From: grahameperry Date: Jun 28 09:52:23 1994 (327 lines) Subject: Proj. Inform Town Mtg-Jan94 (O.I. Update) Project Inform Town Meeting - January 1994 Update of Opportunistic Infections' Prophylaxis and Treatment Project Inform provides treatment information to HIV infected people, their family, doctors and health care professionals as well as HIV service providers. They run a nationwide treatment hotline. Their number is 800-822- 7422 (nationwide) or 415-558-9051 (San Francisco). They are open Monday to Saturday 10am - 4pm (Pacific standard time). New callers can receive the Treatment Information Packet. In addition to this introductory packet, several other fact sheets, recent bulletins, and handouts on HIV-related issues and treatments are available by requests. Project Inform holds monthly Town Meetings in San Francisco. They deal with the latest in treatment information as well as public policy that affects HIV research. If you want more information about the topics covered, please call Project Inform at 800-822-7422 (nationwide) or 415-558-9051 (San Francisco). Brenda Lein, Information Director and Ben Chang who has been at Project Inform for 6 months and heads Project Opportunistic Infections and Project Antivirals ------------------------------------------------------------------------------ This meeting is an Update of Opportunistic Infections' Prophylaxis and Treatment of PCP, MAI, CMV, fungal infections, cryptosporidium, and new OI drugs in development as well as an update on antivirals. PCP PCP is still the leading cause of death in people with AIDS but it is preventable. The 1st line therapy (the preferred treatement) is Bactrim (also called Septra), then Dapsone and then Aerosolized Pentamidine. Bactrim also acts a a prophylaxis for toxoplasmosis and bacterial infections. Dosage is 1 double strength tablet either once a day or 3- 4 times a week. Which is best of these two dosages isn't known. Bactrim also can prevent toxoplasmosis and other bacterial infections Dapsone is taken as a 50mg dose 2 times a day (also good against bacterial infections). Both Dapsone and Bactrim are oral drugs Aerosolized Pentamidine is inhaled and is only good for preventing PCP in the lungs (localized). It is important to look at whether prophylaxis works in a systemic way (throughout the body) or localized (fights a O.I. in a certain part of the body). A newer drug used mainly for PCP treatment is atovaquone - there is not as much information on it. It has mainly been used for treatment but it may be a good alternative for prevention if you don't tolerate the others drugs. But it is not absorbed well - it needs to be taken with 3 grams of fat. Lots of people can't take this drug because of the large amount of fat needed to be taken with it. Maintaining steady drug levels are a problem with this drug. There is a new version of this drug in a suspension form. Just because this is a newer drug it doesn't mean that it's better. It should be used as a treatment if you have failed other treatments and can be used a last resort for PCP prophylaxis. There were some recently released results from a large PCP prophylaxis study (ACTG 081) compare Bactrim vs Dapsone vs Aero. Pentamidine (note: the dose for Bactrim was 2 tablet a day which is a higher dose than normally used - which probably blurred the data). The study used the Intent to Treat Analysis. There were 842 people in the study. The bottom line was that Bactrim was better than Dapsone which was better than Aero Pentamidine. If subjects were intolerant to the drugs assigned, there were allowed to switch to another drug, but they were analyzed according to the drug that they were originally assigned to.. Using an "Intent to Treat" analysis, they saw PCP in 42% of those assigned to use Bactrim, 48% - dapsone, 44% - aero. pent. When they looked at what people actually used (many people switched over because of drug intolerance) there were 14 cases of PCP with people using Bactrim, 89 cases with Dapsone , 72 cases with aero. pentamidine. There was a larger group of people using Dapsone than the other drugs so this number is skewed. This was because people intolerant to Bactrim were switched to Dapsome. Some of these reactions to Bactrim were probably caused by the high dose. But the final results were that Bactrim was #1, Dapsone #2, and Aero Pentamidine was #3. This study was also conducted before sulpha densitization which should be considered in cases of allergic reactions to Bactrim or Dapsone. After taking into account the drugs actually used and taking into account the size of the groups. For Treatments of PCP - Bactrim was the 1st choice for PCP prophylaxis, IV Pentamidine was 2nd, IV Trimetrexate (which is a new drug) and lucavor (which prevents the side effects caused by trimetrexate)was third , Atovoquone - 4th (which should only be used for mild to moderate PCP). Also note that Burroughs Welcome is out peddling atovoquone as a primary treatment even theough it isn't. Important: Supha densensitization is important to try even if you don't use Bactim as prophylaxis because it will allow you to use Bactrim as a treatment if you ever get active PCP for which it is the best drug. Project Inform's Hotline has information on densensitization. There are three densensitization techniques that the P.I.'s PCP Prophylaxis fact sheet outlines. Low glutathione levels may be related to sulpha drug reactions. There are a number of different compounds which may raise glutathione levels - prostitine and NAC may be useful with reducing reactions to sulpha drugs. Desensitization protocols are successful 75% of the time. If someone is severely reactive to either a sulpha drug, they may not want to try the desensitization. MAC The Public Health Service's Taskforce recently issued guidelines on prevention and treatment of MAC. MAC prophylaxis is recomended for people with under 100 CD4 count. The recommended dose is 300 mg of rifabutin daily (this was approved in 1992). The recommendations for treatment is to use combination therapy of clairithromycin or azithromycin plus 1 drug (ethambutol). You could add a third or fourth drug: clofazimine, ciprofloxacin, rifabutin, or amikacin (an IV drug). If you are thinking about starting MAC prophylaxis or treatement with rifabutin, you should take a TB test because rifabutin has activity against TB. So if you are positive for TB, you should probably be treated with more than just one drug to prevent resistant TB. It is really important to take a TB test before starting rifabutin. When should people be thinking about MAC prophylaxis? Rifabutin is recommended if you have under 100 CD4 cells. Also think about limiting exposure to MAC. Some people try to limit MAC exposure from bird droppings, by cleaning vegetables thoroughly (MAC is found in soil). You are predisposed if you have under 100 CD4 count, and possibly if your alkaline photatase levels are elevated (this is found on a standard blood tests). Some people are using clarithromycin or azithromycin as prophylaxis. BUT if you have a breakthrough of MAC which on one of these drugs, you've used up the first line therapy since these two drugs are cross resistant. Also look at what other therapies that you are on and look for drug interactions. Be aware that most HIV drugs metabolize in the liver. A recent study showed rifabutin decreases clarithromycin levels up to 50%, and clarithromycin can increate rifabutin levels up to 80%. Also because people who are are on antibiotics can have increased fungal infections, they are usually taking an antifungal like fluconazole. Fluconazole can also increase rifabutin levels up to 80%. So if you are using all three drugs, clarithromycin , rifabutin and fluconazole, you're probably getting way too much rifabutin. It is important to talk to your doctor and see if there are any drug interactions and/or are there other drugs which you could take that wouldn't cause these interactions. It can be worked out but it is important to be proactive and talk to you doctor. For people with intolerance to clarithromycin or azithromycin, a study showed that a 4 drug combination was as effective. CMV CMV is related to the herpes virus - two drugs that are being tested in preventing CMV, oral gancyclovir and pro-acyclovir (which has better absorbtion than acyclovir). Currently, it is unclear whether they work. Oral gancyclovir can cause neutropenia, which is common side effect, and when combined with DDI, it can cause pancreatitis. Treatment of CMV uses IV gancyclovir and IV forcarnet which have high toxicities. One of the new drugs for treatment is HPCMG, a nucleoside analogue. It has a long half life - and is given once every 2 weeks. So you would not need to have a central line (IV attachment) implanted. Some small studies have shown that the drug is a little bit toxic. The company thinks that if you add probenicid, there may be less toxicities (One study with AZT and probenicid showed AZT levels were decreased) . The drugs toxicities are similar to those of IV foscarnet - renal problems. One person had elevated kidney functions. They are montioring protinerior levels. If protinerior levels are elevated, kidney problems may occur. If you are going into first time treatment for CMV - what would be your choices (of new therapies)? HPCMG gives better quality of life because of less frequent infusions, once on maintainance therapy, and no central line needs to be implanted. We don't know about potential toxicities of HPCMG to say that this is an attractive drug to use. Interoccular implants with Gancyclovir: These are surgicallly implanted in one eye and are good for either 4 or 8 months. Even though they've seen very good early data, implants only act locally (in one eye), but CMV may occur in the other eye or in other parts of the body (e.g. the colon and the esophagus). There is also an interoccular plus oral gancyclovir study proposed for trng active CMV. In balancing the risk of CMV in other parts of the body, shouldn't you look at the incidence of other types of CMV beside in the eye? In people with HIV there is an 1% incidence of CMV Colitis (quite small) but getting CMV in the other eye would be a larger problem. Since systemic treatment can be immunosuppressive, interoccular implants make sense from this standpoint. We also need to look at CMV resistance with interoccular implants - the first study on implants was only was for 8 months, 2 out of 40 people had a relapse. Other experimental CMV therapies * Monoclonal antibodies - Phase 1 showed that it prolonged relapse to CMV but there was messy data. This is going to next phase. * Cyclobut-G - is the first oral CMV compound - there is a safety study at Johns Hopkins. * CMV antisense - there is a safety study in San Diego. The first study of prophylaxis with oral gancyclovir starts in May. Fungal Infections Fungal infections include thrush and cryptococal. This covers a very broad range of fungal disease. Fluconazole, Ketoconazole, Itraconazole, or sometimes Clotrimazole are used in treatment of fungal infections. All have broad antifungal activity ACTG 981 gave fluconazole 200mg a day or Loltrimazole troches, 5 times a day. They found a clear cut benefit for fluconozole such as for prevention of cryptococcal meningitis. Amphotericin B is the gold standard for treatment against moderate to severe cryptococcal meningitis but there are serious toxicities with this drug. Fluconozole can be used for mild disease because it is tolerated better. Intraconazole is a better treatment for Histoplasmosis than fluconazole or amphotericin. There are three types of Liposmal fomulation currently in large scale testing and side effects are better than the side effects from Amphotericin B. These drugs are incapsulated in fatty substances and have a much longer half life (stays in the body longer). ACTG 901 had 98 people in it. There were 8 different cases of fungal infections in people taking fluconazole vs. 22 cases of fungal infection for those taking clotrimazole trouches. 2 cases of thrush on fluconozole vs 15 cases on clotrimazole trouches. 1 case of Crypto meningitis on fluconozole vs 14 cases on clotrimazole trouches. Fluconozole use can cause resistance problems. Using it for prophylaxis could cause problems during treatment becasue of resistance. For women who are using fluconozole for vaginal and esophigeal thrush. It may be better to use other options of treatments in order to minimize problems with fluconazole resistance. For instance, you could use nistatine or vinegar for vaginal candiadiasis. Cryptosporidium - there are a lack of drugs for treatment. Recently, a study of high dose oral azithromycin (1200mg) vs placebo - people who were able to absorb the drug had a clinical benefit but diahrrea and g.i. problems caused problems with absorbsion. These are common symptoms of cryptosporidium. An study using I.V. azithromycin is being planned. This would allow all the patients to be able to absorb the drug. Hoffman-LaRoche is looking at a drug, Aparaprim, that could be used against PCP and as a broad spectrum antibacterial. A saftey was done in Europe but it is floundering within Hoffman LaRouche. Also kinecandin analogues against PCP and fungal infections such as candiadiasis and aspiriliosis but not cryptococcal meningitis are being looked at. What's interesting is that these drugs (e.g. azithromycin) could be used against several O.I.'s so that you might be able to take fewer drugs and face fewer drug interactions and side effects. Antivirals After the AIDS conference, people felt that nothing was happening in AIDS research. This is a false image. Clearly there is a phenomenal advancement from just a few years ago. Many more drugs are in study (which doesn't mean they will all pan out). Three new Protease Inhibitors are going into safety studies. Three Protease Inhibitors are in studies now. Hoffman-LaRoche will start a large clinical study soon. Searle Protease Inhibitors is in safety in Germany. The Merck Protease Inhibitors looks best - no resistance has been found [Note: this is before more recent information on resistance was found]. In HIV replication protease inhibitor drugs blocks viral replication at a late stage - it blocks protease and the HIV in the cell becomes non infectious. It has been shown (in the Merck and Searle drugs) that it kills virus in macrophages. Antisense drugs are analagous to putting peanut butter in a zipper - it doesn't allow HIV to bind properly. In a French study, they have seen some interesting minor increases in CD4 and seen small drops in viral loads. They are only up to 2 injections so far. We'll continue to follow this. This is only the first step in the process. The doctor who has worked on this says that there are some newer antisense compounds in the lab which look better than the drug they are currently testing. Viagene's gene therapy delivers therapeutic vaccines. We should have some preliminary data in the next few weeks. Gary Navel is studying Rebn10 which seems to protect cell against HIV gene constructs. Rebn10 looked better in test than several other compounds. The study is only open for 6 people - they will draw peripheral cells and compare cells to a placebo substance. This is really preliminary work. They will learn a lot about gene therapy and how to apply it in future research. Ribozines - these occur in nature - we've evolved them so that they cut up RNA. Then they've been further evolved to cut up HIV RNA. Dr. Flossie-Wong is proposing a study but there isn't a drug company backing her. 3TC by Glaxo - there are a number of trials enrolling, and there is a compassionate use program (call 800-248-9757 for information). 3TC is a nucleoside analogue, but we haven't seen the same antiviral activity as with other nucleosides, but we haven't seen any toxicities. This is perhaps an alternative for some people. D4T - submitted a new drug application on Dec 28. It should take 4 to 5 monthsfor the FDA to decide whether to approve D4T. We haven't seen the data on D4T and have asked for a meeting with company to look at it. BHAP-E (Upjohn) - U90 which is a non nucleoside reverse transcriptide - Phase 3 saw problems with rapid resistance with this class of drugs. Probably, this drug will have resistance but in test tubes it looked different than the other of this drug's family. N-Butyl DNJ prodrug - in test tubes, it inhibits the sugar coating of the HIV virus - which prevents viral replication. Original composition of the drug had serious side effects (diahrrea). In the new formulation of the drug, researchers are not seeing side effects and have seen some antiviral activity. It may have effect against syncitia inducing (S.I.) virus. They want to check if this prevents S.I. from forming and hopes to use this in combination with other drugs. The company is hoping to start a study on this. IL12 - builds on a certain immune pathogenisis theory associated with the TH1/TH2 shift. In theory, IL12 helps the TH1 subset of cells. Two companies, Hoffman LaRoche and Genetic Institute are pursuing it. Early data saw severe toxicities in animals - frightening toxicities and probably won't move into human studies this year. Autologious stem cell transplants - 1 experiment being proposed (Denver) - very preliminary. Trental - relatively non-toxic - is a TNF inhibitor associated with HIV and KS suppression. Haven't seen phenomenal results on the study. People on drug for 1 year still had 30 CD4 cells (stability). Its a small study but data is being looked at and on Feb 11 they will review it and see if they will continue to look at this drug. <<< END of Meeting >>>