[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 1 January, 1993 Gay Men's Health Crisis: Treatment Issues > New ddI Study Results > Catheters: An Overview > Shortages of Sulfadiazine, a Critical Toxo Drug > Treatment briefs >> World of Difference >> Articles of Interest >> Affording Care >> More on Depression >> TMP/SMX Superior as PCP Prophylaxis >> Cats No Significant Toxo Risk >> Promising Report on IVIG >> Sally Cooper new PWA Health Group director >> CRIA Hydroxychloroquine Trial >> Nutrition Forum > Washington Watch ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ New ddI Study Results by Gabriel Torres, M.D. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ New information on the earlier use of ddI has emerged in the last several weeks from trials conducted in the United States and abroad. DdI is approved by the FDA for use in adults and pediatric patients with advanced HIV infection who have failed (clinical or immunological deterioration) or are intolerant of AZT therapy. In September 1992, after the results of a randomized trial of the two drugs (ACTG 116B/117) showed ddI to be superior in patients with greater than four months of AZT therapy, the labeling of the ddI was amended to include adult patients who had received prolonged AZT therapy. This article will focus on the results of the most recent trials that shed further light onto the dosage regimens and time of initiation of ddI in different patient populations. ACTG 116A: This study conducted by the AIDS Clinical Trials Group (ACTG) and Bristol Myers Squibb was a randomized comparison of AZT (600 mg/day) and two doses (500 and 750 mg/day) of ddI in patients who had never taken AZT or who had taken the drug for less than 16 weeks.[1, 2, 3] It was conducted at 39 sites between October 1989 and May 1992. The study enrolled patients with AIDS and ARC with less than 300 T4 cells and asymptomatic patients with less than 200 T4 cells. The primary endpoint was progression to a new AIDS- defining event, other than early dementia and Kaposi's sarcoma. Of the 617 participants enrolled, one fourth had AIDS, two thirds had ARC and the remainder were asymptomatic. Thirteen percent were black and 12% were latinos; women comprised 8%. The median T4 cell count was 130. The number of patients in each arm was similar: ddI 500 mg/day, 197 patients; ddI 750 mg/day, 212 patients; and AZT 500 mg/day, 208 patients. The sachet (powder) form of ddI was used in the trial. Due to differences in absorption, a 500 mg/day dose of ddI in the sachet form is equivalent to a 400 mg/day dose in the tablet form. Results After a median follow-up of 85 weeks, the study showed that AZT was superior to both doses of ddI in patients who had never taken AZT (AZT-naive) in terms of survival and the development of new AIDS-defining events or death. Among the 380 AZT-naive patients, 18% of those given AZT developed a new AIDS-defining condition or died compared to 31% and 29% of those who received 750 mg/day or 500 mg/day of ddI. However, in patients who had taken AZT for 8-16 weeks, ddI was superior to AZT in terms of both survival and new AIDS-defining conditions. Death rates from ddI were 3% and 2% compared to 11% for AZT. For those patients who had taken AZT for less than 8 weeks, both drugs behaved similarly. Adverse Effects The major side effects from ddI were pancreatitis and elevation in serum amylase (a pancreatic enzyme which is measured in the blood). Patients on the higher dose of ddI developed more pancreatitis within one year than those on the lower dose of ddI or those on AZT. Those on the low dose of ddI had similar rates of pancreatitis as those on AZT. This implies that some of the pancreatitis may be related to complications of HIV infection. Two patients died from pancreatitis in the high-dose ddI group. Rates of peripheral neuropathy were also higher for the high-dose ddI group as compared to the low-dose ddI and the AZT groups. There was no significant difference in incidence of neuropathy between the low-dose ddI and AZT. The only side effect that was more common for AZT was neutropenia (low levels of a type of white blood cell). T4 changes: Among the AZT-naive patients, those assigned to AZT had more significant rises in T4 counts by week 8 when compared to the ddI group; yet by week 48, the AZT group had experienced the greatest decline in counts. Among those who had taken AZT previously, there were no differences in T4 count changes. ALPHA Trial The multinational ALPHA trial, which began in May 1990 and was conducted in multiple European countries and Australia, has been completed and the preliminary results have been published in the British journal, The Lancet.[4] The trial studied two doses of ddI (750 mg/day, the high dose and 200 mg/day, the low dose) in patients with symptomatic HIV disease who were unable to take AZT. It was a double-blind comparison trial using the sachet (powder) formulation of ddI taken twice daily. A total of 1775 patients was enrolled, making it the largest randomized ddI trial in the world. The length of follow-up was on average 12 months and only 5% of the participants were lost to follow-up. On entry into the trial, 61% of the patients had AIDS and 65% had T4 cell counts less than 50; 55% had received zidovudine for 12 months or more. The study found no difference in survival between the two groups, with patients on the low dose of ddI surviving 12.4 months compared to 12.9 months for those taking the high dose. The rate of progression to AIDS or death was similar in the high- and low-dose groups, as was the rate of development of HIV-neuro-cognitive disorder (dementia). The difference in changes in T4 cell counts was very small; -1.7 cells in the low-dose and +2.5 cells in the high-dose group, and these small differences did not appear to influence survival. The most significant difference between the two dosage groups was a far higher incidence of adverse events in the high-dose ddI group. Thirty-eight percent of those in the high-dose group had to stop the drug due to side effects compared to 26% in the low-dose group. Clinical pancreatitis occurred in 41 patients in the high-dose group as opposed to only five cases in the low-dose group. It led to death in seven patients taking the high dose and one patient taking the low dose. Half of the cases of pancreatitis occurred within four months of starting the drug. Peripheral neuropathy also was more common in the high-dose group and was usually reversible on stopping treatment. Diarrhea was reported with equal frequency in both groups. The results of the ALPHA trial must be considered in light of the recently completed ACTG study 116B/117. This study, which demonstrated a benefit of switching to ddI after a mean period of 13.9 months of AZT, also found that 500 mg/day of ddI was superior to 750 mg/day. ALPHA seems to indicate that a dose even lower (200 mg/day) may be just as effective and substantially less toxic. In addition, a lower dose means, of course, a lower price. Individuals who choose the low-dose ddI regimen used in the ALPHA trial should be aware that since it was a sachet formulation, an equivalent dose in the tablet form would utilize even less than 200mg/day of ddI. As with AZT, lower doses of ddI are proving to be superior. Future nucleoside analogue trials must consider the lower doses from the onset to avoid unnecessary adverse effects. Expanded access study A small study of 27 patients enrolled in the ddI expanded access program at North Shore University Hospital in New York was reported in The Journal of Infectious Diseases in January 1993.[5] The expanded access protocol, sponsored by Bristol Myers Squibb prior to the drug's approval, provided free ddI to patients who were intolerant of or failing zidovudine (AZT). In the study, 67% (14 of 21) patients treated with ddI had a decline in the amount of virus cultured from the blood (viremia). Patients treated with ddI who had declines in viral titers also had improvements in weight gain over the first five months of treatment with ddI. Rates of new AIDS- defining illnesses were lower in those who had a drop in viral titer and their survival was longer. On the other hand, changes in p24 antigen levels did not correlate with early or late clinical events, suggesting that this viral marker is not useful as a marker of clinical outcomes. The results of this trial suggest that an increase in body weight associated with ddI therapy may be useful as a marker of antiviral activity, since it seems to correlate with reduction of viremia and thus may be a useful surrogate marker of response to therapy. CPCRA Trial The Community Program for Clinical Research on AIDS (CPCRA) is a branch of the National Institutes of Allergy and Infectious Disease (NIAID) which funds 17 community-based sites nationwide to perform AIDS clinical trials. A bulletin from NIAID dated January 22, 1993 reported the preliminary results of a large comparative, randomized trial of ddI and ddC in HIV-infected persons who were intolerant of or failing AZT.[6] The trial was open-label, meaning both patients and investigators knew which drug each patient was receiving. A total of 467 patients was enrolled from December 1990 to September 1992 at 78 community-based, CPCRA-affiliated sites. One third of the patients were non-white, one quarter were injecting drug users and 10% were women. Two thirds of the patients had a diagnosis of AIDS and the median T4 cell count was 37 for the entire group. The median follow-up period was 16 months. The average duration of AZT use was 17.4 months. The results of the trial indicated that ddI and ddC were similar in terms of progression of disease and survival. Of the 230 patients taking ddI, 156 (68%) died or developed a new AIDS-defining condition compared to 150 (63%) of the 237 patients taking ddC. There was a slight survival advantage for ddC (100 deaths in the ddI arm, 87 in the ddC arm). In addition, subsequent analyses suggested that the ddC group may have been more ill than the ddI arm. Not surprisingly, ddI seemed to cause more stomach pain, diarrhea and pancreatitis, whereas ddC caused more frequent and severe peripheral neuropathy and stomatitis (mouth ulcers). More patients on ddI had to switch to ddC than vice versa. This study seems to indicate that ddI and ddC have similar efficacy in patients with advanced HIV disease yet have different toxicities. The study also redefines the role of ddC monotherapy for patients who are unable to take or have failed AZT. Conclusion The results of several of the most important clinical trials of didanosine (ddI) conducted in the United States, Europe, and Australia have recently been reported. The studies indicate that significantly lower doses of ddI may be more beneficial than higher doses. One trial clearly demonstrates that AZT is superior to ddI in those persons with advanced HIV disease who have never taken AZT. Unfortunately, the results of these trials leave a lot of unanswered questions regarding the practical use of these drugs. One interpretation is that the drugs should be used sequentially, possibly switching from AZT to ddI after eight weeks. Will switching to combination therapy (AZT + ddI or ddC) prove to be superior to this alternative? How durable is the benefit obtainable from ddI? Are 200 mg/day and 500 mg/day of ddI equivalent? How soon does ddI resistance develop? Should a switch back to AZT be considered after a certain amount of time? Is the risk of life-threatening pancreatitis significant enough to choose ddC over ddI for those unable to tolerate or failing AZT? These questions may not be answered by large clinical trials presently underway, yet will be haunting primary care practitioners as they struggle to individualize therapy for their patients and attempt to interpret the data from these trials in their clinical practices. In addition, it becomes even clearer that research on new classes of anti-HIV compounds that are less toxic and provide more clear evidence of efficacy must be accelerated. 1. Folkers G. National Institutes of Health, News from NIAID, December 30, 1992. 2. National Institutes of Health, Backgrounder. 3. Boggan WE, AIDS Weekly, January 11, 1993. 4. Darbyshire JH, Aboulker J-P. Didanosine for zidovudine-intolerant patients with HIV disease. The Lancet, 1992; 340: 1346-7. 5. Shepp DH, Ashraf A. Effect of didanosine in HIV viremia and antigenemia in patients with advanced disease: correlation with clinical response. J Infec Dis 1993; 167: 30-5. 6. Glick ME, National Institutes of Health, News from NIAID, January 22, 1993 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Catheters: An Overview by Judith G. Rabkin, Ph.D., M.P.H. and Damien James Kipton, M.A. ^^^^^^^^^^^^^^^^^^^^^^^^^^ Introduction Many people with HIV illness need a catheter for intravenous (IV) infusions of medication or nutrition. Familiarity with catheters may help patients alleviate anxiety about their use. We describe in this article some of the indwelling catheters that are currently being utilized. A catheter is a tube made of a soft synthetic material, such as silicone rubber, which is used when it is necessary to receive fluids intravenously (within or into the vein) on multiple occasions over an extended period of time. It is inserted into a vein, and can be used to receive chemotherapy (cancer treatments), painkillers (such as morphine), antibiotics, antivirals (ganciclovir or foscarnet), nutritional supplements (such as Total Parenteral Nutrition --TPN), and hydration (intravenous fluids) at home. Types Of Catheters There are two broad categories of venous catheters. One category is the peripherally inserted central catheter (PICC-line), which is usually inserted into a vein in an arm and used for periods of up to three months. This catheter does not need to be surgically implanted and can be inserted at home by a trained nurse. For longer periods, catheters are surgically implanted directly into a central vein in the chest. These are called central venous catheters and can be used for months or years. There are two major types of central venous catheters. One is the Hickman (or Groshong modification) catheter, which exits the chest with an external tube. The second type of central venous catheter ends in a "port," a small chamber under the skin. Ports are reached by inserting a needle through the skin every time fluids are given or drawn. Both Hickmans and ports must be implanted by a surgeon in a hospital setting, commonly with local anesthesia and sedation.[1] Peripherally Inserted Lines and Catheters. When infusions are begun, the first few administrations are usually given through a regular intravenous (IV) line, not a catheter. A regular IV line is a small tube that extends about one inch into a vein in the arm, and for about half an inch outside the skin. It ends in a heplock, a small chamber that contains heparin, a substance that keeps blood from clotting (therefore allowing the catheter to remain open). The heplock can be reused for two or three days. After that, a midline or peripherally inserted central catheter (long-line) is likely to be inserted. Midline catheters are inserted in the arm like a regular IV line. The tubing inside the vein in the arm is longer (about six inches). In the best of circumstances, midline catheters can be kept in place for up to six weeks. Midlines cannot be used for long-term TPN, most chemotherapy, or to draw blood. Long-line or long-arm catheters, known also as peripherally inserted central catheters (PICC's), may be used instead of midlines. With this catheter, the silicone rubber tubing is inserted into a vein in the lower arm and then threaded up the arm into a large vein near the heart. Tubing extends outside the arm at the point of insertion and ends in a rubber cap through which a needle is inserted for infusions and blood drawing. The most common complication of midlines and PICC lines is phlebitis (inflammation of the vein), where the skin overlaying the vein becomes warm, red, and painful. The catheter will then usually be removed and replaced in another vein. Irritation may be caused by the catheter itself or by potent medications which can irritate the veins. Over time, people may run out of good peripheral veins, and an indwelling central line (also known as a right atrial catheter or venous access device) becomes necessary. Another complication of both midlines and PICCs is that they can "migrate out"; that is, the end of the catheter within the big vein near the heart can be dislocated to a smaller vein. When this occurs, the line usually has to be replaced. Indwelling Central Venous Catheters. The Hickman catheter (named after the surgeon who developed it in the late 1970s) is a modification of an earlier catheter developed by a Dr. Broviac in 1973 for the purpose of infusing total parenteral nutrition. The Hickman has a wider tube and thicker tube wall than the Broviac catheter, and is more widely used today.[2] The Hickman consists of a long internal tube that extends from a vein above the heart through a "tunnel" in the chest to what is called an exit site. About one inch before the exit site there is a small Dacron cuff that serves as an anchor and barrier to infection. Catheters may have one or more separate external tubes or "lumens" branching from the catheter outside the body. Each lumen is four or five inches long and ends in a rubber cap. When the catheter is used, a needle is inserted in this cap. The lumens are looped and taped to the chest when not in use. Many catheters used today by people with HIV illness have two lumens so that two procedures can be done simultaneously. The Groshong catheter is a newer version of the Hickman, in which the internal catheter tip is closed. Instead of an open tube, there is a valve or slit on the side of the tube. The valve remains closed when not in use. During an infusion, the pressure of the incoming fluid opens the valve, letting the fluid enter the bloodstream. When suction is applied (usually by a syringe), this negative pressure causes the valve to open inward, letting blood flow through the catheter into the syringe. A Groshong catheter does not need heparin flushes, slightly simplifying routine maintenance procedures. The valve is intended to minimize blood backflow problems.[3] The Groshong's tube is not as wide as the Hickman's. As a result, more time is needed for procedures such as transfusions. Inserting a Catheter. The catheter is inserted into a vein under the collarbone through a small incision in the chest, then threaded through the veins until one end is located in a big vein above the heart.[4] The other end is placed more or less vertically under the skin in a "tunnel" through tissue to a point in the mid-chest (or, recently, in the abdomen). A chest X-ray is taken to verify the catheter's position. The upper incision is closed, and the lower, "exit" incision is made to allow the catheter to emerge from the body. Surgeons may leave a loop of extra tubing under the skin at the insertion site for protection against inadvertent tugs on the external line and displacement of the line. Some hospitals consider catheter insertion a simple procedure and do it in examining rooms. This increases the risk of infection and is not recommended. Catheter Maintenance. The exit site of the catheter must be kept meticulously clean to prevent infection. Hands must be thoroughly washed with antiseptic solution every time the catheter is used. The exit site is covered with a dressing (a lightweight bandage) except when showering. The dressing should be changed two or three times a week, after a shower, or if it becomes loose. The injection cap at the end of the lumen(s) is usually changed weekly. The catheter must be flushed with saline before and after every use. A low dose of heparin is also needed for Hickman catheters after each use, or at least three times a week, to keep the catheter from clotting. People can shower, bathe, or wade as long as the exit site of the lumen is not submerged. People can also engage in vigorous activities (including sex) with a catheter. Spheres and Bags. The fluids provided through catheters are often administered using an IV pole on which a plastic bag is hung. Some medications, such as ganciclovir, are now available in prepackaged clear plastic spheres which hold medication for a single occasion. The plastic sphere precludes the need for an IV pole because the medication is pressure-driven rather than gravity-driven, and can be kept in a pocket or backpack. Such spheres allow normal activities during the infusion. They also cost more and are not covered by all insurance policies. Catheter Repair or Removal. Occasionally, a lumen cracks or ruptures. This can be quickly repaired in an emergency room, preferably at the hospital where the catheter was implanted, so that a suitable repair kit is stocked. In people with HIV, the most common reason for catheter removal is infection. A Hickman or Groshong catheter can be removed at the bedside, in a doctor's office, or in an emergency room. Ease of removal depends on how firmly the Dacron cuff has become anchored inside the chest. Using a local anesthetic, the catheter is gently pulled out. Occasionally a small incision is needed to accommodate the cuff. Ports The internal tubing of the port is the same as that of the indwelling catheter, but instead of having tubing extend outside the body, a "port" made of metal or a synthetic material is placed mid-chest under the skin. The skin is punctured with special needles (Huber needles) every time the port is used. There are no external components to the port. Initially, the skin over the port may be bruised and sore from the operation, but often becomes numb after a couple of weeks. Ports are most suitable for medication administered once or twice a month, but are now being used for daily procedures by people with HIV illness. Ports are attached to four or five inches of silicone tubing with a clamp and rubber cap at one end and a needle at the other. The needle is inserted through the skin into the port, creating a temporary lumen. Medication is inserted by a needle into the tube's rubber cap, not the port itself. Ports are available with either one or two chambers; however, the double size is somewhat large. When two "channels" are considered appropriate, surgeons often prefer to use an indwelling catheter instead of a port. A recent development is a port that can be placed in the forearm under the skin, instead of in the chest. Port Insertion. The procedure is done in an operating room by a surgeon and is like that of indwelling catheters. Both the port and the catheter are sewn into place and then the skin is closed under the pocket which holds the port. Once this is done, the port is completely under the skin and the only sign of its presence is a small bump under the skin. Port Maintenance. Doctors and home care agencies offer different recommendations about the frequency of needle change with ports. Surgeons may recommend changing the needle after every use as this is the safest possible procedure to prevent infection. Internists and home care agencies sometimes suggest changing the needle only twice a week, or even once a week, leaving the needle and attached tubing in place in the interim. The amount of care is variable, depending on how often the needle and attached tubing are changed. If the needle is removed after every use (which is particularly recommended for people with low white blood cell counts), a small dressing should be placed temporarily over the exit site, but otherwise care is minimal. If, however, the needle is left in place, the attached tubing has to be taken care of in the same manner as that of Hickmans and is in fact more vulnerable because it is more easily dislodged. The ports should be flushed with heparin about once a month when not in use. Ports must be removed in an operating room. There are few restrictions on activities for people with ports if the needle is changed after every use. If the needle is left in place, activity restrictions are the same as for Hickmans. Infections The major complications of central venous catheters are bacterial infections. The catheter exit site and impurities in infusion liquids are potential ports of entry for bacteria. Signs of Infection. The first signs of infection often occur in the skin around the exit site, which should be inspected frequently for this reason. Common early signs of infection are low-grade fevers (daily temperature checks are very important) and/or local symptoms at the catheter's exit site. The exit site may be puffy, tender, and red, with or without pus. If the tunnel becomes infected, a red streak may be seen on the chest above it. Systemic signs of infection (increased white blood cell count, fevers, chills) can occur with or without local signs. If you notice such symptoms or signs, call your doctor.[5] Types of Infections. A review of 54 people with AIDS, 102 people with non-HIV-related immunosuppression and 98 immunologically competent people with either Hickman catheters or ports found that people with AIDS are significantly more prone to catheter infection than were the other groups.[6] However, a smaller study found no difference in Hickman catheter rates of infection between people with and without HIV.[7] In eight studies, the percent of people developing catheter infections ranged from 6% to 52%, with a midpoint of 26%[8-15] Rates of Infections: Hickmans vs. Ports. In one study, eight of 30 people with Hickman catheters (27%) and seven of 24 with ports (29%) developed infections.[16] Similarly, another study found no difference in infection rate for 23 people with AIDS with Hickmans and 19 with ports over an average period of three-and-a-half months.[17] Nevertheless, proponents of ports continue to argue that ports have lower infection rates. Two trends emerge from the limited studies that have been done. First, infection rates seem to be declining. Contributing factors may include decreased operating time and more experienced surgeons; more specialized nursing care; better patient education; and earlier antimicrobial therapy when infection is suspected.[18] Second, once infected, catheters are less likely to be removed than in earlier years. Treatment of Infections. Local infections at the exit site, without tenderness along the tunnel, usually can be treated locally. Tunnel infections may require catheter removal and replacement on the other side of the chest. Septicemia (systemic infection) is currently treated with IV antibiotics for three weeks, followed by oral antibiotics for another three weeks, while leaving the catheter in place.[19] Apart from tunnel infections, there seems to be a trend to be more conservative about catheter removal unless the infection does not respond promptly to antibiotic treatment. Some received prophylaxis with antibiotics such as Ancef prior to insertion of the line, although this has not been studied. Conclusion Central venous catheters make life easier, more pleasant and more independent for those requiring frequent infusions over extended periods. There is no absolute limitation on any activity due to catheters except for swimming. In nearly all cases, people rather quickly learn to administer their medication by themselves, even (when the person is determined and tenacious) if their vision is impaired or absent. It is useful, but not essential, to have a friend, partner, or relative learn maintenance and administration procedures, particularly in later stages of illness, with backup from home care agencies always available. Infusion Lines and Catheters: The Basics Intravenous (IV) Line -- small tube that extends about one inch into a vein and about half an inch outside the skin. Can be used for two- three days. Midline Catheters -- inserted in the arm like an IV line, but tubing is inserted about 6 inches into the arm. Can be used for up to six weeks. Cannot be used for long-term TPN, chemotherapy, or to draw blood. Long-Line Catheters (Peripherally Inserted Central Catheters -- PICC) -- Tube is inserted into arm and then threaded up the arm into a big vein near the heart. Other end of tube extends outside the arm and ends in a rubber cap. Can be used for up to three months. Hickman Catheter -- long tube that extends internally from a central vein above the heart and exits the body through a tunnel in the chest (the exit site). Groshong Catheter -- new version of Hickman in which internal catheter tip is closed except when in use. Tube is not as wide as in the Hickman. Port -- same internal tubing as Hickman, but instead of tubing extending outside the body, a chamber or "port" of metal or synthetic material is placed under the skin. A needle is inserted through the skin each time fluids are given or drawn. Different brands include "Mediport" and "Porta-cath." Using the Catheter There are minor variations in procedure depending on the type of catheter used, the institution where it was implanted, and the agency that provided nursing care. In general, the following major steps are entailed whenever you give yourself medication (if your catheter has a clamp, it must be opened during the procedure): 1. Prepare two saline syringes for flushing (and a heparin syringe if using a Hickman). 2. Wipe injection cap with iodine pad, then alcohol pad. 3. Flush with one syringe of saline. 4. Insert needle connected to medication into injection cap and put tape over the junction to hold in place. 5. Wait for infusion to end. 6. When sphere or IV bag is empty, remove needle and discard in safety container. 7. Wipe injection cap with iodine and then alcohol pad. 8. Flush with saline (and heparin). Catheters vs. Ports: Advantages and Disadvantages of Each Institutional contracts with suppliers may determine whether Hickmans or Groshongs are used. Some hospitals do not consider PICC lines cost-effective, and patients go directly from intravenous lines to indwelling central venous catheters. Not all systems are available at every hospital. There are some clear-cut advantages to one system or the other, and also some relative advantages depending on medical indications. Ports are cosmetically superior and easier to maintain (if the needle is changed after every use). A significant disadvantage of the port is that it must be surgically removed. Also, an infected Hickman catheter can be removed on the spot in an emergency room, while a port requires transfer to an operating room for surgical removal. This can cause a delay in removing the source of the infection. There are also some relative disadvantages of the port. Some people don't like to stick themselves with needles, and so prefer catheters where the needle goes into the lumen through a rubber cap, not their skin. When made of stainless steel or titanium, ports interfere with diagnostic imaging (MRI and CT scans) and radiation. People with significant visual impairment cannot handle ports. When two lumens are indicated rather than one, surgeons often prefer Hickmans or Groshongs to ports although double ports are available. At advanced stages of illness, people might not be able to insert the special needles used with ports and will need assistance. In addition, when people lose a lot of weight, the port becomes quite prominent, particularly if it has two reservoirs. There are no absolute disadvantages to Hickman-type catheters. However, there are relative disadvantages. The lumens are visible to yourself and to others. More equipment is entailed. This involves keeping track of supplies (dressings, swabs, injection caps) and their delivery. These are also needed with ports, but in smaller amounts. You can't swim with a Hickman. Nursing visits may be needed more often (once a week or every two weeks) to check on procedures and the condition of the exit site. These are primarily practical and aesthetic disadvantages, and, while far from trivial, they are not in the same league as potential port-related major medical problems. All of these disadvantages also apply to ports if the needle and attached tubing are left in place for several days at a time. 1. Viall, CD. Your complete guide to central venous catheters. Nursing 20:34-41, 1990. 2. Hickman R, Buckner CD, Clift RA et al. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surgery, Gynecology & Obstetrics 148:871-875, 1979. 3. Burke M, Wilkes G, Berg D. et al., Eds. Cancer chemotherapy: A nursing process approach. Boston: Jones & Bartlers, 1991, pp. 409- 418. 4. Burke M, Wilkes, G, Berg D, et al. Ibid, pp. 409-418. 5. Skoutelis A, Murphy RL, MacDonell KB et al. Indwelling central venous catheter infections in patients with AIDS. Journal of Acquired Immune Deficiency Syndromes 3:335-342, 1990. 6. Skoutelis A, Murphy RL, MacDonell KB et al. Ibid. 7. Dick L, Mauro MA, Jaques PF et al. Radiologic insertion of Hickman catheters in HIV-positive patients: infectious complications. Journal of Vascular and Interventional Radiology. 2(3): 327-9, 1991. 8. Skoutelis A, Murphy RL, MacDonell KB et al. Op cit. 9. Henry K, Thurn J, Johnson S. Experience with central venous catheters in patients with AIDS (letter). New Eng J Medicine 320:1496, 1989. 10. Negri C, Saracco A, Lazzarin A. Use of central venous catheterization for AIDS patients (letter). J AIDS 4:543, 1991. 11. Salmon-Ceron D, Douard MC, Fegueux S et al. A randomized trial of Hickman-broviac vs. totally implantable central venous catheters in AIDS patients. Abstract WB 2406, VIIth International Conference on AIDS, Florence, 283, 1991. 12. Raviglione MC, Battan R, Pablos-Mendez et al. Infections associated with Hickman catheters in patients with AIDS. Am J Med 86:780-786, 1989. 13. Santana M, Molina V, Mullen M et al. Decreased incidence of Hickman catheter associated infections in patients with AIDS. Abstract PuB 7498, VIIIth International Conference on AIDS, Amsterdam, 1992 14. Afheldt M., Phillips J, Walmsley S et al. Infection rate from indwelling catheters. Abstract poB 3889, VIIIth International Conference on AIDS, Amsterdam, 1992 15. Gisselbrecht M, Eliaszewicz M, Pialoux G et al. Low rate of central venous catheter-related infection in HIV-infected patients. Abstract PuB 7212, VIIIth International Conference on AIDS, Amsterdam, 1992. 16. Skoutelis A, Murphy RL, MacDonell KB, et al. Op cit. 17. Salmon-Ceron D, Douard MC, Fegueux S et al. Op cit. 18. Santana M, Molina V, Mullen M et al. Op cit. 19. Skoutelis A, Murphy Ri, MacDonell KB et al. Op cit. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Shortages of Sulfadiazine, a Critical Toxo Drug by Derek Link ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Sulfadiazine is a critical first-line therapy for toxoplasmosis. In the U.S. the drug is manufactured by Richland Pharmaceuticals. Recently, Richland was closed by the Justice Department for matters apparently unrelated to its production of sulfadiazine. Within weeks of the company's closing, stocks of the drug began to disappear from distributors' shelves. (See MMWR, 12/18/92.) Some small stocks of sulfadiazine may still be left in pharmacies. However, there are no new replacement supplies once these stocks are depleted. At this point, most pharmacies in Greenwich Village, NYC, along with Bellevue Hospital and St. Luke's Hospital, are out of the drug. Within a few weeks, the nationwide effects will be felt and all New York City stocks will have been depleted. The Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) responded to this problem by acquiring all remaining stocks of the drug in December 1992. Since the shortage was identified so late, though, the CDC has very little of the drug. The CDC and the FDA have created a mechanism to release the remaining drug to patients until a new manufacturer is found. However, the CDC stated that PWAs with toxoplasmosis are second in line to receive the drug. Infants with congenital toxo are the first priority. (Although this kind of rationing seems creepy, it is really the only ethical alternative, since clindamycin is an acceptable alternative to sulfadiazine in adults, but not in children.) Therefore, adults will have to show that they are unable to take, or have failed, clindamycin before they get sulfadiazine from the CDC. The number to contact the CDC to get the drug on a compassionate use (free) basis is (404) 488-4435. This shortage is expected to last at least several months--until another manufacturer is found. Reports indicate that the CDC is presently trying to develop a mechanism by which it is legally able to import sulfadiazine from Canada. However, it will likely be months before bureaucratic hurdles enable this to occur. In the meantime, the PWA Health Group, the nation's largest not-for- profit buyers' club, has acquired a large supply of sulfadiazine from Britain. The group intends to keep importing the drug until the shortage is resolved. A doctor's prescription will be necessary to order the drug and it will cost $60 for 100 500mg tablets. The PWA Health Group can be reached at (212) 255-0520. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ treatment briefs by David Gold ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ World of Difference ^^^^^^^^^^^^^^^^^^^ WORLD (Women Organized to Respond to Life-threatening Diseases) is an organization "by, for and about women facing HIV disease." WORLD's important work includes publishing a newsletter, providing desperately-needed information and support, and sponsoring retreats for women with HIV. For more information, call (510) 658-6930, fax (510) 601-9746, or write WORLD, P.O. Box 11535, Oakland, CA 94611. Articles of Interest ^^^^^^^^^^^^^^^^^^^^ Some interesting and thought-provoking articles: "On the Matter of Survival" by Donald Abrams in BETA (November 1992); "Pitting Victims Against Victims" by Elizabeth Glaser, Washington Post (October 15, 1992); "A Review of HIV Disease in Women: Current Knowledge and a Research Agenda," Journal of Acquired Immune Deficiency Syndrome (October 1992 vol.5:957); "A Review of Drug Hypersensitivity Reactions and HIV Disease," Journal of Acquired Immune Deficiency (December 1992, vol.5:1237). Affording Care ^^^^^^^^^^^^^^ Affording Care is a nonprofit organization dedicated to promoting the "financial empowerment of individuals who are seriously ill." The group publishes a newsletter providing information designed to help people make maximum use of the current health care system and avoid medically-caused impoverishment. Call (212) 262-9449 for more information. More on Depression ^^^^^^^^^^^^^^^^^^ Joan Priestley, M.D. of Los Angeles has written to suggest that, in her view, nutritional deficiencies common in HIV-positive individuals can cause cognitive and emotional changes. She believes that restoring these nutrients (especially vitamin B) should be considered when treating depression in HIV-seropositive patients. Dr. Priestley advises us that in the last six years she has utilized high-dose vitamin B (including B-6 and B-12) injections on over 600 PWAs. She claims that since utilizing these vitamin B injections she no longer sees cases of depression or "AIDS dementia" (now referred to as "HIV-related neuro-cognitive disease") in her practice. TMP/SMX Superior as PCP Prophylaxis ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A study recently published in the New England Journal of Medicine (327:1842-8, 12/24/92) has concluded that trimethoprim- sulfamethoxasole (TMP/SMX, trade names Bactrim or Septra) is more effective than aerosolized pentamidine (AP) in preventing recurrences of PCP in PWAs. The study's Data Safety Monitoring Board stopped the trial when it was found that PWAs taking AP had a 3.25 greater chance of developing PCP a second time than those given TMP/SMX. All patients received AZT. There were no significant differences in blood or liver toxicities or rates of survival. The study included 310 PWAs who had an initial bout of PCP. Individuals were randomized to receive 1200 mg per day of AZT and either one double-strength tablet of TMP/SMX (160 mg/800mg daily) or 300mg AP every four weeks (with a nebulizer). Of the 50 recurrent cases of PCP, 14 were in the TMP/SMX group and 36 were in the AP group. However, 27% of those on the TMP/SMX arm were switched to AP because of side effects, while only 4% of those on the AP had to switch. There was no attempt to use a sulfa desensitization program (see "Sulfa Desensitization," Treatment Issues, November 1992). Nevertheless, this study seems to confirm the prevailing belief among many clinicians that TMP/SMX should be the choice for PCP prophylaxis, especially since other studies have suggested that the drug may also help prevent cases of toxoplasmosis among PWAs. Cats No Significant Toxo Risk ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A report in the Journal of the American Medical Association (269:76-77, 1/6/93) found that people with HIV who owned cats were not at significantly greater risk of developing toxoplasmosis. The study of 23 HIV-positive individuals found that 70 (9.7%) were positive for toxo antibodies and that 13 (2%) became toxo-positive over a one- to five-year follow-up period. Of the 12 of 13 who gave pet history records, only one individual had owned, lived with, or had close contact with a cat during the period of toxo seroconversion. The researchers also conducted a random survey of 87 HIV-positive individuals and found that 65% of these had owned or lived with a cat in the past five years, and that of these, only 12% tested positive for toxo antibodies. The authors conclude "that the routine use of serial testing for toxoplasmosis antibody is not likely to be cost-effective in HIV-infected adult patients in the U.S." Promising Report on IVIG ^^^^^^^^^^^^^^^^^^^^^^^^ A letter in The Lancet (340:1347, 11/28/92) reports promising results in the use of a monthly infusion of intravenous immunoglobulin (IVIG) in PWAs. Studies have suggested some benefits of IVIG in children with HIV. In the study, 24 adult PWAs with low T4 cells received either monthly IVIG (200mg/kg, Endobulin, Immuno France) or no treatment. Serious bacterial and viral infections were fewer in the treatment arm. Additionally, after 12 months, 9/12 in the treatment arm but only 3/12 in the control arm were still alive. Clearly, more research needs to be done in the use of IVIG for both children and adults with HIV. Sally Cooper new PWA Health Group director ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Sally Cooper, a well-known and well-respected AIDS activist, educator, and counselor, has been selected as the new Executive Director of the PWA Health Group. The PWA Health Group is the nation's largest buyers' club for experimental AIDS therapies. We wish her well in this important position. CRIA Hydroxychloroquine Trial ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The Community Research Initiative on AIDS (CRIA) and Mt. Sinai Medical Center are initiating a trial to test the anti-HIV effects of Hydroxychloroquine. This drug has been used to treat malaria, rheumatoid arthritis, and lupus, and, in the test tube, suppresses HIV reproduction in macrophages (cells in the immune system which destroy infectious organisms) and inhibits the production of cytokines believed to increase HIV production. Hydroxychloroquine has anti-inflammatory effects which may limit HIV-related inflammations. The placebo-controlled eight-week study is open to asymptomatic, HIV-positive individuals with between 200-500 T4 cells. Call Jacquiline Proner at (212) 241- 0764 for more information. Nutrition Forum ^^^^^^^^^^^^^^^ The Physicians Association for AIDS Care is sponsoring free symposiums on "HIV and Nutrition" on Thursday March 4, 1993 at 6:00 pm and at 8:00 pm. The symposiums will be held at St. Vincent's Medical Center at 153 W.11th St. in New York City. Todd Lazarus, M.D. and Cade Fields Newman will speak. For more info, call (800) 238- 7828, ext. 426. Washington Watch by Derek Hodel ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Editor's Note: Derek Hodel is the Treatment Issues Director for the AIDS Action Council (AAC) in Washington, D.C, the only national organization that focuses exclusively on shaping federal AIDS policy. As Treatment Issues Director, Derek lobbies Congress for funding for AIDS research and for legislation that will enhance the federal AIDS research effort, and oversees AIDS research activities at NIH, CDC, FDA, and the Department of Defense. He is also a member of the Treatment Action Group (TAG). Beginning with this issue, "Washington Watch" will alternate with "Drug Company Watch" as regular features of Treatment Issues. Legislative reforms that could dramatically alter the conduct of AIDS research at the National Institutes of Health (NIH) are included in the first bill to be considered in the Senate, The NIH Reauthorization Bill (S.1), introduced immediately following the Presidential inauguration. The bill is co-sponsored by a bipartisan majority of the Senate Labor and Human Resources Committee. In the committee mark-up, Senator Edward M. Kennedy (D-MA), chair, and Senator Nancy Kassenbaum (R-KA), ranking minority, presented a joint compromise version of the bill which was unanimously adopted by the committee and which will be considered by the full Senate. The reforms were drawn largely from two independent analyses of AIDS research at the NIH, and are being heavily lobbied by a wide coalition of AIDS advocacy organizations including AAC, the American Foundation for AIDS Research (AmFAR), the Pediatric AIDS Foundation, and the Treatment Action Group (TAG). Although it is not known whether President Clinton supports the reforms, the bill is one of three (the so-called motor voter and family leave bills are the other two) that were vetoed by President Bush, which are expected to be passed rapidly by the 103rd Congress. The reforms would dramatically strengthen the Office of AIDS Research (OAR) at the NIH, creating what amounts to a horizontal institute, or as some have dubbed it, an "Institute Without Walls." The OAR Director would be authorized to develop and implement a trans-NIH AIDS research budget based on a scientifically justified strategic plan, an approach never before employed at NIH. An advisory council comprised of biomedical, behavioral, and social scientists, similar to the councils that oversee operations at NIH institutes, would advise the director. In addition, the director would be empowered to utilize a discretionary fund, free from cumbersome government personnel and procurement restrictions, for emergency fast-track research programs. Such a funding mechanism could constitute the groundwork for a Manhattan Project for AIDS research should the director choose to pursue such a path. At the core of the reform proposals is the call for a bypass budget, also known as a professional judgment budget, for AIDS research. Such a mechanism, long employed by the National Cancer Institute (NCI) to develop the cancer research agenda, provides for the creation of a scientifically justified and prioritized budget that is submitted directly to the President for review and transmittal to Congress. Unlike other institute budgets, which are reviewed (and usually reduced) at three levels before they reach the President and which are submitted only in summary, a bypass budget is submitted intact, thus accurately reflecting the professional judgment of the institute director. The proposals were formulated largely by TAG and based in part on the group's exhaustive review of the NIH AIDS research program, AIDS Research at the NIH: A Critical Review. This report received considerable attention, both at the NIH and in Congress. A similar report, The AIDS Research Program at the National Institutes of Health, issued by the Institute of Medicine (IOM), forms the basis for the remainder of the reforms. Ostensibly, the NIH AIDS research effort is already coordinated by the OAR, which was created by Congress in 1988 and is directed by Anthony Fauci, MD. Dr. Fauci is also the Director of NIAID. In establishing the office, Congress called for a comprehensive strategic plan to focus and coordinate AIDS research across the institutes of the NIH. Both reports cite two pitfalls in the current approach which the reforms seek to correct. First, although the office was initially conceived to have budget authority across institute lines, this authority was omitted from the final legislation, creating instead what TAG brands " a paper tiger." Because the OAR director has no real say in how money is allocated, the office can merely suggest how the research portfolio should be constructed--not exactly most people's idea of strategic planning-- and does not really participate in the creation of the AIDS research budget. (In Washington, no budget means no power.) Second, although Dr. Fauci is a highly regarded scientist and has, at times, exhibited creative leadership in heading the federal AIDS research program, the combined responsibilities of his three jobs (he also heads the laboratory of immunoregulation) would be impossibly demanding for even the most capable administrator. (Editor's note: Some believe that Dr. Fauci has failed to provide effective, creative, and courageous leadership, and must bear some responsibility for the lackluster federal AIDS research effort. In addition, since this article was first written, reports have indicated that Dr. Fauci has been engaging in a campaign to thwart the TAG reforms now before Congress.) Even if the legislation is passed by the Senate, which now appears possible, it must be passed in the House of Representatives. This is considered to be a less formidable task. Should the two bills differ, or should the reform proposals be contained in one but not the other, the differences between the two bills would be negotiated in conference. Because of the accelerated schedule for these three previously vetoed bills, it is conceivable that the entire process could conclude as early as March 1. As S.1 is considered authorizing legislation, it does not actually provide funding for AIDS research or for any other program at NIH, but rather provides the authority to spend money. Funding for AIDS research (and for all other programs at the NIH) must subsequently be provided in an appropriations bill and also generated separately in each chamber by the 13 subcommittees of each house's appropriations committees. NIH funds are contained in the Labor, Health and Human Services, and Education agency bills. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ For a hard copy of Volume 7 #2 or subscription information write to: Paul Warren Medical Information, 2nd Floor 129 West 29th Street New York, NY 10011