BBS Edition Distributed By HIV Information & Support BBS +61 2 818 2876 HIV Herald, Volume 5, Number 2, March 1995. The HIV Herald is the monthly magazine of the National Treatments Project and is devoted to providing reliable information on treatment options for people with HIV/AIDS and associated illnesses. At no time does the National Treatments Project recommend particular therapies. The National Treatments Project is funded by the Commonwealth of Australia through the Department of Health and Human Services. This funding is given through the auspices of the Australian Federation of AIDS Organisations. The National Treatments Project PO Box H274 Australia Square Sydney, 2000 Phone: (02)231.2111 Fax: (02)231.2092 AFAO Treatments Working Group Colin Batrouney Geoffrey Harrison Ross Duffin Ian McKnight-Smith Andrew Fenton Don Baxter Paul Van Ryke (convenor) HIV Herald Editorial Advisory Group Gerald Lawrence Peter Hornby Dr Jenny Hoy Dr Graeme Neilson National Treatments Project Officer: Ian McKnight-Smith Sub-editor and Publications Officer: Megan Nicholson Thanks to Bristol Myers Squibb for supporting the HIV Herald. STOP PRESS STOP PRESS STOP PRESS THE SPECIAL ACCESS SCHEME FOR 3TC CHANGES At a meeting held on March 1 1995, involving representatives from Glaxo, health providers and the HIV affected community, there was a general agreement on changes to the 3TC Special Access Scheme (SAS). The conditions of immediate availability to 3TC are: 1. Anyone who has a CD4 count that is less than 25 2. Anyone who is intolerant to AZT. The program is an honour system and will only require a 'tick of a box' and the SAS application will be processed. At this stage, it is advised that applications for use of 3TC should be made by registered prescribers of anti-retroviral therapy, that is the nucleoside analogues (AZT, ddI and ddC). The company is investigating this restriction to see if the SAS can be expanded to other clinicians. The second phase of the SAS will begin when the clinical trial using combinations of AZT, 3TC and alpha APA (loviride) is fully enrolled. Alpha APA is an additional antiviral that is one of a class of drugs known as non -nucleoside analogue reverse transcriptase inhibitors. The National Treatments Project estimates that this trial will enrol quickly and the second phase of the special access scheme will open around the middle of this year. The second phase will permit anyone who has less than 300 CD4 cells to access 3TC. This may be as single treatment, or in combination with AZT; the most promising results have been occurred when using this combination. A PROTOCOL CHANGE There is a small change to the entry criteria for the clinical trial of 3TC combinations. In the original protocol people currently using AZT were required to have been taking it for at least four months to enter the trial. This restriction has now been removed from the protocol. 3TC UPDATE By Ian McKnight-Smith The process of making 3TC available to people with HIV in Australia has been difficult, largely due to bureaucratic forces in Australia and the United States, impeding the process. The Federal Drug Administration (FDA) in the US must approve an export license to enable the export of drugs such as 3TC to Australia. This normally takes about six weeks if the government regulatory bodies of the two countries talk to each other, and up to eight weeks if the US is left to its own devices. After ten weeks, the export license for 3TC has now been approved. 3TC is currently available on special access schemes in the USA, Canada and Europe. Until the recent approval of 3TC for export to Australia, only a small amount of 3TC was available in Australia. A small shipment of 1000 bottles of 3TC was imported from Canada where there are no export restrictions. Each bottle contains 70 tablets and provides 35 days treatment of 150 milligrams (taken twice daily). Under the Special Access Scheme protocol, each recipient of the drug will immediately receive two months treatment. There should be enough 3TC being currently held by Glaxo to treat 500 people over the next couple of months. The FDA approval of the drug export license will mean that further stocks can be imported. The expanded access scheme in the UK and most European countries has been for those people who have less than 300 CD4 cells, or T4 cells (the immune cell which HIV infects), and who have used or are unable to take AZT and the other anti-retrovirals. However the evidence suggests that the use of 3TC is most effective when combined with AZT and much of the ongoing studies are on this basis. In fact early reports suggested that 3TC alone was virtually ineffective. More recent reports show that 3TC does have some antiviral effect when used as a single treatment, although this effect is relatively short lived because of the rapid development of resistance. When putting it all together however the data still suggests that greater benefit is achieved by using 3TC in combination with AZT, even for people who have developed resistance to AZT. The Special Access Scheme for 3TC in Australia is currently restricted to people who have less than 25 CD4 cells and who demonstrate an ability to tolerate AZT or for those who have less than 300 CD4 cells and have a demonstrated intolerance to AZT. The latter group being able to access the drug as a single drug treatment. These conditions are to remain in place until the 300 places in the AZT/3TC study are filled. Glaxo has given an undertaking that they will then provide 3TC to all people with HIV who have less than 300 CD4 cells and are also able to tolerate AZT. There will be little difficulty in filling all trial places. The National Treatments Project (NTP) contacted some of the sites conducting the trial and many have a waiting list of people wanting to enter the trial. We understand from Glaxo that the trial will begin recruitment in early April since the FDA approved the export license in early March and there appears to be no further hitches in the shipping the 3TC to Australia. If you are considering entry into this study, contact your local AIDS Council or NTP to find out centres near you that will be participating in this study. The detailed conditions for participating in the study were included in the December 1994 issue of the HIV Herald (Vol 4 No.11) and can be obtained by calling us at Australian Federation of AIDS Organisations on (02) 231.2111. Entry and Conditions of the Special Access Scheme If you have a CD4 count less than 25 or you are under 300 and intolerant to AZT you should discuss entry into the Special Access Scheme with your doctor. The procedure involves your doctor writing to Glaxo for the documentation to start a person on the scheme, called the 3TC SAS Treatment Protocol and a Category A Authority to Supply form. These forms have to be filled our by your doctor and include some details about your current health status, such as your CD4 count. The doctor sends these forms back to Glaxo and a copy of the Authority to Supply form must also be sent to the Therapeutic Goods Administration (TGA) which is part of the Department of Human Services and Health in Canberra. If you meet the criteria, Glaxo will issue drugs for two months immediately. The company also assures the National Treatment Project that follow up therapy will be promptly supplied if paper work completed by your doctor is sent back regularly. This treatment is free. The participants have some obligations. Your doctor has agreed to report changes in surrogate markers such as CD4 count, before, during and after treatment. In addition, any side effects you experience while on the trial should be reported to Glaxo, who will inform the TGA. Your doctor will ask you to have monthly visits to collect this information, to ensure ongoing supplies of 3TC. Delays in the 3TC Study The starting date for the study has been put back to early April, due to the delay in the approval of the export license, which effected the stock to be used in the trial. The institutional ethics committee have recently approved the trial protocol and patient information sheet, a process which must occur before any trial can begin. In early March, the export license for 3TC was approved. COMMENTS ON THE 3TC STUDY Researchers and Glaxo refer to the 3TC study as the vital study that will produce data about the 'clinical endpoints' associated with the use of 3TC. Trials using 3TC have so far just looked at markers such as CD4 counts. This new trial will look at the health and survival of people taking 3TC, that is test to see if the drug has real clinical benefits. Clinical endpoints include progression of the illness, and survival. Some researchers in Europe will also measure changes in the amount of virus in the blood and relate these changes to differences in the clinical endpoints, however this will not to be a part of the Australian study. The trial will provide important pieces of information; for example, it will establish if thecombination of drugs offers a sustained clinical benefit in this group of people with HIV. Certainly we do not want to repeat the history of AZT which was used without some knowledge of factors such as rate of progression to illness, . However, the question that people are asking is whether this knowledge can be gained successfully while providing the drug to those people who need to get the therapeutic benefits now. This would include people who have more advanced stages of the illness, those who are resistant or who are intolerant to AZT, those who are geographically remote from the sites conducting the trial, and others not participating in the trial. I think in all cases there are powerful arguments regarding why their access to 3TC should not be restricted. However there may not be a problem as the reports from around the country are that the trial will fill rapidly, in a matter of weeks, and the pharmaceutical company Glaxo has given an undertaking to expand access to all people with less than 300 CD4 cells. There are a lot of reasons to participate in the trial, including a 75% chance of getting 3TC in combination with AZT. In addition, the trial will test the safety of these combinations as well as viral activity measurement by way of PCR viral load testing (to be done in Belgium). One of the disincentives to participating is the 25% chance of being assigned to AZT (plus current treatment) alone. Another disincentive is that it is relatively hard to withdraw from the study and start receiving 3TC. Even if you are showing some significant signs of health deterioration, you will need to have a 50% fall in your CD4 count, or develop a serious AIDS illness before you can be withdrawn and receive open label drugs. However, it must always be remembered that it is your right to withdraw at any time, particularly if you feel that your health is being compromised. This trial incorporates a new way of classifying disease progression. In previous trials, the development of any AIDS-defining illness was a marker of disease progression, even in someone who had AIDS already, and regardless of the seriousness of the illness. In the forthcoming trial, people who enter this trial are assessed and allocated to one of three groups: asymptomatic; mild AIDS; severe AIDS. The idea is to distinguish someone with a serious AIDS-defining illness from someone who has a milder illness. Then each participant can be traced to see if they go on to have another illness or a more serious illness as an endpoint. For example, a person who is asymptomatic would have endpoint of disease progression if they were to develop symptoms of a mild illness such as candidiasis. In contrast, someone with severe AIDS who develops candidiasis will not be considered to have reached the endpoint of disease progression. By making this distinction, the trial will measure more accurately the effects of 3TC. The innovatory design has been developed in consultation with many community and medical groups. All participants can continue their current treatments as long as this treatment includes AZT. These criteria conform to the guidelines prepared by the Treatment Action Group in New York. However the US Federal Drug Administration considers the trial to be less than scientific and it has rejected American involvement in the study. The trial will last for twelve months, involving 1200 people from around the world. Three hundred people living in Australia will participate in the trial, of whom 225 will receive a combination of AZT and 3TC. A person in the trial who has serious side effects, develops resistance to the treatments or exhibits a decline in health (defined as a 50% fall in CD4 count) will be permitted to change treatments. If they experience disease progression, they will be offered open label 3TC and alpha APA (loviride) in addition to their current treatments. All participants will be offered continuing treatment with the trial drugs at the end of the study period. New Positive Results about 3TC At the recent Second National Conference on Human Retroviruses held in Washington DC, there were two papers that reported clinical trials with 3TC. One study compared 3TC and AZT as single drug treatments (monotherapies), and compared two different doses of 3TC in combination with AZT. This group of people had not previously taken any antiviral therapy and had CD4 counts between 200 and 500. The trial enrolled 364 people in the following groups: 94 people - 600 milligrams AZT 92 people - 600 milligrams AZT and 150 milligrams 3TC 94 people - 600 milligrams AZT and 300 milligrams 3TC 84 people - 300 milligrams 3TC The study was conducted over a 24 week period and all groups showed a significant fall in the viral load in that period of time. As in previous studies, both combinations of AZT and 3TC showed a greater and more sustained rise in CD4 counts and suppression of viral load than either monotherapy groups receiving only one drug. The results favouring the combination treatments were sustained after 52 weeks in some of these participants. Interestingly, there was no difference in the responses of the two groups who were only taking one drug. That is, the effects of 3TC (as a single treatment) on CD4 counts and viral load were not significantly different to the effects of AZT as a single treatment. There were also no differences between the two combination arms of the study. The evidence suggests that the lower dose of 3TC may have the same effect as the higher dose. If this result is confirmed, their will be less chance of side effects from combination 3TC and AZT. Both the single and combination treatments were well tolerated and there were no significant differences in the safety profiles of each treatment arm of the study. This study was relatively small and the trial period was quite short. Larger and longer studies need to be conducted before firm conclusions are reached. However the study does suggest that 3TC monotherapy may be a short term treatment option. There is no data for the longer term. This and other studies clearly indicate that the most promising treatment is AZT and 3TC in combination. VIRAL MEASUREMENTS AND HIV MANAGEMENT By Ian McKnight-Smith The progression of HIV infection to the point where there is profound immune system failure and an AIDS-defining illness, follows a well documented and fairly predictable sequence of events. Tracing HIV illness has depended upon imprecise measurements. The amount of viral activity is thought to be directly corelated with the risks of progression and hence to symptoms of disease. The ability to accurately and economically measure viral activity is now reaching the stage where it may be performed routinely. A 'viral load test' will allow better general monitoring and indicate when the virus is no longer sensitive to antiviral treatments. Viral activity varies with the stages of HIV disease. The following section reviews these stages. I Primary Infection Following exposure to the virus, there is an immediate response by the body, and many people may experience symptoms. Common symptoms include a flu like illness. In some cases there is a distinctive rash that can be confined to one area of the body or is more widespread across the trunk and limbs. During this period the virus is very active and rapidly multiplies. As a consequence there is a massive increase in the amount of HIV in the blood stream. In response the body's defence mechanisms are activated and the immune system starts to produce a specific antibody against the virus. The production of antibodies takes a period of time, classically called the 'window period' before antibodies are present. A viral load test at this time would show very high levels of the virus circulating in the blood. II Clinical Latency After a period of several months the immune system is able to get the upper hand and it is able to control the virus to the extent that the person will return to normal health. That is not to say that the virus is totally under control; recent data has shown that it continues to reproduce, particularly in the lymph nodes. Containment of the virus is due to the relative efficiency of the immune system. There is a high turnover of CD4 cells or T-cells during this period, as the body calls on extensive reserves of these immune system cells to take the place of those that are lost due to the activity of the virus. When viral load tests are conducted during this period the detectable levels of HIV in the system will be low. The duration of this low viral load can vary widely from individual to individual. In many people, low viral load may continue for ten years or more, however in others it can be a shorter period of time. The reasons for this variation are not fully understood, but can include inherited characteristics or previous illnesses that may have damaged the immune system. This is not to say that during this period, the virus is not reproducing - far from it. Recent data shows considerable CD4 cell depletion which is a result of high viral activity. III Viral Emergence After a period of time, there is a significant increase in viral levels and a corresponding decline in the CD4 counts. The immune system becomes progressively weaker and hence less able to fight off infections or control pathogens (bugs that cause disease) that may already be present in the body. Increased amounts of HIV in the blood unfortunately herald a fall in CD4 counts and the need for greater medical intervention and prevention of opportunistic illnesses such as PCP (a form of pneumonia). In many cases the person will remain well for extended periods of time, particularly if effective prophylactic (preventive) treatments are used. IV. AIDS During this stage of HIV infection, the virus levels continue to increase. At this point, the immune system has become weakened to such an extent that it can not protect the person against many infections. Thus there is high likelihood that the person will develop symptoms of a series of defined illnesses. These are called AIDS defining illnesses, and indicate severe immune dysfunction. Opportunistic illnesses can be treated, and brought under control. In many cases, the person will return to a reasonable state of health. VIRAL LOAD MEASURES AS PREDICTORS OF ILLNESS A number of tests have been associated with predicting progression of HIV disease. Immunological blood tests can test for increases in levels of beta-2 microglobulin and neopterin, and decreases in CD4 counts. Other tests look at HIV antibody and cellular responses. Some consistent and robust immune test results between the various approaches are directly associated with clinical stability, better health and long term survival. There are some other markers that can indicate increased viral activity. These tests look at the ongoing rapid replication of the virus, or the increased capacity of the virus to form the more virulent syncytia or clumps of viruses. The relationship between the levels of virus and disease progression were first discussed in the late 1980s. It was suggested at that time that there was a 'threshold' level of virus and that when this level was exceeded the person would have a significantly increased risk of developing symptoms of HIV disease. Certainly some follow up studies on small groups of people supported this theory. These studies show that people remained well while the viral levels were stable. However, there was a direct correlation between the development of opportunistic illnesses and increases in viral load in these people. Recently more precise tests have been developed to measure viral levels, such as the Polymerase Chain Reaction (PCR) test. This is a useful test that is able to directly detect the level of virus being produced at any one time. Studies using the PCR test have shown that there is a direct relationship between increasing viral load and the progression of HIV disease. A LINK BETWEEN VIRAL LOAD AND DRUG RESISTANCE The most common and serious problem associated with the long term use of AZT as a single antiviral treatment is that the therapy decreases in its effectiveness. This is largely due to the emergence of resistance. Indeed it is also true that drug resistance will develop more quickly in people with more advanced stages of the illness. Therefore the clinician needs to be able to monitor for the development of resistance so that appropriate treatment and management alternatives can be quickly considered. Clinical studies have been able to show that there is a direct relationship between the emergence of drug resistance and increases in viral load. Resistance has also been linked to an increase in the risk of disease progression. For example in a Canadian study, 17 out of 19 people who had identified resistance to AZT, showed a corresponding increase in viral load as well as an increased incidence of disease progression. Interestingly the 2 people in this group who were resistant to AZT, did not show increased viral load and remained at significantly higher CD4 counts (more than 300). In the same study, 12 people were responsive to AZT, and only two showed symptoms of disease progression with falls in their CD4 counts (less than 50) and increases in viral load. This evidence suggests that routine viral load tests can be an effective means of monitoring viral responses to antiviral treatments. Viral load testing would allow faster medical intervention. Hopefully, viral load testing may lead to better medical management, which may delay disease progression and lengthen people's lives. THE VIRUS TYPE AND ITS IMPACT ON DISEASE PROGRESSION The type of virus strains that are found in each person appear to have a significant impact on the prognosis for disease progression, however there is no routine viral type test available at this stage. One type of virus is the Syncytia forming (SI) HIV. The viruses produce a phenomenon where a number of infected cells clump together and become a very virulent mass. The clinical effect when SI strains occur is usually marked by a rapid progression of illness and a corresponding decline in the immune system. The non-syncytia forming virus (NSI) is usually associated with a slower decline in health. Clinical studies support this claim. For example, the 1993 study from Dr Fauci's unit showed that when they tracked two groups of people with and without the SI form of the virus, there was a significant difference in the clinical outcomes. In 20 people followed for two years, who had the non-syncytia forming virus, only one was seen to develop symptoms of disease progression during this time. However in another group of 12 people who were identified as having the SI form of HIV, 8 were seen to progress to AIDS over a period of less than 2 years. The progression to SI forms was associated with a corresponding increase in viral replication rate overall. This study indicates that the use of efficient tests to monitor virus types are a priority. More importantly, research must direct itself to ways of efficiently reversing or eliminating the development of the SI types of HIV. It is to be stated however that there has been much controversy about the validity of SI strains as a human phenomenon. Many cynical researchers have suggested that it is but a laboratory phenomenon. As a result the interest in this phenomenon has declined in recent months. CONCLUSION Although research is far from complete, preliminary results about viral activity can be placed into a more general theory about HIV disease progression. A person with HIV begins with a given viral load and is then placed on antiviral treatments. Over time, the viral strains remain susceptible to the agent(s) being used or may develop resistance. If this susceptibility is sustained in the context of a relatively low viral load, immune function will probably be relatively stable. If however, the viral load increases, the person appears to be at greater risk of disease progression. A number of factors may cause the viral load to increase. such as a change in the viral type to the more rapidly replicating SI types. Once drug resistance develops, clinical disease may remain stable in a low viral load setting. However, the evidence suggests that resistance permits an increase in viral load as the virus resumes normal production, which in turn increases the risk of progression. The challenge is to intervene and maintain sensitivity to the treatments, a low viral load and hence therapeutic efficacy for longer periods of time. Recent work suggests that one way of achieving this is to combine different types of antiviral treatment. As the new PCR tests for the measurement of circulating viral load is standardised and becomes cheaper, it should be incorporated into this treatment model. Many researchers believe that analysis of these measurements will allow us to determine a 'threshold' beyond which disease progression is likely to occur if there is no intervention. This could provide more effective guidelines as to how and when treatments should be used. At the present time however, there is no standardised methodology for measuring and comparing viral load. The PCR test is not simple to conduct or interpret since there is enormous variability between persons at varying stages of the illness. As yet there are no guidelines as to what actions should be taken by the doctor when a patient presents with a particular viral load reading. Large observational studies are required to ascertain what degree of variability occurs within one patient and what this then means in terms of changes to health and progression of HIV overall. It will also be important to correlate such results with the effects of the virus on the other surrogate markers such as CD4 count. VALACICLOVIR STUDY STOPPED By Ian McKnight-Smith On February 13 the AIDS Clinical Trials Group (ACTG) halted the study looking at the new drug valaciclovir as a prophylactic, or preventive, treatment against CMV. The news was not good. The interim analysis showed lower survival rates for the people taking valaciclovir when compared with the other two groups who were taking two different doses of the drug acyclovir. Valaciclovir is a pro-drug for acyclovir. (A pro-drug undergoes a chemical change in the body to become an active pharmacological agent.) Valaciclovir converts into acyclovir when it gets into the body. In theory this permits a person to take higher doses of the drug orally without increasing tablet numbers and to avoid difficulties in absorbing high levels of acyclovir. In the past, people needing very high doses of acyclovir have had intravenous injections. The trial, ACTG 204, had three groups participating. Two of these groups received conventional acyclovir: one group at a high dose, one had a lower dose, and the third group received a standard dose of valacyclovir. The participants were all HIV positive with CD4 or T4 counts less than 100, and therefore at risk of developing CMV disease. The aim of the study was to determine if any of the treatments were able to successfully prevent the onset of CMV symptoms, and to see if the use of the pro-drug, which produced higher levels of acyclovir in the blood, was more effective than the conventional drug doses in prolonging survival. The rationale for the trial came from previous studies which showed that the use of acyclovir prevented CMV in organ transplant patients (who are immune suppressed). However this has yet to be demonstrated in people with HIV. Initial studies were not successful, although studies have shown that people with advanced HIV, who took high doses of acyclovir (3200 milligrams per day) did show a better overall survival time compared to those who did not. The current news about the reasons for stopping ACTG 204 are sketchy; there were more deaths in the group taking valacyclovir compared with the acyclovir groups. Furthermore, there is some suggestion that valacyclovir was not as well tolerated as acyclovir. Consequently, people taking valacyclovir did not remain on the treatment for as long as the group who were taking the regular acyclovir. However the decreased survival time for the valaciclovir group does not appear to be the result of some nasty toxic side effect. The reported reasons for the deaths were the same in all three groups, namely progression of HIV disease. Until the detailed results are available we can only speculate about why the valaciclovir group did not do well. One suggestion has been that since the group taking regular acyclovir were ongoing in their treatment, it afforded a continuous suppression of the herpes viruses that may accelerate the progression of HIV, and that this protection was not provided to those taking the pro-drug. This theory is supported by evidence from the Multicentre AIDS Cohort Study which showed continuous use of acyclovir at doses between 600 and 800 milligrams per day does have a significant effect on survival. The European/Australian study has shown a significant increase in survival when high doses of regular acyclovir were used on a continuous basis. The results are not conclusive, however it seems that the ongoing use of the drug is important, and high doses may not be required to achieve this effect. We must await the detailed results of the trial before conclusions can be drawn about valaciclovir and acyclovir dosage. However two recent US trials presented in Washington, have caused a total state of confusion since they both have shown that the use of anti-retroviral treatment in combination with acyclovir did not confer any significant survival benefit. We will discuss these studies in greater detail in the next issue of HIV Herald. Back to Basics PROPHYLAXIS PREVENTING OPPORTUNISTIC ILLNESSES What is an Opportunistic illness? During the course of time when you are living with HIV, there is a likelihood that your immune system will slowly weaken. If this occurs, you are at greater risk of developing one or more 'opportunistic illnesses'. Opportunistic illnesses refer to a number of infections that commonly occur in many people. Under normal circumstances these pathogens (bugs that cause disease) only cause very mild symptoms, or in many cases do not cause any symptoms at all. Some organisms remains in the body even after the symptoms have disappeared. The infections are usually kept under control by your immune system. However, if the immune system is not working properly there is an increased risk that these organisms can begin to multiply and cause symptoms, hence the term 'opportunistic'. The organisms become active when the immune system is weakened and the symptoms of that illness are then experienced. In some cases this can be serious. Many AIDS opportunistic illnesses are relatively mild and can be easily and successfully treated. However some people may become very sick and some opportunistic infections can be life-threatening. Treatments can often successfully control serious infections and people can return to good health. For some illnesses, there are no effective treatments. At best the treatment may be able to slow down the course of the infection. The Opportunistic Illnesses Associated with HIV In all cases the development of opportunistic illnesses puts an added pressure on the functioning of the weakened immune system. The activation of a pathogen and the development of symptoms may cause increased and irreversible damage to parts of the immune system that are involved in fighting HIV. Therefore it makes good sense to try and prevent the illness from occurring if possible. There is considerable knowledge about how HIV acts and the course of the illness, and a reasonable understanding when people with HIV are at greater risk of developing a particular opportunistic illness. This is shown below in the graph. The points on the scale are only approximate, and indicate where the risk of developing symptoms increases, due to a weakened immune system. The illnesses shown in bold type have treatments that can effectively prevent the onset or return of the particular illness. Prophylaxis Prophylaxis literally means the prevention of an event. In HIV medicine there are two points in time where prophylaxis may be useful. Prophylaxis can prevent a person having their first outbreak of a disease. This is called primary prophylaxis. Prophylaxis can also involve the use of treatments to prevent the return of the illness, called secondary prophylaxis or maintenance treatment. The approaches to both primary and secondary prophylaxis are essentially the same. Prophylaxis involves the use of drugs or treatments that are able to keep the infectious agent under control. Fortunately, much lower doses are used for prophylaxis than would be used for treating an outbreak of symptoms of the illness. Often when prophylactic treatment is prescribed, it will only have to be taken once each day or every few days. The low dose means the risk of developing unwanted side effects is reduced, however side effects may still develop. For example, the use of co-trimoxazole to prevent PCP has had a history of causing side effects in a small proportion of the people who take the drug. In most cases, when prophylaxis is started, the treatment will be continued for the rest of your life. This makes sense, for it is acting to prevent an illness. If you stop the treatment after a given period of time, you are placing yourself at risk of developing the illness. The development of prophylactic treatments against HIV illnesses has meant some people are taking a lot of tablets. Attempts to minimise the numbers of tablets has been to some degree successful with drugs like co-trimoxazole as it is effective preventative therapy against both PCP and toxoplasmosis. PCP Prophylaxis a Success Story PCP stands for pneumocystis carinii pneumonia, and is a serious infection that primarily attacks the lungs. Like many of the opportunistic infections, the microorganism that causes PCP lives in the lung tissue and under usual circumstances causes no problems. About 75 percent of the general population will have been exposed to the microorganism that causes PCP by the age of four years. People with intact immune systems very rarely develop symptoms to the disease during their lifetime. However when the immune system is weakened, symptoms of pneumonia can occur. In the early years of the HIV epidemic in Australia, the most common cause of death associated with HIV was due to PCP, with more than 80 percent of people with HIV being affected by this illness. The variety of treatments and prophylactic regimens that are currently available, means the incidence of PCP has drastically declined. With early diagnosis of HIV, proper immune system monitoring and the timely commencement of prophylaxis, this illness can be prevented. Consequently, PCP is no longer the most common AIDS-related illness that claims peoples lives and the incidence of PCP continues to decline. It has been recognised that people who have CD4 counts above 250 rarely develop PCP. However a CD4 count around the 200 mark means the risk of developing PCP is high unless preventive therapy has been started. If treatments are not started, the illness can become serious. The standard treatment for PCP is a drug called co-trimoxazole. It actually contains two antibiotic agents called trimethoprim and sulphamethoxazole. The sulphur content of the latter agent has been responsible for the development of allergic side effects in a small percentage of people. While in the past this may have prevented people from continuing treatment with this agent, it is now possible for people to be desensitised so that they can still take co-trimoxazole when needed. In Australia there are three identical brands of this drug available: Bactrim, Septrin, and Resprim. The usual recommended dose of co-trimoxazole as prophylactic treatment is one to two double strength tablets taken two to three times per week. Some clinicians may suggest that one double strength tablet is taken daily. The drug is currently listed on the pharmaceutical benefits scheme in Australia, so it is an inexpensive treatment. Side effects include an allergic rash seen in 15-25 percent of people who start this treatment; other side effects are few and relatively rare. They include: nausea; vomiting; abdominal cramps; altered taste; weight loss; fatigue and insomnia. However most doctors would suggest that the potential benefits of this treatment well outweigh the risks of developing these side effects. More details about this drug can be found in the NTP HIV Briefs Fact Sheet that was issued in August 1994 and included with the September 1994 issue of the HIV Herald. Copies can be obtained by calling the National Treatments Project in Sydney on (02)231 2111. INTERLEUKIN STUDY UPDATE By Ian McKnight-Smith The PEG Interleukin-2 study continues enrolments in Sydney, Perth and Melbourne with 73 participants as at the end of January. Eight of these have now completed four cycles of treatment and a further seventeen have completed three treatment rounds. The objective is to have 120 participants by the close of the enrolment period. This trial is looking to see if IL-2 a natural cytokine that stimulates a particular part of the immune system has an effect on delaying disease progression or increasing survival. This trial was covered in some detail in the April and July 1994 issues of the HIV Herald. Most trial centres have been enrolling people for about six months; it is hoped the study will be fully enrolled by the end of April. The trial still has a number of places available. If you are interested in participating, please call your local Treatments Officer at your state AIDS Council or you can contact us here at the National Treatments Project. The study sites include: Sydney * Prince Henry's Hospital * Royal Prince Alfred Hospital * St. Vincents Hospital * Westmead Hospital Melbourne * Fairfield Hospital Perth *Royal Perth Hospital Of the 73 participants in the study, only three have withdrawn; one with HIV-related idiopathic thrombocytopenia (a blood problem), and one with multifactorial CNS dysfunction (a nerve problem) which was possibly related to the use of interleukin-2. Another person was enrolled in the study,and then withdrew. Side effects that have been reported include: From the standard IV Interleukin-2 : Diarrhoea 1 Elevated Bilirubin 2 Fever/nausea 2 Vomiting 1 From the PEG Interleukin-2; Thrombocytopenia 2 CNS dysfunction 1 Nausea/Vomiting 1 3TC ACCESS TO BE INCLUDED INTO THE TRIAL A meeting of the trial steering committee decided to change the protocol to add the new antiviral drug 3TC to the list of antiviral drugs included in the study. To ensure that this amendment has minimal impact on the data, 3TC will be given to participants when they have completed 38 weeks of this study. As discussed in other articles in this edition of the HIV Herald, there is evidence that 3TC and AZT suppresses virus replication very effectively. Interleukin-2 treatment must be combined with anti-viral drugs which suppress the virus for two reasons. Antiviral drugs reduce viral replication which may be enhanced when interleukin-2 is present. It is also probable that low virus load might predict a good response to Interleukin-2. The trial is in the final stages of negotiation. It is hoped that the drug will be available for people in the 38 week trial by sometime in March. Trial nurses at your site will be kept informed. INTEGRASE By Ian McKnight-Smith New knowledge about the workings of HIV has raised the possibility of new antiviral treatments. The process of integration, when the viral DNA becomes part of the human cell DNA, may be the target of drug research. When integration occurs, the cell becomes a virus production factory. This process is helped by a chemical called an enzyme. As the process of copying (reverse transcription) of the genetic material of HIV (RNA) to viral DNA is facilitated by the enzyme reverse transcriptase, and the assembly of new viral protein is controlled by an enzyme protease, the enzyme helping integration is integrase. US researchers have announced that they now understand the structure of the integrase enzyme. This knowledge opens the door for new drug development. If treatments can be developed that are able to interrupt the process of integration, then this would prevent the virus from converting that cell into a virus factory. The researchers believe that the new information raises the hope that integrase inhibitors could be ready for the first human clinical trials within the two years. GEMS FROM WASHINGTON By Ian McKnight-Smith The Second National Conference on Human Retroviruses and Related Infections was held in Washington DC from January 29 to February 2. The following reports discuss the more interesting bits and pieces presented at the conference. More detailed information will be published in the next few issues of the HIV Herald. VIRAL REPLICATION RATE MUCH HIGHER THAN THOUGHT Recent research indicates that HIV is constantly multiplying. This contradicts the previously held view that HIV does not replicate following seroconversion and before symptoms of HIV develop. The reasearchers estimate that there are more than 1 billion new virus produced each day during this period. In turn, the body's immune system is equally active, suppressing and removing the virus from the body. The immune system is effective and keeps people well for a period of years. It is only after this period that the virus is then able to get the upper hand. INTERLEUKIN - 2 Dr Fauci, Director of US National Institute of Allergy and Infectious Diseases, presented information about one of the immune system's important regulatory molecules called interleukin-2 (IL-2). He said, "Our studies show that IL-2 is a potent inducer of CD8 cell suppression of virus production". This means that the CD8 cells are pushed into controlling HIV production. Ongoing studies with IL-2 continue to produce positive results. "They suggest that along with blocking virus production using antiviral agents, we may be able to amplify elements of the immune response itself," Dr Fauci said. This means that each part of the immune system may be built up by artificial means, allowing the natural immune defences to cope better with the HIV infection. There is a trial being conducted with interleukin-2 (PEG IL-2) in Australia, and 73 people had entered in the study at the end of January. See article in this issue of the HIV Herald. MORE ABOUT AZT USE DURING PREGNANCY A study from New York suggests that oral AZT taken by women during pregnancy reduces the chance of mother to child HIV transmission as effectively as AZT use by the mother prior to and during delivery, as well as AZT given to the newborn. Reports late last year showed that AZT taken during pregnancy, infused at the time of birth and given orally to the newborn, reduces the rate of HIV transmission from mother to infant by two thirds. The new study indicates this level of protection may be provided by the mother simply taking AZT while pregnant. Dr Matheson from New York found that the rate of HIV transmission was 14 percent in women who were treated with AZT during pregnancy, compared with 22 percent in those who were not. Importantly the protection is similar regardless of the woman's CD4 cell count. COMBINATION ANTIVIRAL TREATMENT ENDORSED. It is now clear that the rapid development of viral resistance to treatments such as AZT, when used as single treatment (monotherapy), means that no single drug will currently control HIV infection for any extended period of time. This has led to the current belief that the use of a combination of several treatments will give a longer period of viral suppression. So far, most of the research has involved combinations of the antiviral drugs called nucleoside analogues (for example, AZT, ddI, 3TC and ddC), however researchers are beginning to look at other classes of treatments. For example, non-nucleoside reverse transcriptase inhibitors such as nevirapine are being studied, as well as protease inhibitors, such as saquinavir, which attack a completely different point in the lifecycle of HIV. The Washington conference heard encouraging reports about an antiviral drug called VX 478, which is a type of protease inhibitor. Test tube studies show VX478 to be a good inhibitor of HIV replication. Further, it was shown to be highly synergistic when used with other anti-retroviral treatments (that is, the combination of drugs enhances the overall effect). While this is very good news, the drug must be clinically tested and the effects reproduced in people with HIV, before it can be considered an effective treatment. It was suggested at the meeting that three or four drug combination studies should be started as soon as possible, and that they should be done earlier in the course of the illness. Dr Joep Lange of the World Health Organisation said, "hit the virus hard and hit it early". Dr Markowitz of the Aaron Diamond AIDS Research Centre said, "It is naive to think that one drug used alone will give a sustained antiviral response. Resistance will develop to any single agent that you throw at HIV, so let's start making drugs available in combinations that we know will not hurt people and that may just help." "Zidovudine and 3TC is the most active combination of the nucleoside analogues. We should immediately try them together with a protease inhibitor," urged Dr Markowitz. Dr Lange differed only in saying that he would choose to add in two protease inhibitors, drawn from different classes of drugs which hopefully would not be cross resistant. EARLY TREATMENT MAY BE BETTER IN SOME CASES There was new evidence presented in Washington supporting the use of early anti-retroviral treatment. In an study involving more than 1000 HIV positive people, Dr Gardiner and colleagues from the Walter Reed Institute for Medical Research, compared early AZT treatment (CD4 count above 400 and no symptoms) with delayed treatment (CD4 count below 400). Among those people whose CD4 counts declined rapidly just prior to treatment, early use of AZT was shown to significantly slow the progression of the disease. PCR TESTS A POWERFUL MEASURE OF VIRAL LOAD and DRUG EFFICACY The PCR test is a recently developed means of directly measuring the amount of HIV in the blood. This technique will increase the speed with which the anti-HIV effects of new drugs are evaluated. Data presented from an analysis of blood samples that have been held in storage from previous clinical trials suggests that the amount of virus in the blood is a powerful predictor of both disease progression and of the effects of treatments used to combat the virus. When combined with the measurement of CD4 cell numbers, which reflect the overall status of the immune system, PCR testing will enable accurate testing of the effects of new drugs. For example, some protease inhibitors, a type of antiviral drug, are ten to twenty times more effective than nucleoside analogues and reverse transcriptase inhibitors, in clearing HIV from the blood. However, like the nucleoside analogues, when used alone protease inhibitors induce viral resistance. In some cases this is more rapid than with established treatments. Researchers hope that resistance can be overcome with the use of combinations. "If you can reduce the viral burden from 100,000 copies per millilitre of blood to 100 and if you can do that at the time when the immune function is still good then we have a real prospect of influencing the course of the disease," Dr Markowitz said. These changes in viral load in the blood can now be effectively tracked using the PCR test. This information will become more accessible when the test is produced as an affordable kit that can be used in every pathology laboratory. MORE 3TC NEWS Dr Katlama from the Pitie-Salpetriere Hospital in Paris opened a session saying, "For the first time it is possible to have patients better off a year after they started therapy than they were at the beginning." She proceeded to present results of the European trial of combination therapy with AZT and 3TC, similar to that presented in Glasgow and reported in December issue of the HIV Herald. The French study and data from three other trials using the same combination treatment, reinforced the prevailing optimistic mood about the AZT and 3TC treatment regimen. All four studies show the combination to be potent, producing large falls in plasma HIV levels and substantial increases in CD4 cell count. Moreover there is evidence that these positive responses are sustained for at least six to twelve months. The two trials involving people who had not previously taken AZT showed the most promising results. For example, the North American study showed that the levels of virus were reduced by around 95 percent after four weeks of treatment. There was some loss of effect with time, but at six months the viral load was still suppressed by about 90 percent. At one year the CD4 counts remained 60-100 cells higher than they were before they commenced therapy. Results from the European study of AZT and 3TC confirmed the US work and showed equally promising outcomes. At six months, viral load was 90 percent below starting point and the CD4 counts were on average 80 cells higher than when they began. As expected the combination produces less effective responses if the person has been using AZT for long periods of time and s/he is in the late stages of HIV. But even in this group, reductions in viral load and increases in immune function are significant. In the European trial CD4 counts were on average 33 cells higher than baseline after 24 weeks of treatment. This was almost identical to the results that were seen in the North American trial. Dr. Robert (Chip) Schooley, the chairperson of the Washington Conference Scientific Committee said, "The data presented today are interesting from two standpoints. First is the magnitude and duration for the virological and immune response. The other intriguing aspect is whether this is due to specific interaction between the mutations induced by this combination, and the idea that induction of the 3TC mutation may decrease the ability of the virus to deal with zidovudine."