated, with fewer than expected side effects reported. Then came the news that laboratory tests had shown that when 3TC was used at the same time as AZT, the two drugs were synergistic in terms of their activity against HIV. In other words, the two drugs, when used together, work better than would be expected by adding their separate effects. It was proposed that this effect may be due to the 3TC acting as a protective agent against the development of resistance to AZT. That is, when the virus has the mutation which makes it resistant to AZT, it cannot exist in the presence of 3TC. Conversely, when the mutant strain to 3TC develops, this then renders it susceptible to AZT. Other researchers believe this effect is not the whole story, particularly as the synergistic effects are seen from the very first time that the two drugs are taken together. This of course is far too early for the development of resistant mutations to either of the drugs. AZT alone does not produce the same immediate improvement, even in people who have not taken AZT before and who would not have resistance. More work is ongoing to try and determine the true effect. 3TC MAY ALSO BE USEFUL TO TREAT HEPATITIS B IN HIV NEGATIVE PEOPLE Early reports also suggest that antiviral effects may be broader than the confines of HIV, and recent results suggest it is effective as a treatment for hepatitis B. In a study reported at the American Association for the Study of Liver Disease, the viral DNA to hepatitis decreased to such an extent that it was no longer detectible by the current testing methods. This occurred in 22 people treated with either 100 or 300 mg per day of 3TC. However after 12 weeks the treatment was stopped and within a four week time period the viral DNA levels had returned in 16 of the 22 participants. Interestingly the other six remained free of virus, of whom five had previously failed interferon therapy. The bonus of using 300 mg /day as the standard treatment dose used continuously for people with HIV will be the provision of sufficient effect against the hepatitis B virus, should they be exposed to both. Combined therapy using 3TC with AZT increases antiviral activity over longer time, study shows Using a combination of AZT (Zidovudine) and 3TC (Lamivudine) increases the drugs' ability to fight the virus and allows them to remain effective for longer, researchers reported at the Second International Congress on Drug Therapy in HIV Infection. A trial of the two drugs enrolled 129 people who had not taken AZT before, and who had CD4 cell counts of between 100 and 400. Participants were randomly divided into two groups -- one group received AZT at a dose of 600mg/day, while the second received a combination of 600mg AZT and 600mg 3TC every day. They were then followed over six months. At the end of the trial, all participants were offered open label 3TC for a further 24 weeks. The group receiving combination treatment showed a mean CD4 cell increase of 85 after between four and eight weeks of treatment. This was in contrast to the group receiving only AZT which showed an increase of 34 cells. Of greater interest, however, was the finding that the rise in CD4 cells in people receiving only AZT was quickly lost, with their CD4 cells returning to their original level before the study started. In fact, there was a mean fall of seven cells by week 24. This decay of CD4 cells was not seen in the group receiving combination therapy. In this group, CD4 levels remained significantly above baseline for the whole of the six months after being offered the open label 3TC. In some people, the levels remained high after 11 months. When viral load was measured in these groups, it was found that people given the combination treatment had a substantial drop in virus (as detected by the PCR test). More importantly, this drop in viral load (below 1 log) was maintained for the entire 48 weeks that they were followed. However, in those who were only treated with AZT, the viral load dropped by only 0.6 log, and these levels slowly returned to the starting point by the end of the 24 week period. The people who had been taking AZT only, and who started to take 3TC in combination at the end of the 24 weeks, showed a median increase of 40 CD4 cells and their viral load was reduced similarly to those who had been on 3TC and AZT from day one. The side effects reported by the group receiving both AZT and 3TC were not significantly different than those reported by the group taking AZT alone. Certainly the well known problems of neutropenia and anaemia (reduced blood cell counts) were not seen in any greater numbers in the combination group. A paper presented on the first day of the conference may shed some light on why this combination is working so well. It showed that 3TC added to AZT may not cause an increased antiviral effect on its own, but rather appears to strengthen the effects of AZT. In particular, it appears to prevent the development of strains of the virus that are highly resistant to AZT, which in turn are able to slowly weaken the effects of AZT treatment alone. So what does this mean to the person who is considering treatment with drugs like AZT? Clearly the use of the combination of AZT and 3TC may have a better effect than using AZT alone. If this effect is seen you should be able to stay on the treatment for a considerably longer period of time before resistance eventually develops. However, it's important to stress that from the results of studies looking at the effects of one year of treatment, it's not possible to say how long it will be before resistance develops. In addition it would appear that you would not be putting yourself at greater risk of side effects than if you were to use AZT alone. Of course it is still too early to say whether this will translate into greater delays of disease progression with survival benefits. Longer and bigger studies are needed to answer these questions. There is also good news for people who have already been using AZT for up to two years. A second study, similar in design to the one described above, was presented at the conference. There were three groups in this study -- one remained on AZT; another was given AZT and 3TC at 300mg per day; and another was given AZT and 3TC at 600 mg per day. Preliminary results from this study showed that the combination groups had increases in CD4 cell counts and decreases in viral load, despite the fact that they had already been taking AZT previously. Interestingly, there were no significant differences between the two doses of 3TC, suggesting that the 300mg dose may be just as effective as the 600mg dose. Again the responses to the drugs were sustained over the full 24 weeks of the study. The number of reported side effects was no higher in the combination group than in those who remained on AZT. Unfortunately there is no data to show whether the same kind of effects can be seen if ddI or ddC is used in combination with 3TC. However, there seems to be a consensus that the answer would be 'no', given the rational behind how 3TC works as a protector against AZT resistance. While people in Canada, Europe and the USA can now access 3TC through clinical trials or expanded access programs, it is not possible, at the time of going to press, to get the drug in Australia. These results show that the use of this combination of drugs offers benefits to both people who are starting treatment for the first time and to people who have already been taking AZT. It is a matter of extreme urgency that Glaxo, the manufacturers of 3TC, immediately starts making this drug available to people with HIV in Australia. It has been suggested that the prospect of further trials looking at three drug combinations -- AZT, 3TC and other antiretroviral drugs -- has led to 3TC being held back. These trials are very important and they should be done. But not at the expense of people who can derive real clinical benefits now, as has been clearly demonstrated in the three reports presented at the Glasgow conference. 3TC to be made available in Australia With the release of the results in Glasgow there has been an immediate need to make the drug available to PLWHA in Australia. As a result the Glaxo company, manufacturers of 3TC, has moved quickly to provide two ways that people may access the drug. However it must be emphasised that the effective use of 3TC is dependant upon your ability to take AZT, as there is little or no effect when taken alone. As a result, if you cannot take AZT due to side effects or any other reason, then 3TC will not be for you. The immediate actions proposed for making 3TC available are two fold: * The rapid commencement of a wide ranging phase III trial in Australia * The rapid introduction of a special access program for 3TC for those who would not be eligible to participate in the study. The trial will be a collaborative effort between the National Centre for HIV Epidemiology and Clinical Research (NCHECR) and The Community HIV/AIDS Trial Network (CHATN). Access to the study will be wide and will include most major cities throughout Australia. At the time of going to press, this will definitely include Sydney, Melbourne, Adelaide, Perth, Brisbane, Nambour, Cairns and the Gold Coast. Other sites are still being considered. This large International study is planned to start enrolling early in the new year (February) and will have at least 300 places available in Australia. Half of these will be given AZT and 3TC, a quarter will be given AZT and 3TC and another new antiviral agent called alpha APA (loviride). The remaining 25 per cent of trial participants will continue with their current antiviral treatment, which has to include AZT. To be eligible you should have a CD4 (T) cell count of between 25 and 250. Beyond that the restrictions are few, with people who have successfully used AZT before, and those who have never used the drug, being able to obtain a place in the trial. The National Treatments Project encourages people who are eligible to participate in the study to do so, since the early results are so encouraging. However, we still need to find out how good this combination is slowing the progress of the disease and whether it can provide a significant survival benefit. The trial will be conducted over a 12 month period and on conclusion, all participants will be offered any of the treatment combinations available in the study at no charge. A special access scheme is also to commence very early in 1995 and this scheme will have two initial components: * Immediate access to 3TC free of any charge, for anyone who has a CD4 count that is less than 25. * Free access to 3TC for anyone who has a CD4 count below 250. However, this will not commence until the clinical trial is fully enrolled. It is our belief that this study will recruit very quickly and therefore we anticipate that this component will be activated before mid-1995. Initial discussions with Glaxo appear to be very open and the company is keen to work closely with the community. In particular it is open to change as more information comes to hand, or if the conditions in the community were to change significantly. Finally Glaxo hopes to deliver its marketing submission to the Australian Drug Evaluation Committee in early- to mid-1996, but much of this is dependent on obtaining meaningful results from the current trial program. BETTER UNDERSTANDING OF COMBINATION TREATMENTS CHOICES By Ian McKnight-Smith It is becoming clear that single drug therapy using the current antiviral agents is going to lead to resistant forms of the virus. In some cases this resistance can develop very quickly, making the use of the drug alone impossible. We would hope that if we can reduce viral replication by using more than one treatment at a time, then we would be able to reduce the emergence of resistance. However this is still very much up in the air. The questions that still remain of course are what combinations we should choose, and when should such drugs be used in the course of illness? Dr Brendan Larder from the UK presented an interesting overview of the effect that two drug combinations have on the understanding of drug resistance and hence the way that decisions about treatments may be made. Apart from selecting combinations based upon our knowledge of side effects -- one of the objectives of selecting and increasing drug numbers is to keep the levels of side effects to a minimum -- we can get some information from looking at the effects of putting the two drugs together in the test tube, particularly in terms of whether there is an increase in the overall effects of the two drugs on the virus (this is called synergy) and to avoid a situation where the two drugs antagonise each other. Much can also be gained from understanding the ways that resistance develops when the two drugs are used together. For example it is not a good idea that when two drugs are used together they develop cross resistance to each other. Ideally combinations would be more useful where there is difficulty for the virus to develop resistance to both of the drugs at the same time. If we consider cross resistance for example, we know that AZT does not readily develop cross resistance with most of the other nucleoside analogues that are being used. That is to say it does not readily develop cross resistance to ddI, ddC, 3TC etc. Therefore this makes AZT a good candidate for combination with these antivirals. In terms of ddI and ddC they are closer related, particularly in terms of the sites where the resistance patterns develop, and indeed we now know that there is a high potential for cross resistance between these drugs. Therefore it would not be a wise move to use these two drugs in combination. The information included here will concentrate on the combinations of AZT and the other nucleoside drugs ddC, ddI and 3TC. Firstly a Wellcome study looked at the development of viral resistance in 180 people with CD4 counts below 300 who were given either the combination of AZT and ddC, or AZT and ddI. This was compared to the use of AZT alone as the "placebo". When looking at the effect of treatment on CD4 counts there was some advantages seen with the use of the combinations when compared with the AZT alone group. Interestingly there was no difference in the development of specific AZT mutations between any of the three groups. However there was a considerable difference in the levels of viral load. The AZT and ddI, and AZT and ddC, combinations showed a considerably greater decrease in the levels of virus as compared to the AZT alone group. Interestingly there was no statistical difference between the two combinations and in both cases there was a gradual increase in the viral levels by week 48 of the study, although they remained below the levels at the start of the study. In contrast the use of AZT alone resulted in levels returning to baseline during this time. When investigated further, evidence was still found of resistance to AZT, but there did appear to be suppression of the development of resistance to ddI or ddC, which probably translated into the sustained change in the blood markers. In the case of 3TC it was clear that the development of strong resistance to this drug, when used as monotherapy is very rapid. However when 3TC is introduced into an environment where there is highly AZT resistant virus, this resistance to AZT appears to be strongly suppressed even to the original wild type. The way this may occur is a greater ability of the virus to become resistant to 3TC, but if and when this occurs this mutant form of the virus is sensitive to AZT. In addition it appears that the development of co-resistance to 3TC and AZT at the same time is quite difficult. When a clinical trial was conducted to see the effects of using monotherapy and all three combinations in people with HIV and counts of between 100 and 400, the results clearly show that the best suppression of viral load was observed in the group given AZT and 3TC in combination. Again in this study when researchers looked at the types of resistance that was present at week 24, there was significant resistance to 3TC but either very low level or no resistance was present for AZT. However in the case of AZT and ddC, and AZT and ddI, the resistance to AZT was present but only low levels of resistance to the ddC or ddI. In summary, it would appear from this very early data that the AZT and 3TC combination may provide a longer lasting and more effective therapy against HIV, due to its ability to suppress and protect AZT from high levels of resistance by the virus. Clearly this needs to be tested in terms of clinical effects. SEXUAL TRANSMISSION OF AZT RESISTANT STRAINS By Ian McKnight-Smith Professor David Cooper of the National Centre for HIV Epidemiology and Clinical Research presented a paper on the isolation of AZT resistant strains of HIV in people who were examined during the seroconversion phase of HIV infection. Background Information that the transmission of AZT-resistant strains of HIV was occurring was first published in the New England Journal of Medicine, which documented a single case of transmission that was directly attributable to a person who was already resistant to AZT. The very same resistance profile was observed in the person who had become infected and the host partner. Further, this resistant form was seen to persist beyond the seroconversion phase. A further study demonstrated very similar results after looking at 26 people who were seroconverting. In this group three people who had received AZT resistant forms of the virus at the time of infection were identified. Researchers also managed to track the virus to the resistance profile of the sexual partner who had been the source of infection. In another case that looked at two children, one was infected by perinatal contact and subsequently developed AZT resistance after treatment. This was then transmitted via bodily fluids to a second child in the same household. The second child demonstrated the same AZT resistant strain as the first even though the child had not been treated with AZT. Furthermore, this resistance persisted beyond the seroconversion phase. A further study looked at an injecting drug user who had been treated with AZT and who subsequently infected his female partner with an identical form of the virus. The Australian Study A total of 52 isolates were studied for people who had seroconverted between 1987 and 1994. In all cases the mode of infection could be identified. In most, the isolates have come from young gay men who were infected by sexual transmission and who were then followed through the period of the seroconversion illness. The average time to seroconversion was 22 days after the onset of the symptoms. Five people in the group were identified as having resistant isolates to AZT. The source of infection could be identified in all five. In one case there was the same resistant strain in the infecting partner and who had a history of taking AZT for a period of 25 months prior to this event. In five cases, both of the sexual partners had been well documented. In all cases the isolates were identified as being non-syncytia forming virus, and were the same in each pair of partners examined. In one case, a follow up study showed that although he had resistant virus at the time immediately after seroconversion, this changed with time and by one year the resistance had been lost and the person was again fully sensitive to AZT. This suggests that resistance may not persist in all cases and this may be due to the immune system having sufficient strength at this stage of the illness to provide some protection against the mutant forms of the virus. Professor Cooper went on to give some indication as to how common AZT resistant transmission is within the overall incidence of HIV infection. Assumptions made were as follows: In a population of people with HIV and AIDS taking AZT the levels of resistance in that group are : with HIV with AIDS 1 year 30 per cent 90 per cent 2 years 50 per cent 95 per cent 3 years 70 per cent >95 per cent In a number of studies around the world, evidence is mounting of an increase in the levels of AZT resistant virus being transmitted, and the kinds of levels suggested and supported by the Australian experience are of the order shown below: 1988-91 3 per cent 1992 8 per cent 1993-4 19 per cent Clearly this is an increasing problem that may well translate into some people in the community having persistent AZT resistant strains and who may develop HIV disease that is more difficult to manage. As a result, these people may progress more rapidly than those who are sensitive to AZT therapy. First trial of Abbott protease inhibitor shows 'promising' early results By Ian McKnight-Smith The first trial results for the Abbott protease inhibitor, ABT-538, were presented at the Second International Congress on Therapeutic Drugs in HIV Infection. A protease inhibitor is a drug that works by blocking an enzyme responsible for HIV replication in infected cells. The study (a phase I/II trial) was designed to look at the safety and efficacy of this new drug in people with HIV. Participants were randomly divided into two groups, one of which received a placebo. It also tested for different doses of the drug (300, 400, 500, and 600mg given twice daily), and was conducted in Spain and Australia. All participants had stopped all antiviral treatments for at least three weeks before starting the trial. The people in the study were male, with CD4 (T-cell) counts above 50. The average CD4 cell count on entry to the trial was 130. Previous use of protease inhibitors was not allowed. The study measured CD4 counts, p24 antigen levels (a part of the virus in the blood) and viral load (amount of genetic material free in the blood stream). The results showed that the 400mg dose had a dramatic antiviral effect. A slightly less antiviral effect was seen with the 300mg dose. There was some evidence of a dose- related effect, with the higher doses giving the greatest effects. The average increase in CD4 cells was 100-150 cells/mm3 above baseline. In the higher doses, this was greater than 200 cells/mm3. The increase was sustained for the full four weeks of the treatment. When treatment was stopped, there was a general decline back to baseline. All people in the trial were given the opportunity to continue treatment on an open label basis for a further eight weeks. The increases of CD4 cell counts in people who continued treatment remained sustained. The median increase of CD4 cell counts during this period from baseline was greater than 200 cells/mm3. The good responses in CD4 cell counts was seen in people with low or high cell counts on entry into the trial. The measurements of viral load, as gauged by branched chain DNA tests, also showed a dramatic fall in the levels of detectable virus. The average reduction was as great as 100 per cent at the higher doses, which reduced the viral load to levels too low for the test to be able to detect the virus. There were few side effects. The only reports that were directly attributable to the drug were rises in trigylcerides (fats in the blood) and some reports of people's tongues becoming numb up to two hours after taking the drug (anaesthesia of the tongue). In patients who continued to take the protease inhibitor in the maintenance phase, huge increases in CD4 counts were maintained for the 12 week period. In some cases the increases were quite dramatic, with one person increasing from 200 cells to 700 cells/mm3. In many cases with this group, the viral load remained undetectable. However, at the lower doses (300/400mg), there was evidence in some people of viral load increases after five and six weeks. This viral load increase was not evident in the higher doses (500 - 600mg). Conclusion ABT-538 is well tolerated and is safe. It causes a significant reduction in viral load when taken in higher doses that is sustained for 12 weeks, indicating an almost complete shut down of viral production. Although these results are encouraging, we must not lose sight of the fact that it is early days, and questions still need to be answered: how long will the effect be sustained? When does resistance develop and how strong is it? Is there cross resistance with other drugs of the same class? Will this translate into clinical benefit? Further dose/efficacy studies are ongoing, particularly using doses given three to four times a day, so that the peak blood levels of the drug can be held at higher concentrations to possibly combat the virus more effectively. SAQUINAVIR RESULTS REPORTED IN GLASGOW By Ian McKnight-Smith A number of papers on early clinical trials of the new protease inhibitor saquinavir were presented at the Glasgow conference. Protease inhibitors are a relatively new class of treatments that prevent the assembly of the pieces of the virus once they have been produced within the cell. This is in contrast to the current antiviral treatments called nucleoside analogues which try to prevent the integration of the viral genetic information into the cell so that it can become a factory for producing new virus. Initially three early dose ranging trials from France, United Kingdom and Italy were reported, for a total of 202 patients treated with saquinavir at different stages of their illness. Some of the studies also looked at combining saquinavir with AZT. In these studies four doses were used -- 25, 75, 200 and 600mg -- and were given three times a day. The study period was 16 weeks. The English study evaluated the effects of these four doses of saquinavir on people who had not taken antivirals and who had little or no symptoms, but a CD4 count of less than 500. The French study was performed in 61 previously treated (AZT) people with CD4 counts between 50 and 300. In this study only the three higher doses were used and as single drug therapy. The Italian study investigated both mono and combination of saquinavir with AZT and involved 92 (CD4 < 300) people who had not taken antiviral treatment before. In this trial the participants received one of five treatments: saquinavir 600mg three times a day alone, AZT 200mg three times a day alone, or 75, 200, or 600mg saquinavir three times a day in combination with AZT, 200mg given three times a day. Saquinavir was very well tolerated by all participants in these trials and there were very few side effects. Many of the participants elected to continue treatment after the 16 week study was completed. However, the effects of this agent on surrogate markers was disappointing at the doses used in these trials. Only the highest dose of 600mg when given three times a day resulted in any significant increases in the CD4 counts. Furthermore this increase was not sustained beyond six weeks of treatment. However, the researchers indicated that in many cases the treatments were given at advanced stages of HIV disease and many had more than a year on AZT prior to this study. The results as would be expected indicated that the combination of saquinavir and AZT was more effective than the single drug therapy. Similar trends were seen when viral load measurements were made using HIV-DNA and RNA by PCR testing. However, the overall effects did not appear to be great. It was also clear that resistance develops by mutations of the virus and a significant number (20 per cent) of the participants had developed saquinavir resistance by week 20 if the treatment is used alone. Resistance appears to develop much more slowly when used in combination with AZT. A further report of the ACTG 229 study was presented by Dr. Michael Saag from the University of Alabama. This study looked at the safety, tolerance levels and antiviral activity of saquinavir in combination with AZT and/or ddC. The group recruited had CD4 counts between 50 and 300 and had already been taking AZT for at least four months prior to entry into this trial. The treatment duration of this study was 24 weeks. Among the 302 participants in this trial, 91 per cent were male and had a mean age of 38 years and a median time of AZT use prior to the study was 25 months. So many had been using AZT in excess of two years. 36 per cent of the participants had also been using AZT and ddC for more than one month prior to entering the trial. The median CD4 count was 158. The triple combination of saquinavir,ddC and AZT was seen to give the greater reductions in viral load and the greatest increases in CD4 count (30 per cent above baseline at highest point) and were sustained above the starting points over the 24 weeks of the study. There was evidence of decay towards baseline in both the double and triple drug treatment groups. The measures of viral load also indicated that the triple drug user group had the greatest fall in viral load as compared to the two drug combinations, with 44 per cent showing greater than one log fall in the former group but only 22 per cent had the same falls in the two drug groups. This relatively weak reduction may in part be due to the fact that the group as a whole had already been using nucleoside analogues (AZT/ddC) for a significant time prior to entry into this trial. It is interesting to note that there was very little increase in the levels of side effects experienced with the already established effects of the two drug groups as compared to the addition of saquinavir as a triple drug treatment. It may be concluded from these results that saquinavir certainly is active as an antiviral agent, but at the doses that were used in the studies reported the effects were weak, even if in combination with other antiviral treatments. The benefit however, appears to be that the drug has a relatively low level of side effects and that the addition of the drug to current combinations of treatment does not increase the overall side effects experienced. It is known that one of the problems associated with this drug is that the current formulation is particularly poorly absorbed into the blood stream. Indeed these results suggest that the doses used in these studies may be too low to get an adequate amount of the drug to the sites where it can be effective against the virus. There is need to study higher doses or ways that higher blood levels can be obtained. PBAC Removes fluconazole out of hospital reimbursement scheme By Ian McKnight-Smith The Pharmaceutical Benefits Advisory Committee (PBAC) has, without notice, announced that fluconazole (Diflucan) will be taken off the section 100 listing as of January 1, 1995. This means that the dispensing of this drug through hospital pharmacies will no longer be reimbursed by the health scheme. After the National Treatments Project made some enquiries, it found that little or no consultation has been entered into when making this decision. Certainly the manufacturer (Pfizer) and the Highly Specialised Drugs Working Party were not consulted. To date fluconazole has been reimbursed both through the section 85 (PBS) and section 100. The PBS allows for dispensing and reimbursement of drugs that are prescribed by your general practitioner, which you then have filled at your local chemist shop. Section 100 applies to reimbursement for scripts presented to the hospital pharmacy. PBAC has indicated that it does not support such dual listing. However the need for a section 100 listing in addition to the PBS listing for this drug is based on the fact that serious AIDS illnesses such as cryptococcal meningitis, that respond to the use of this drug, are more likely to be managed by specialists in hospital/clinic settings than by the general practitioner. As a result, there is considerable amounts of dispensing of this drug through outpatients departments in the larger HIV/AIDS dedicated hospital units. It is important to note that Fluconazole is still available, as it remains on the PBS. General practitioners and specialists will be able to prescribe once they receive an authority approval by the Department of Health. However, the impact of this change on people living with HIV/AIDS is likely to be significant, since hospital pharmacies will find it difficult to absorb the cost of fluconazole. This is due to two reasons. Firstly the drug is usually given at high doses, and second it is already a relatively expensive drug. Some major centres already canvassed by NTP have indicated that they will not be able to absorb the cost and will be sending patients to their general practice. People with HIV/AIDS who normally attend hospital/specialist clinics will in many cases have to then see a general practitioner to obtain a script for fluconazole. Some specialists can prescribe, but this at best will still have to be taken to a retail pharmacy. There is also a potential cost impact for the patient. Sharpe's Pharmacy in Sydney, for example, detailed their charges for fluconazole after being contacted by the NTP. Standard scripts for one month of therapy are estimated to cost the patient $16.20. Health card holders and pensioners will have a cost of $2.60 per script. Those who have reached health net limit will have no charge. In essence this move increases the stress of obtaining essential medication for people living with HIV and AIDS, both in terms of the physical inconveniences and the further financial burden on what is already a hard task when trying to make ends meet. The gains to be made in terms of savings on the overall health care budget are relatively small and it seems that this decision has been made without a complete understanding of the situation, and should be reversed. THE ORAL GANCICLOVIR STORY By Ian McKnight-Smith Some background Information Initial presentations on this product compared the ability of the oral and the intravenous formulation to establish similar blood levels at the sites where they act in people with CMV disease. Unfortunately the bioavailability of the oral formulation of ganciclovir is not high, with only between six and nine per cent of the administered dose actually getting into the blood stream. However as would be expected once the drug enters the blood stream it behaves in a very similar way to that seen with the intravenous formulation. It was reported that the poor absorption could be improved by up to 20 per cent when the oral form was taken with food. The results of pharmacokinetic studies therefore suggest that if the drug is given in the presence of food and at a dose of 3000 mg per day, (given either three or six times a day) the blood levels can reach adequate therapeutic levels and this cleared the way for use in a clinical setting. It was noted that there is a significant interaction between oral ganciclovir and a number of the antivirals that are used to treat HIV (AZT etc.). However the most significant and most likely to have a clinical impact was the effect with didanosine (ddI), which was seen to more than double its serum concentrations when given with ganciclovir. This of course may well place people at greater risk of experiencing the side effects that are associated with ddI and hence dose adjustment will need to be considered. However it was also noted that while the concentrations of ddI went up the absorbed concentrations of ganciclovir fell by about 20 per cent and this again may have to be considered since there is already a poor absorption of the drug. The European Experience of Oral treatment for Maintenance Treatment Two European researchers (from Paris and Amsterdam) presented information about two trials that have looked at the efficacy of oral ganciclovir in the treatment of CMV retinitis. Some of this work was conducted here in Australia. A 20 week study looked at the effectiveness and side effects of using 3000mg/day of oral ganciclovir as compared to the standard maintenance regimen of 5mg/kg/day given intravenously. It is important to note that this is a trial of people who have already completed induction therapy and have entered the maintenance phase of treatment. A total of 112 people were given the oral preparation while 47 received the intravenous formulation. Two techniques were used to assess if there was any change in the progression of the retinitis, firstly by physical examination of the eye by the clinician (funduscopy) and secondly by use of photographic techniques. There appeared to be little difference in the progression of the disease when comparing the two groups by either technique used. However, the photographic assessment showed a clear trend to providing more accurate and quicker diagnosis of changes to the disease status. By assessment of photographs, CMV retinitis progressed in 72 per cent of people who were taking oral ganciclovir and 76 per cent of those using the intravenous formulation. These two figures were not significantly different. The average (mean) time to progression starting in people using the oral ganciclovir was 51 days from the time of starting treatment, while it was 62 days in the group given the intravenous formulation. Again this was not significantly different at the 0.05 level. When these results were compared to the direct examinations made by the clinician (funduscopy), CMV retinitis progressed in 59 per cent of people on oral ganciclovir and 43 per cent if given the intravenous form. Interestingly the time to progression was 86 days in the case of the oral form and this was significantly different (at 0.02 level) to the intravenous group with 109 days before detecting progression. It was interesting to note that the study also looked at people who were antiviral treatment naive as against those who had had experience with treatment previously. There was some trend to longer time to progression in the naive group as compared to those who had treatment previously, but this did not reach statistical significance. In terms of side effects being reported the conclusion made by the researchers was that both formulations were well tolerated. The oral formulation however reported significantly lower levels of sepsis -- three per cent in the oral group versus eight per cent in the intravenous (toxic infections often at the site of intravenous) -- and neutropenia, with 14 per cent in the oral group versus 23 per cent in the intravenous group (a decrease in a particular form of white blood cell called a neutrophil). In contrast, there appeared to be a trend towards higher levels of diarrhoea in the oral treatment group. Increases in reports of rashes were also reported in the orally treated group. It can be concluded that the use of the oral treatment appears to be effective in terms of slowing the progression of CMV retinitis in a group of AIDS patients. In addition the oral formulation is well tolerated, and may therefore provide an effective alternative to the inconvenient and often traumatic use of intravenous ganciclovir therapy. Confirmation from the other side of the Atlantic Kathleen Squires from the United States presented results from two similar studies (1653 and 1774). One trial looked at people who were newly diagnosed with CMV retinitis, while a second study looked at people who had already had CMV treatment before the trial entry. There were 123 participants in the newly diagnosed group, therefore all went through a standard regimen of 21 days of induction onto treatment with intravenous ganciclovir. In contrast there were 237 participants in the previously treated group. As with the European studies, they looked at the time that lapsed before there was evidence of progression of the CMV, i.e. where the treatment no longer appeared able to keep the disease under control. Participants were randomised to either standard intravenous ganciclovir or one of two groups that received 3000mg of oral ganciclovir. The only difference between the latter groups was how often they had to take the treatment. Time to progression and the differences in times to disease progression between the intravenous and the oral groups were similar in both studies as shown in the table below: STUDY 1653 STUDY 1774 Newly diagnosed Previously treated Intravenous Time to Prog. 62 days 66 days ORAL Time To Prog. 57 days 54 days Differences 5 days 12 days Again there is a trend towards a shorter disease free period for the oral group, but they were not statistically different to the intravenous groups. Again as in the European studies there was a lower incidence of neutropenia in the orally treated group (see table below). Again as expected the incidence of sepsis was lower. I.V Treated Orally Treated Neutropenia 25 per cent 18 per cent Conclusions *Oral ganciclovir is an effective alternative to the intravenous formulation to treat CMV retinitis in people with AIDS. *Oral ganciclovir may have a more rapid progression to treatment failure and disease progression than the intravenous formulation. *Oral preparations appear to have lower levels of the side effects of neutropenia and sepsis. What about the use of oral ganciclovir as prophylaxis against CMV retinitis? A late breaker paper was presented by Dr. Squires about some preliminary data about the use of oral ganciclovir as a means of preventing (prophylaxis) the development of CMV retinitis. This trial looked at primary prevention, i.e stopping the onset of the first attack of CMV disease in a group of people who had not had symptoms of illness previously, However this group had a CD4 count (less than 50 or up to 100 if the person had experienced another AIDS illness) that would put them at increased risk of developing the illness. All participants were identified as being CMV positive -- that is, they had been exposed to the virus at some point in the past. A total of 725 participants were randomised to receive either oral ganciclovir or placebo, the absolute numbers are shown in the table below. The active treatment given was 1000 mg a day given in three doses over the day. The study was conducted on an intent to treat basis and these are but interim results of an ongoing study. Ganciclovir Placebo Numbers 486 239 Mean CD4 count 21 23 Time on study 361 days 340 days Average time of treatment 304 days 251 days* *This being due to the increased number of AIDS events All incidents for drug discontinuation 56 (12 per cent) 58 (24 per cent) Incidence of CMV disease 76 (16 per cent) 73 (30 per cent) ** Incidence of CMV retinitis 52 (11 per cent) 47 (20 per cent) ** Survival. There is a trend toward better survival times in the ganciclovir group, but it is yet to reach a statistical difference. (**statistically difference at p 0.05) Pancreatitis 2 per cent 1 per cent As would be expected there was a higher incidence of side effects in the ganciclovir treated group. In particular there was an increase in the incidence of leucopoenia and anaemia. There was some suggestion that there may be some negative effects on the kidney and liver functions (see above re pancreatitis), but this needs to be more closely studied. Conclusions: *Oral ganciclovir prophylaxis reduces the incidence of CMV disease in people with low CD4 counts. *Oral ganciclovir also delays the development of CMV disease. *Oral ganciclovir may increase the time of survival in people with HIV who are CMV positive and have low CD4 counts. * Oral ganciclovir is relatively well tolerated but is associated with increased levels of side effects such as leucopoenia and anaemia. There is some concerns about creatinine clearance that warrants further investigation. From this study it may also be concluded that rapid development of broader access programs needs to be considered for people who fit these criteria in Australia. Like the conditions set with the use of Glaxo's antiviral drug 3TC, this may be best achieved with a new and wider ranging clinical trial that is started as soon as possible, and the concurrent development of a special access program for those who cannot participate in the trial. There is a meeting of the Syntex Advisory Board on the 20th of February 1995 where it is anticipated that these issues will be raised. SOME CURIOUS RESPONSES USING FOSCARNET FOR KAPOSI'S SARCOMA By Ian McKnight-Smith A late entry into the proceedings was a presentation by Dr. Linda Morefield, from New York, who reported her findings on the use of foscarnet in treating people who had advanced KS disease. The report was only for five patients and was in open label uncontrolled conditions. Each patient was described individually and will be summarised below: Patient #1 Person with advanced KS who had also been treated for PCP. He was treated with standard doses of foscarnet for a period of 10 days. All lesions exhibited regression with time and in some cases they resolved almost completely. They remained in remission for a period of 10-12 months when the lesion numbers and size returned. Patient # 2 The patient had experienced an episode of active TB and when this was resolved he was then treated with foscarnet. As in the first case he exhibited significant reduction in the size and intensity of the lesions associated with his advanced stages of KS. Nineteen months after treatment he still was considered to have significant regression of the KS. Patient #3 This patient had not experienced any other opportunistic illnesses apart from the development of KS. Again he was given a standard 10 day course of foscarnet. As was the case in the other patients he exhibited a significant slowing of his KS with no new lesions being reported and in some cases evidence of regression. Eight months after the initial treatment he was given a further course of foscarnet and has remained in remission for a period of 18 months. Patients #4 and #5 There was little evidence of change in the progress of the KS. However the author pointed out that they were both severely immuno-compromised and had a history of opportunistic illnesses which continued. Clearly we cannot draw any firm conclusions from what is essentially anecdotal information. However it is interesting enough to suggest that more work should be done and under conditions that allow easier clinical evaluation. Maybe this is the starting point for a clinical trial, which could very easily be conducted either by the National Centre or probably more appropriately at the community level by the Community HIV AIDS Trials Network. It would also be of interest to hear any similar reports that might have occurred here in Australia -- for example, in association with the use of foscarnet to treat CMV and where an individual concurrently witnessed a decline in KS. If you have such experiences we would very much like to hear about them at the National Treatments Project. You can subscribe to all of the publications produced by the National Treatments Project. Just send your name and address to: The National Treatments Project c/o Australian Federation of AIDS Organisations P.O. Box H274, Australia Square Sydney NSW 2000 Australia. Apart from the HIV Herald we also produce: HIV Briefs.....A comprehensive coverage of individual treatments issues HIV Brief, Fact Sheets...A summary of a drug or illnesses associated with HIV. Booklets... Dealing with broader topics such as entering clinical trials and the development of a working relationship with your general practitioner. Australian Trials Directory...A summary of HIV/AIDS trials in Australia NEW TITLES ARE IN PREPARATION ALL THE TIME A complete list of titles can be obtained by contacting the project