DISTRIBUTED BY HIV Information * Support BBS +61 2 818 2876. Sydney, Oz. HIV Herald, Vol. 5 No. 1, February 1995 Produced by the National Treatments Project of the Australian Federation of AIDS Organisations AFAO PO Box H274 Australia Square Sydney, 2000 Ph. 02. 231.2111 Fax. 02.231.2092 National Treatments Officer: Ian McKnight-Smith Publications Sub-editor: Megan Nicholson Rifabutin (Mycobutin) made available. By Ian McKnight-Smith The Health Minister Dr Carmen Lawrence has returned from her holidays and approved the drug rifabutin for use as a prophylaxis (preventive treatment). This action followed a recent meeting in Sydney of people with HIV, clinical specialists and other members of the HIV affected community, where speakers condemned the delay in making rifabutin available as prophylaxis for Mycobacterium Avium Complex (MAC). The drug must now be approved by the Minister for Finance. MAC is a devastating illness that people develop in the advanced stages of HIV. A number of studies show that rifabutin is effective in preventing MAC in people with T- cell or CD4 cell counts less than 100. The chance of developing MAC increases when a person's T-cell count falls below 100 (the T-cell count gives a rough indication of the state of the immune system). The prevention of MAC using rifabutin as a prophylaxis should become routine, as is the prevention of PCP (a type of pneumonia) with the drug co-trimoxazole. Rifabutin has had dramatic effects, with a significant fall in the incidence of MAC in the HIV positive population. Rifabutin has few side effects; many studies show that people on rifabutin report similar side effects to those taking the placebo. Side effects include neurological (nerve) problems and gastric upsets (diarrhoea, nausea,vomiting) and can be reduced by taking the drug with food. Rifabutin appears to cause fewer side effects than most other treatments for MAC. The main concern of some clinicians has been the development of resistant strains of MAC if rifabutin is used alone as prophylaxis. To date the research has not shown this to be a problem, but the treatment has only been tried with a relatively small number of people in highly supervised conditions. In June 1994, rifabutin was approved by Australian Drug Evaluation Committee (ADEC) for use as a prophylactic treatment. The ADEC recommended that rifabutin should be included on the section 100 scheme, which would make it available through hospital pharmacies to people with advanced HIV. The six month delay in ministerial approval has meant there has been no reimbursement for the expense of the drug. This has meant that hospitals have had to pick up the cost through its allocation of pharmaceutical funds or the individual has to pay for it themselves. The latter option is virtually impossible due to the high cost of the drug. Chemists pay $147 for thirty 150 milligrams capsules. The standard prophylactic dose is two capsules per day. Therefore, two packs of the drug will be needed each month at a cost of $294 per month. In addition, dispensing costs mean rifabutin prophylaxis costs more than $300 per month. Hospitals have not been able to cover these cost although some hospitals have recently been given one-off help with funding from their area health services. However this is a temporary assistance designed only to cover the situation until the listing on the Section 100 goes into effect in the next few weeks. Speakers as the recent meeting were scathing about the delay in ministerial approval. Professor David Cooper, director of the National Centre for HIV Epidemiology and Clinical Research, told the meeting that the delays in access to rifabutin are inexcusable. "Rifabutin was approved last June by the Australian Drug Evaluation Committee, but the funding arrangements still aren't in place. The Federal Minister, Dr. Carmen Lawrence, failed to sign the approvals before she went on holidays, so we are still waiting," Professor Cooper said. "There are significant survival benefits for people with HIV/AIDS in taking rifabutin as prevention or treatment for MAC infection. The problem is the dreadful delay in funding". Tony Keenan, President of the Australian Federation of AIDS Organisations (AFAO) wrote to Dr Lawrence about delay in funding rifabutin. In the letter he said that "several hospitals in New South Wales have expressed their reluctance to prescribe rifabutin for people with HIV/AIDS until these funding agreements are in place. AFAO finds this withholding of life saving medication intolerable". Dr Lawrence has responded to these calls, and signed the approval of rifabutin. The papers have gone to the Minister for Finance for his approval. Let's hope this will be a very rapid process. Co-trimoxazole Controversy By Ian McKnight-Smith Recently in the United Kingdom, Professor Lacey from Leeds University called for pharmacies in England to stop supplying co-trimoxazole, also known as Bactrim and Septrin. He considers co-trimoxazole too dangerous to use as a general antibiotic. He claims that there have been many thousands of deaths attributed to the use of the drug, and suggests that these problems have been deliberately concealed by drug companies and the regulatory authorities in Britain. Co-trimoxazole is an antibiotic that is made up of two different active agents called trimethoprim and sulphamethoxazole. It has been widely prescribed for more than twenty-five years and is particularly effective against a number of infections, including urinary and respiratory tract infections. More recently, clinical research has clearly shown that co-trimoxazole is an effective drug to both prevent and treat certain life- threatening opportunistic illnesses that are associated with AIDS. It is particularly useful for pneumocystis carinii pneumonia, or PCP, a serious infection of the lungs, and Toxoplasmosis, a nasty infection of the brain. The use of co-trimoxazole has been so effective in treating PCP that there has been a significant decline in the numbers of people who are reporting this illness as their first AIDS defining opportunistic illness. Treatment with co-trimoxazole has delayed the onset of AIDS in many people with HIV. Many clinicians and treatments' advisers believe that co-trimoxazole is probably the most significant advance in HIV/AIDS treatments. Millions of scripts for co-trimoxazole have been written in the last twenty-five years and the side effects associated with the drug are well known and extensively documented. Between fifteen and twenty-five percent of people who take the drug experience side effects. A skin rash is the most common side effect, indicating an allergic reaction to the sulphur component of the drug. In most cases, skin rashes subside as soon as the drug is stopped. If you develop a skin rash, see your doctor to discuss your options. In very rare cases, mainly among elderly patients, this allergic reaction may be more severe and can be life-threatening if treatment is continued. This is called the Stevens- Johnson syndrome. Recently, a procedure called desensitisation has been introduced to eliminate the allergy by gradually exposing the patient to sulphur. Once the person is desensitised, co-trimoxazole therapy can continue. This has been particularly successful for people with HIV and reports indicate that up to eighty percent of people are able to tolerate the drug after desensitisation. A complete protocol of desensitisation was included in the November 1994 HIV Herald, Vol. 4, No.10. If desensitisation is not successful there are a number of other treatments that can be considered. These include dapsone with trimethoprim (which contains no sulphur) and in some cases, pentamidine, clindamycin in combination with primaquine or pyrimethamine, and possibly atovaquone. These drugs are effective although not as successful as co-trimoxazole. Other side effects of co-trimoxazole are more often seen in the elderly or in people who have poor kidney or liver function. The latter results in a build up of the drug in the body which may reach toxic levels. However, there are also reports of the following side effects: reduced red blood cell numbers or anaemia; reduced white blood cell numbers; weight loss;nausea and vomiting; and an altered sense of taste. These side-effects should be discussed with your doctor. The National Treatments Project contacted the Therapeutic Goods Administration (TGA), the government body who document all reports of side effects from around Australia. The TGA reported forty-four deaths could possibly be attributed to co- trimoxazole over the twenty-five years it has been in use. In the context the widespread use of co-trimoxazole, the incidence of death is very low, similar to paracetamol, a very common analgesic. In summary, the preventative use of co-trimoxazole and its use in the treatment of PCP and toxoplasmosis in people with advanced stages of HIV has been shown to be highly effective. Co-trimoxazole has delayed the onset of AIDS by a significant period of time for many people. It is acknowledged that some people do exhibit an allergic rash when starting treatment. Although allergic reactions to co-trimoxazole occur, these reactions are rarely life-threatening. However, it is clear that the potential benefits from preventing serious opportunistic illnesses make co-trimoxazole the drug of choice. Generic brand of acyclovir available By Ian McKnight-Smith The drug acyclovir has been a common treatment for both outbreaks of herpes and as a prophylaxis against herpes. Recently it has also been approved for use as treatment against HIV in people with CD4 or T-cell counts of less than 150. In the past, only the brand called Zovirax was available, supplied by the pharmaceutical company Wellcome. The company has decided to supply acycolvir to the manufacturers of generic brands, although the product patent has not expired. This means acyclovir will be available under a number of trade names. The first such product has the trade name Zyclir and is supplied by Amrad Pharmaceuticals. There will be a second brand shortly, supplied by another Australian company Alphapharm. At this stage, there will be no change in the price of acyclovir for the consumer. The cost of acyclovir to the pharmacy has decreased marginally, which will help the pharmacies meet their costs in a market where they are struggling. Australian-based production will mean the dollars are kept in this country. The 200 milligram Zyclir tablets are identical to Zovirax in terms of the ingredients. The difference is that Zyclir are round, rather than octagonal shape of the Wellcome tablets. This may provide some advantages for people who have problems swallowing the Zovirax tablets. Back to Basics Column WHAT IS THE DIFFERENCE BETWEEN A "NUCLEOSIDE ANALOGUE" AND A "PROTEASE INHIBITOR" By Ian McKnight-Smith A few years ago, anti-viral treatments against HIV was relatively simple. However, things are changing, and there are a number of new classes of drugs being introduced into clinical use, such as protease inhibitors. With the recent good news from the Second International Congress on HIV treatments in Glasgow, we are going to hear a lot more about new treatments and drugs. How do anti-viral drugs differ? Why can some be used together while others can not? This article discusses two main classes of drugs; nucleoside analogues and protease inhibitors. The nucleoside analogues include the well-known drugs such as AZT, ddI and ddC. Recently, two new members of this group have been introduced and they are d4T and 3TC. The protease inhibitors include drugs such as saquinavir and the Abbott protease inhibitor, ABT538. NUCLEOSIDE ANALOGUES Nucleoside analogues are also referred to as reverse transcriptase inhibitors. This is a broad grouping which includes many anti-virals that work on inhibiting the process of reverse transcription where the genetic information of the HIV is inserted into the human DNA. Another group of reverse transcriptase inhibitors are also known as non nucleoside reverse transcriptase inhibitors or NNRTIs and these drugs work in a slightly different way to the nucleoside analogues. What are nucleoside analogues and how do they work? When the virus enters the T-cell or CD4 cell (the immune cell which HIV infects), it injects a strand of a substance called RNA. This is the basic unit of genetic information that is needed to reproduce the various components of the virus, such as the nucleus, the outside coat and the enzymes (small proteins) that drive the activities of the virus. RNA must be converted into a form that is compatible with the genetic material, or DNA, of the T-cell. As audio tape stores music, RNA and DNA store human genetic codes. These codes are made up of small units called nucleosides. As the viral RNA code is read within the T-cell, a chain of DNA is created. This process involves an enzyme, called reverse transcriptase, which makes the process occur. The reverse transcriptase facilitates the conversion of RNA to DNA. Where do the nucleoside analogue drugs fit into this picture? The word analogue means that it is a "look alike". These drugs look like the building blocks that are used to make up the chain of DNA. When the nucleoside analogue is picked up and put into this chain, the process of building the viral DNA is disrupted, because the next unit is unable to join the DNA chain. Ideally, the infection of this cell is stopped and hence the cell does not go on and become a factory for producing new viruses. The nucleoside analogues reduce the amount of virus in the body and reduce the number of new cells being infected and damaged. There is evidence that these drugs slow the progress of the disease and give people a longer period of being well. Unfortunately, after a period of time, the virus is able to get around this point in the transcription and hence is able to complete transcription. While the nucleoside analogues do work, they are only useful for a period of time. You may need to consider swapping or adding treatments after a you have been on one drug for an extended period of time. Certainly you should monitor how you are going; if there are signs that the drug is no longer being effective, then you should consider alternatives. There are a number of nucleoside analogues that are currently available to people with HIV in Australia. The most well-known and commonly used is AZT (zidovudine with the brand name of Retrovir). Two other drugs are currently licensed: ddI (didanosine with the brand name Videx) and ddC (zalcitabine with the brand name Hivid). The drugs d4T (stavudine) and 3TC (lamivudine) are also available through trials or special access programs. In Australia, most people begin treatment for HIV with this group of anti-viral drugs; in particular, treatment often begins with AZT at a dose of about 500 to 600 milligrams per day. There is increasing evidence that two or more drugs may be the most effective treatment available. The virus finds it more difficult to get around two drugs than one, which slows the progress of the virus for longer periods. Common combinations of nucleoside analogues include AZT+ddI, or AZT+ddC and most recently AZT+3TC. Early reports suggest that AZT and 3TC may be the most effective anti-viral treatment. There are also many studies looking at combining one or more of the nucleoside analogues with other anti-viral drugs that work at different points in the reproduction cycle of the virus. The next section will discuss the class of drugs called protease inhibitors and how they work. PROTEASE INHIBITORS The protease inhibitors are also anti-viral drugs that attack the effects of HIV. However they work at a different point in the reproductive cycle of the virus in the T-cell. What are protease inhibitors and how do they work? Once the virus has converted the RNA into the DNA, the viral DNA is inserted into the main DNA of the human cell. The cell then becomes a 'factory' for producing new HIV. The codes on the DNA dictate the production of the components of the new virus. A long chain of protein is constructed. This chain of protein is then chopped up and assembled as parts of the new virus. The process of cutting up the protein is controlled by an enzyme called protease. Interfering with the protease enzyme will hopefully disrupt the process of new viral construction, which in turn may slow the progress of the illness. There are a number of compounds that have been designed to interfere with the enzyme protease. In the last year, early trials with a number of the new protease inhibitors have been completed. The results look very promising, however some protease inhibitors are difficult for blood to absorb. In some trials, only small amounts of the protease inhibitors are getting into the T-cell. When the compounds reach the protease target, they are highly effective in stopping the production of new HIV. However, as with nucleoside analogues, the virus is able to get around the effects of the protease inhibitors. Over a period of time the virus can become resistant to this group of drugs. Therefore researchers think that protease inhibitors will probably not be used as single drug treatments. Instead they will be used in combination with other types of anti-HIV treatment. For example, one nucleoside analogue may be taken in combination with a protease inhibitor. Clinical trials are under way around the world to see if this is a more effective treatment. At this stage there is insufficient information to say how long the combinations of drugs will be effective and to what degree the progress of the illness will be delayed. It is too early to know the side effects of protease inhibitors. In the early trial with the Abbott protease inhibitor ABT 538, the only side effects reported were an increase in triglycerides (a form of cholesterol that indicate some viral activity) and some local numbness. However, larger studies are needed to provide more information on the side effects of ABT 538. Saquinavir is another protease inhibitor being trialed and again there are few side effects being reported. There is evidence that the body has trouble absorbing saquinavir which raises doubts about its effectiveness. Conclusion There are now two different approaches to preventing HIV reproduction in the human T-cells. The nucleoside analogues are designed to prevent the conversion and integration of the viral RNA into the human DNA. The aim is to stop the cell from producing new viruses that go on to infect other T-cells. The protease inhibitors work at a later stage in the cycle, once viral DNA is inserted into the cell's DNA. Protease is the enzyme that builds the new virus from protein. When this enzyme is inhibited, the process is stopped or slowed and therefore new virus can not be made in that cell. Neither of the anti-viral treatments are perfect. The only work for a period of time before the virus is able adapt and no longer be affected by the drug. This is called resistance. The use of single drugs does not provide long term benefit. It is hoped that studies looking at the use of anti-virals in combination will be more effective in fighting the HIV infection. DRUG RESISTANCE By Ian McKnight-Smith (adapted from article by Edward King/AIDS Treatment Update) Most reports about antiviral treatments against HIV include discussions about the development of HIV strains that are resistant to these treatments. Resistance seems to occur due to a kind of 'natural selection'. When someone starts taking an antiviral drug against HIV, such as AZT, the virus that is highly sensitive to the drug is rapidly killed. This leaves behind strains of HIV that are naturally less susceptible to AZT. When HIV reproduces, the new viruses often have small changes or mutations in their structure. Some of these mutations occur in the HIV enzymes, such as the reverse transcriptase and the protease enzymes, that are targeted by the antiviral drugs (see article in this issue of HIV Herald). Particular mutations can result in virus strains that are less susceptible to the effects of antiviral drugs. That is, antiviral drugs do not effectively inhibit the reproduction of the mutated or resistant HIV virus. Over a period of time, the 'pool' or amount of viruses that are sensitive to the treatment decreases and this leaves only strains of virus that can survive and grow in the presence of the antiviral being taken. A new pool of resistant viruses is created. Tests can now identify the presence of the HIV mutations that provide resistance to antivirals. Researchers can artificially produce HIV particles that have specific drug resistant mutations, allowing them to study their effects and interactions. There is now a growing body of information indicating that the development of HIV strains that are resistant to AZT may have a significant and negative impact on the survival time of the person who has this resistant form of HIV. Some research suggests that the development of high level AZT resistance is linked to an increased risk of disease progression even in people who switch to antivirals such as ddI or ddC. The development of resistance is not confined to the antivirals used against HIV; it occurs with many of the drugs that are used to treat the opportunistic illnesses associated with HIV. A number of antibiotics and antifungals see resistance develop relatively quickly if used as a single drug therapy. For example, resistance to many antibacterial agents used against tuberculosis has been documented. Cross Resistance At the Second International Congress on Drug Therapy on HIV in Glasgow, researcher Dr. Brendan Larder reported that some mutations caused by anti-HIV drugs can make the virus resistant to drugs which the individual may never have taken. This phenomenon is called cross resistance. The mutations caused by AZT do not appear to be cross resistant to other anti-HIV drugs. However there does appear to be cross resistance between ddI, ddC and 3TC, so HIV strains that are resistant to one of these drugs also have reduced susceptibility to the others. Research presented in Glasgow raised questions about the possibility that cross resistance may also occur between the members of the group of drugs called protease inhibitors (see article in this issue ). Consequently, current drug treatment may affect the benefits of other drugs in the future. This is particularly true of drugs such as AZT, ddI and ddC. However, there are benefits to be had from the current treatments and delaying use may adversely affect a person's prognosis or quality of life. Cross resistance is caused by a mutation which confers resistance to several drugs. This is different to multi-drug resistance in which a single strain of HIV develops several mutations which create resistance to a specific drug. Multi-drug resistant strains can develop in people who have taken several anti-HIV drugs at one time. Using Resistance For Benefit In 1992 researchers in Boston reported that by exposing HIV to three drugs simultaneously, HIV developed mutations, which made it unable to reproduce or go on to infect other cells. There was considerable interest in encouraging the virus to mutate into a form that was not able to live or reproduce. However, it soon became clear that the experiments had been flawed. Researchers found that HIV could develop resistance to several drugs and still be able to infect and kill cells. Nevertheless, research presented in Glasgow suggested that there may be still a role for exploring virus mutation. One explanation for the promising results seen with the combination of AZT and 3TC is that the combination prevents the development of AZT resistant strains of HIV, or makes them susceptible to treatments again. The pressure to mutate may have been toward forming resistant strains to 3TC that were in turn sensitive to the effects of AZT. Dr. Larder further reported that in the test tube, it had been impossible to produce strains of HIV that were resistant to both AZT and 3TC. New CMV Retinitis Treatment By Ian McKnight-Smith A study conducted by the National Eye Institute (NEI) in the United States has reported that the use of ganciclovir implant pellets are effective in treating CMV retinitis, a sight threatening illness that affects a high proportion of people with HIV. The implant consists of a small pellet measuring four millimetres in diameter, which contains a sustained release formulation of the drug ganciclovir. This pellet is inserted directly into the inside of the eye, where it releases a small but steady amount of the drug over a period of several months. When the drug supply is exhausted a new pellet will be inserted. The study results show CMV is slowed or halted in people recently diagnosed with the illness. The average period of remission was approximately eight months. In the control group, who received no immediate treatment, the retinitis was seen to be significantly worse within fifteen days of entering the study. "The findings provide strong scientific evidence that this experimental device can help to improve treatment and potentially the quality of life for thousands of AIDS patients worldwide," said Dr Kupfer, one of the principal researchers. Currently CMV retinitis is treated with the use of intravenous infusions of ganciclovir or foscarnet. While these treatments can be effective in slowing progression of the illness, they are also invasive because the recipient undergoes daily intravenous infusions throughout his or her life. This has prompted investigations into a better way of taking the drugs. The eye implants will require people with CMV to have minor surgery to insert the device. The procedure is performed quickly under local anaesthetic, taking less than one hour to perform in an outpatients setting. The American Federal Drug Administration has not yet approved the ganciclovir implant, however the results from this study may accelerate the approval process, and the subsequent approval of ganciclovir for use in Australia. Pharmaceutical company takeovers may further delay the use of ganciclovir in this country. Roche has taken over Syntex, and Syntex was negotiating the licensing of the implant formulation of ganciclovir with the manufacturers. Negotiations were not completed and this process appears to be back at square one. The study evaluated the safety and efficacy of the ganciclovir implant as the first line of treatment for the newly diagnosed people with AIDS and peripheral CMV retinitis. Twenty-six people were studied; thirty eyes were randomly assigned to either immediate treatment with the pellets (within 48 hours of entry into the study) or deferred treatment (when there were indications of progression of the illness). The study found that in the people who received immediate treatment, the ganciclovir implants eliminated all signs of active CMV for an average of 226 days, or about eight months in total. In the deferred group this time to progression was reduced to 15 days. The optimal time to replace the implants still has to be determined, but researchers suggested that the life of the implant would around thirty-two weeks to ensure that the risk of relapse was minimised. The researchers commented, "we found that the implants released the drug into the eye at variable rates, making it hard to know when the device actually needed to be replaced." The researchers further reported that the participants enjoyed good vision with the implant. By the final follow up eye examination, thirty-four or the thirty-nine eyes treated with the implant had nearly perfect vision. However most patients reported blurred vision immediately after receiving the ganciclovir implant; normal vision took about four weeks to return. A number of other difficulties emerged during the study. Detachment of the retina, a common problem for people with CMV retinitis, occurred in eighteen percent of the eyes in the study. The researchers said that they were unclear as to whether the detachments were due to the implants or to the CMV illness itself. Because the implant releases ganciclovir into one eye, the researchers are concerned that such an approach may result in one eye being protected against retinitis and the other then being free to develop symptoms, and possibly at an accelerated rate. In addition, eight of the participants in the study developed CMV infections in other parts of the body. These people then had to be treated with the conventional forms of intravenous ganciclovir or foscarnet. Further studies are being conducted overseas to expand the experience with this form of treatment. In Australia, a few people have had experience with the treatment when the parent company offered the National Centre of HIV Epidemiology and Clinical Research some sample kits to use with selected patients. The HIV Herald does not know of any plans to market the product. Hepatitis C infection does not influence survival in AIDS By Ian McKnight-Smith Hepatitis C and HIV co-infection does not appear to have a significant impact on the survival of gay men with HIV/AIDS, according to a report from San Francisco. Researchers compared co-infection in a group of gay men who were not intravenous drug-users, and a control group of general blood donors. They found that unprotected gay sex may be a means of transmitting hepatitis C. Both hepatitis C (also known as HCV) and HIV are known to be transmitted by injection (parenteral), and co-infection with these two viruses is common among people with a history of unsafe intravenous drug use or transfusion. Researchers commented, "It is less clear whether hepatitis C, like HIV is sexually transmitted; and there is limited information available about the prevalence of hepatitis C and HIV co- infection among gay and bisexual HIV-infected patients without a history of intravenous drug use". Initial reports indicated that HIV accelerates the course of hepatitis C illnesses, in particular liver disease, however the overall impact on people with both illnesses has been unknown. This recent study looked at the prevalence of HCV infection in a population of HIV-positive, non-users to determine if there are any differences in the course of the HIV illness in the group who were co-infected with HIV and HCV compared with the general HIV population. The study included 512 participants, 224 of whom had AIDS, 11.7 percent of the total group were hepatitis immunoassay positive. This was confirmed by use of more sensitive tests such as PCR. The finding was in direct contrast to a randomly selected control group of blood bank donors, where the incidence of hepatitis C was a little greater than one percent. The results showed that there was no significant difference in the survival time for the group shown to be hepatitis C positive and those who were negative. When the groups were looked at in terms of AIDS defining illnesses, again there was no difference between those who were co-infected with the two viruses and those who only had HIV. "Our study suggests that among patients with HIV infection, HCV infection is transmitted by homosexual contact; anti-HCV was several times more common (11.7%) in homosexual or bisexual patients from this HIV positive population (53%) without acknowledged drug use than in volunteer blood donors (less than 2%)", said the researchers. "Epidemiological studies now support the idea that HIV infection may facilitate the sexual transmission of hepatitis C, although the basis for this apparently increased transmission is unknown." they said. "Actuarial survival in HIV infected patients with or without AIDS has been shown to be unaltered by the presence of hepatitis B co- infection", they continued. "This study indicates that HCV, like hepatitis B, does not influence the survival time of HIV positive people, whether or not they have clinical symptoms of AIDS". Vitamin C and the common cold in people with HIV Adapted from Treatments Update Canada October 1994 Background Many people with HIV/AIDS in Australia and other developed countries buy nutritional supplements as part of their treatment programs against illness. Some take multi- vitamin and mineral supplements, while other people have detailed regimens for each vitamin. People use a wide range of supplements including extra proteins, fatty acids, co-enzyme Q10 and carnitine. In illnesses where malabsorption, diarrhoea, altered energy cycles and poor appetite occur, people may look to other ways to maintain health and nutrition. Vitamin C may be a common supplement. Vitamin C and HIV Several years ago researchers reported that vitamin C could block the production of HIV in the test tube. To achieve a concentration of the vitamin in the body equivalent to that used in the test tube, it was estimated that a person would have to take a minimum of twelve grams per day, which is more than six times the normal dose. Subsequently, some studies have suggested that the use of these very high doses may cause more harm than good, however the results were conflicting. While many compounds can block HIV in the test tube, they do not always provide the same benefit to people with HIV/AIDS. Nevertheless, some doctors and therapists who care for people with HIV have found that extra vitamin C can accelerate recovery from illnesses such as the common cold. Prevention against the common cold Every year infection from the common cold affects millions of people. Over twenty research studies have tested vitamin C as a preventative against infection. Overall the vitamin did not appear to be effective as a preventative agent, although one study did show the vitamin was protective against infection. The dose needed to achieve protection against the cold was in the order of three grams or higher. Reducing symptoms Information from twenty-one studies suggests that the use of vitamin C can reduce the severity and the duration of symptoms. Twenty of these studies were double blind studies, where neither the doctor nor the patient knew whether they were getting the vitamin or a placebo. In fourteen of these studies the differences reached statistical significance, and other studies indicated trends in favour of the people taking the vitamin. Doses These studies do not provide recommendations on the best dosage. Most studies used a starting dose of one gram which was then increased to four grams when the symptoms appeared. The highest doses reached six grams per day. Some side effects, such as diarrhoea, were associated with high doses of vitamin C. However, as a person becomes sicker, the chance of diarrhoea was reduced in people taking large doses of vitamin C, such as thirty grams per day. How could it work? Researchers are not clear how vitamin C works against illness, nor why high doses have an influence on the symptoms of the common cold. The immune system appears to need more vitamin C when people have a cold. When a person has a cold, the body produces more "free radicals", active compounds which damage cells. It is thought that the vitamin protects cells from "free radicals" . Bits and Pieces By Ian McKnight-Smith Nevirapine combination study The American AIDS Clinical Trials Group has conducted a study (ACTG241) comparing the use of combinations of anti-viral drugs. Researchers compared AZT+ddI to AZT+ddI+ Nevirapine in people with less than 350 CD4 cells or T-cells (the immune cells that HIV infects) who have been on AZT for more than 6 months. The doses used were 200 milligrams of AZT three times a day, 200 milligrams of ddI twice a day and 200 milligrams of nevirapine twice a day. Participants who received the three drug combination had greater increases in T-cell count after the forty-eight week study, compared to the participants who received the two drug combination. Additionally, participants who received the three drug combinations had a greater reduction in viral load (the amount of virus in the blood) when compared to the group receiving only AZT and ddI. However the disappointing news was that there was no difference in the rate of progression of illness between the two study groups. Source: Gay Men's Health Crisis (GMHC), New York City, Nov. 1994 Viral Resistance to Protease The Merck pharmaceutical company have been testing a new antiviral drug, which is a type of protease inhibitor. Resistance to L-735,524 the Merck protease inhibitor, has been shown in recent clinical studies. Initial research showed that some degree of resistance occurs after 12-16 weeks on the drug, with a corresponding decrease in T- cells and an increase in viral load. Data on a small group of volunteers who continued to take the Merck drug after the initial trial showed resistance to the protease drug, as well as cross resistance with other protease inhibitors that are in development. Merck is now exploring higher doses of this drug as well as combining it with nucleoside analogues such as AZT or ddI to determine whether these strategies may delay the development of resistance to both types of anti-virals. Source: Project Inform, San Francisco Dec. 1994 More Protease Research Protease inhibitor research is being expanded by the company Upjohn. Upjohn's first protease inhibitor U 96988 is currently in multi-dose studies in England. A second drug, U 103107, is being researched on healthy volunteers in the United States. Both of these drugs are non-peptide based protease inhibitors, and as such are easier and cheaper to manufacture than peptide derived drugs such as saquinavir. If these drugs get into general use, they may be about ten times cheaper than other drugs. Source: Project Inform, San Francisco Dec. 1994 A possible cause of KS Karposi's Sarcoma (KS), which causes skin lesions in some men with HIV, may be caused by a virus. Researchers at Columbia University in the United States, have found evidence of a previously unknown herpes virus in KS lesions of people with AIDS. People who do not have HIV and KS do not appear to have the new virus. It is occasionally present in non-KS tissue in people with AIDS. The association between KS and the virus does not necessarily mean that the virus causes KS; it could be a normally occurring virus which prefers to grow in KS tissue. If the virus does cause KS, the finding will be very important in developing treatments, determining who is at risk, and preventing the spread of the virus. It is not known whether the new virus is sensitive to any existing drugs. The December 1994 HIV Herald noted anecodotal patient reports that a drug called foscarnet, which is used to treat cytomegalovirus (CMV is a type of herpesvirus) had a positive effect on KS. Researchers have long believed that KS is not a true cancer; KS is thought to be caused by an infectious agent other than HIV which only becomes a problem in people who are immune compromised. KS is twenty times more likely to be found in gay men with AIDS than in haemophiliacs with AIDS and may be transmitted by unsafe sexual practices. The new research used an advanced biotechnology technique called representational differential analysis (RDA). In RDA, two different tissues are taken from the same person. In this case, samples are taken from a KS lesion and tissue that is not KS affected. RDA uses gene amplification (PCR) in order to find genetic sequences which are uniquely present in the tissue of interest. Once such a sequence is identified, more conventional techniques can be used to identify it in other tissue samples. Source: AIDS Treatment News, Dec. 23 1994