Subject: KS; CD4; Stockholm (final); Immunizations Date: Oct 20 1988 (1116 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 7 October 20, 1988 In this issue: Kaposi's Sarcoma (KS) CD4 Stockholm: The Final Chapter Immunizations for PWAs New Studies In Brief Kaposi's Sarcoma by Allen Maniker, M. D. Kaposi's sarcoma (KS), while new to our everyday vocabulary, is not a new entity. As a new sarcoma, it was first described by Dr. Kaposi, a pathologist, in 1872, and it remained rarely seen until very recently. Not until 1980-81, when the simultaneous appearance of KS in twenty-one homosexual or bisexual men in New York and California was noted, along with Pneumocystis carinii pneumonia in five previously healthy gay men in Los Angeles, did this sarcoma become "rediscovered" (1). This poorly understood, seemingly benign, tumor signaled the fact that a new disease was with us, and heralded the onset of the AIDS epidemic. Before AIDS, KS was most commonly seen in three population groups. These included : 1) elderly males, especially those of Jewish or Mediterranean descent; 2) black Africans, among whom younger cases were not uncommon; and 3) patients whose immune systems were suppressed by medication, a group represented most commonly by kidney transplant patients. The clinical course of KS in these pre-AIDS populations was relatively indolent (slow-growing). In the elderly males KS remained typically confined to the skin of the feet and lower extremities, until very late in the disease (2). Due to the advanced age of the patients and the fact that median survival remained between eight and thirteen years, systemic chemotherapy was usually deemed unnecessary. In Africa, KS was first recog- nized as a common cancer in 1960 (3). In this population group, especially before the mid-1970's, KS, while occasionally aggres- sive in the young, was not accompanied by underlying immune defi- ciency. The final population group, that of the immuno- suppressed renal transplant patients exhibited a much more aggressive form of KS. The KS seen in transplant patients behaves in a way similar to that observed in AIDS patients. In several cases of KS seen in transplant recipients, the tumor was well controlled by discontinuing the immunosuppressive medications (4). This sug- gests two possibilities. First, that the tumor is really a man- ifestation of immunosuppression or immune deficiency and second, that a drug-induced restoration of immune competence might well control the progression of the malignancy. The presence of KS might at some future time even be used as a clinical marker of the response to immunologic therapies. At one time, KS was seen as the most common presenting feature among gay males with AIDS. However, with greater under- standing of AIDS epidemiology this has been shown to be the case in only thirty-five percent of patients. Furthermore, KS is seen much more frequently in male homosexual AIDS patients than in heterosexual AIDS populations (5). There are some suggestions in the current literature that coinfection with cytomegalovirus and/or the use of inhaled nitrites might be responsible for the differences noted in incidence (6,7). The exact reason for these observations is unk- nown at this time. AIDS related KS has several unique clinical features. AIDS related KS patients are young, with a median age of 35 years (versus 70-79 for the non-AIDS KS patients), and the clinical spectrum at presentation is quite variable, probably reflecting the severity of the underlying immune deficiency. In general, patients present with skin or mucous membrane lesions or lymph node involvement. Although KS lesions may begin in any site, initial lesions on the face or in the oral cavity are especially common (8). While lesions frequently involve the sole of the foot, the palms are rarely involved. KS lesions are easily recognized. Typically, they are palpable (slightly raised), red or violaceous (purple) and do not blanch on pres- sure. Rapidly enlarging tumors are often surrounded by a yellow-brown bruise. Lesions are usually discrete, but with advanced disease, plaques of coalesced lesions are common. Lesions tend to be circular, but on the back or around the neck- line can be linear. KS lesions in early stages are painless, but pain may be experienced in more advanced disease, especially in the feet and lower extremities (9). Areas other than the skin may be involved with KS. Visceral KS, meaning that involving the abdominal organs, is not uncommon but often it is clinically silent (10). KS involving the lungs is less common, but considerably more aggressive. Diagnosis Diagnosis of KS requires a tissue biopsy for confirmation. While any site of involvement would be suitable, the skin is most often selected for reasons of convenience. For most cancers, methods of staging have been developed that facilitate correlation of disease spread to prognosis and recommended treatment. With AIDS-related KS, the traditional methods of tumor staging are often not applicable. KS, in these cases, represents a manifestation of the underlying immune defi- ciency and markers of immune dysfunction often prove more valu- able than the usual staging descriptions. Scientists are currently working on a reliable staging system for AIDS- associated KS. Non-specific indicators of severity of underlying disease have been especially important as prognostic indicators. In a preliminary analysis, hematocrit (red blood cell count), number of so-called "B" symptoms (fevers, night sweats, weight loss) and helper/suppressor T-lymphocyte subset ratio were more important prognostic factors than the number of KS lesions, lymph node, or visceral (internal organ) involvement (11). Additions to this list indicating poorer prognosis should include prior opportunistic infections, anemia, elevated erythro- cyte sedimentation rate, an absolute helper cell count of less than 100 and gastrointestinal KS. In spite of these many predic- tors, the natural history of KS patients is extremely variable. Some patients have long intervals without disease progression, while in others the disease is rapidly progressive (12). The reason for this is unclear at this time. Since these predictors are also valuable in predicting the occurrence of subsequent opportunistic infections, their value becomes obvious in light of the fact that the most common cause of death in the AIDS-related KS patient continues to be opportunistic infection. Treatment The therapy for AIDS related KS has taken several different tracts in recent clinical trials, each with its own set of pluses and minuses. The first is conventional cytotoxic or chemoth- erapy. Here, the same principles for treatment of conventional cancers are applied. However, chemotherapy remains controver- sial, as it may further impair cellular immunity and thus increase infections. The second is those groups of agents com- monly known as "immunologic stimulators". These include the interferons. These agents work on the principle that KS is a manifestation of immune deficiency and that a bolstering of the immune system surveillance will allow the body's own defenses to prevent the progression of the sarcoma. These agents, however, may be ineffective given the ongoing HIV infection and may para- doxically stimulate viral replication. The third is the antiviral agents, an area of intensive investigation. A large study is underway to determine whether AZT has an appreciable effect on KS. Chemotherapy: Using the guidelines from the 1981 National Institutes of Health (NIH) workshop on the chemotherapy of AIDS related KS, most investigators have been treating patients in the early stages of disease with single agents and those in later stages or with aggressive disease, with multiple agents. Several drugs have been found to be active and these include vinblastine, vincristine and etoposide (VP-16-213). Drugs that have been tested and shown to have minimal activity include vinzolidine, ICRF-159 and mitoxantron (13,14). Other drugs, including the common chemotherapeutic agents of bleomycin and adriamycin are still undergoing clinical trials. The use of vinblastine was based on previous experience with traditional forms of KS in the elderly (15). While not extremely potent, it is relatively non-toxic and minimally immunosuppress- ing. Most patients do not experience nausea, vomiting or hair loss while receiving this medication. Given as a weekly intravenous dose, it is increased to maintain a total leukocyte (white cell) count of 2500 to 3000. While there is a true hema- tologic toxicity, this is easily controlled by reduction of the dose. These therapies have reported an objective response rate of about 25%, with an additional 50% of patients having stable disease (16). Response is not rapid with vinblastine and it is recommended that therapy should be continued for six to eight weeks before considering it unsuccessful. Vincristine, a drug similar to vinblastine, is also effec- tive in the treatment of KS. A response rate of 60% was observed, with minimal toxicity, in one report (17). However, in the work of Dr. Paul Volberding of the University of California in San Francisco, the drug was frequently seen to adversely affect the nerves in the legs, even in younger AIDS patients. Thus, as per his experience, it is used cautiously, and should only be considered for KS patients with severe white blood cell and platelet reductions, where the use of vinblastine would be ill advised. Dr. Volberding has found a useful approach in alternating between the two drugs. In a preliminary study he found that he could use higher doses of each agent, with no increased toxicity, but with a higher response rate. This combi- nation has become their "standard" therapy for AIDS-related KS. VP-16-213, or Etoposide, was first studied by Dr. Linda Lau- benstein at the New York University Medical Center. This drug has had some excellent results, and in one published report, a response rate of 76% was noted with an acceptable toxicity (18). The subjective side effects were minimal and the objective side effects were limited to hair loss, which was experienced by most, and a white blood cell depression, which was modest. While VP- 16-213 is the most active agent reported in the literature at his time, some caution should be used when interpreting the New York University study. In that study, patients with prior opportunis- tic infections, and so-called "B" symptoms (fevers, night sweats, weight loss) were excluded. The study includes only patients with none of the poor prognostic factors that were present in other chemotherapeutic studies. It would appear that these patients were treated at an earlier stage of their disease. Should patient selection be less rigorous, the objective response in larger groups might be somewhat lower. The use of combined chemotherapy in the form of adriamycin, bleomycin, and vinblastine, has been attempted in some centers with advanced, aggressive disease. The overall response rate appears to have no appreciable difference from than single agent therapy. This, combined with the fact that an inordinate number of patients developed subsequent opportunistic infections (up to 50% in one study), has led to the conclusion that this therapy is not appropriate for AIDS-related KS. The combination has essen- tially been abandoned (19). Immunologic Stimulators: Many potential immune restoring drugs have been studied in several recent trials. These include recombinant alpha interferon, gamma interferon, isoprinosine, cimetidine, thymic hormones and interleukin-2. While all of these drugs modulate the immune system by differing mechanisms, they all attempt to expand the body's pool of functional T- lymphocytes. Three problems complicate treatment with these immune stimu- lators. First, the AIDS virus may have damaged the early precur- sor cells needed to regenerate the functioning T cells, thus lim- iting immunologic recovery. Second, even if new T cell produc- tion is induced, these new cells may be rapidly infected and dam- aged. Third, if the agent is stimulating replication of cells already infected with the virus, then the agent may in fact be contributing to the spread of infected cells and thus immune dam- age (20). Alpha interferon is probably the most studied of this group of agents. The first of these studies was conducted at Memorial Sloan Kettering Cancer Center in New York (21). In this study, recombinant alpha interferon was used daily for twenty eight days, followed by a maintenance period. This group reported a 40% response rate of which 25% were complete responders. The side effects included flu like symptoms such as headaches, fever, and malaise. There was also noted a white blood cell depression, and an elevation of serum transaminases (a sign of liver toxi- city), both of which were easily reversible with dose reduction. The exact reduction rate of subsequent opportunistic infections was not reported; however, it was claimed to be "infrequent." While some patients had an improvement in their immunologic parameters, these were not dramatic, and no patient exhibited restoration of immune competence. Similar studies were conducted at the San Francisco General Hospital, under the aegis of the University of California, San Francisco, and the University of California, Los Angeles (22). The studies differed in protocol, but essentially reported the same results as the Sloan Kettering study. While the above studies show that recombinant (synthetic) alpha interferon is an effective drug in the treatment of AIDS- related KS, it does not appear to restore immune competence. Lymphokines are another set of biologic regulators that induce T cell proliferation. One of these agents, interleukin-2, is under investigation for use with KS. While studies in vitro (in the test tube) have demonstrated the ability of recombinant interleukin-2 to produce proliferation of T lymphocytes in AIDS patients (a theoretically good sign) (23), no anti-tumor effect has been noted in other current studies. As pointed out by Dr. Volberding, this lack of anti-tumor effect may be due to the use of non recombinant drugs, and in dosages which are probably inadequate. Similar evidence of lack of anti-tumor effect was noted in a study of gamma interferon at the National Cancer Institute. While current studies of this potential therapy have not been encouraging, a final verdict has not yet been delivered. Other treatment possibilities which should be included only for the sake of completeness are: bone marrow transplantation and radiation therapy. In bone marrow transplant, no definite evidence of immune competence restoration has been reported, and in no case was the course of KS reversed (24). Furthermore, transplant was followed by overwhelming cytomegalovirus (CMV) infection, that was lethal. Given the widespread presence of CMV infection in AIDS patients, this post-transplant complication will surely limit the use of this avenue of investigation. AIDS- related KS is a radiosensitive tumor, that is, it is sensitive to the effects of radiation. However, radiation therapy appears to be useful only to ameliorate symptoms, and not for cure. Large erosive oral lesions, painful lesions on the feet, lower extremi- ties, and face respond well to this therapy, with good relief of pain. Care, however, must be exercised when utilizing radiation for reduction of lesions in the oral cavity as a defect in mucosal healing has been noted in post-radiation AIDS patients and the resultant inflammation can be severe (25). Finally, attempts have been made using cryotherapy (freezing lesions with liquid nitrogen) and direct injection of chemoth- erapy (very dilute vinblastine) into KS lesions, thus avoiding the systemic toxicity of intravenous chemotherapy. Results of these therapies have not yet been published, although they are reported to have a better effect on new, flat lesions. Conclusion This article was meant to serve as an overview of AIDS- related Kaposi's sarcoma, and to update current avenues of inves- tigation. In summary, while several treatments have been explored, none has proven to be the answer. Restoration of immune competence appears to be required to control this tumor. Unless this can be accomplished, conventional therapies in use at this time are unlikely to improve a patient's prognosis. Soluble CD4 by David Roche Of all the approaches currently under study as possible anti-viral treatments for AIDS, perhaps none is as novel and exciting as recombinant soluble CD4. CD4 is the first compound developed specifically to combat HIV infection in human beings. After a series of tests in cell cultures and in animals revealing a striking inhibition of HIV infectivity and no observable toxi- city, human clinical trials (Phase I) were launched in August of this year. By way of background, the first step in any viral infection is the binding of a virus particle to a component of a host cell membrane. In the case of AIDS, scientists have discovered that HIV binds to a molecule known as the CD4 antigen (26). Since the CD4 molecule is found on cells of the immune system called T helper (or T4, CD4) cells which are instrumental in fighting bodily infections (CD4 is found on other cells in the body as well), the primary immunologic abnormality resulting from HIV infection is the infection, functional impariment and ultimate destruction of these crucial disease-fighting cells. The sur- face, or envelope protein of HIV, called gp120, is actually the part of the virus that binds to CD4, and this initial interaction between gp120 and CD4 is what permits entry of the virus into the target cell (27). Once infected, the cell becomes a virtual virus-producing factory, re-copying many times over all of HIV's components including gp120. As gp120 collects on the surface of the host cell, new viruses assemble, leave the cell and infect healthy cells containing CD4. Furthermore, the gp120 on the cell surface can attract uninfected target cells and cause large numbers of cells to fuse together in clumps, forming what are known as syncytia, providing yet another mechanism for cell des- truction (28). Through genetic engineering techniques, several groups of scientists have been able to develop soluble CD4 in the labora- tory that binds extremely strongly to the viral protein gp120. Once this interaction occurs, the virus is incapable of binding to and infecting healthy cells. Several reports presented at this year's International AIDS Conference in Stockholm indicate that in sufficient concentrations, soluble CD4 completely blocks both viral infection of healthy cells and syncytium formation in cell cultures (29). In a sense, then, soluble CD4 can be thought of as a kind of "Star Wars" approach to AIDS therapy, in which the soluble CD4 seeks out the invading viruses and renders them harmless by binding to them before they can enter and destroy the CD4-bearing host cells that are their natural target. In order to reduce the possibilities that soluble CD4 would interfere with normal immune function when introduced into the body, scientists have developed soluble CD4 using only the smallest portion of the CD4 molecule that is needed to bind with gp120. Human Clinical Experimentation On August 10, 1988, the first human trials of CD4 were begun. The initial Phase I trials included a total of approxi- mately 50 PWAs who have had one opportunistic infection, at three centers: San Francisco General Hospital, New England Deaconess Hospital in Boston, and the National Cancer Institute in Bethesda, Maryland. The trials were designed to last about six months and are being conducted in overlapping segments, with groups of 3-4 patients receiving increasingly potent dose levels of CD4. The Phase I trial actually consists of two separate pro- tocols, the primary difference being that the San Francisco and Boston centers are administering the CD4 intravenously once a day for 10 days followed by an 11 week period of intravenous adminis- tration three times per week, while the Bethesda center is study- ing the effects of continuous IV administration. None of the patients is currently taking other anti-viral medications, including AZT, but PCP prophylaxis is permitted. At the time of this writing, the San Francisco and Boston centers were begining the third of five escalating doses, the fifth of which is about 100 times stronger than the first. Although the primary purpose of the Phase I trials is to guage the safety of CD4, the investigators will naturally be looking for signs of efficacy as well. Since the trials are now just over two months old, it is not yet possible to draw solid conclusions on CD4's toxicity, not to mention its usefulness. However, conversations with the scientists conducting the experi- ments indicate that, as of now, no observable toxicity has been reported due to CD4 (30), and the trials are continuing as origi- nally planned. Considering the formidable toxic effects of other anti-viral substances such as AZT, this is obviously good news, but preliminary conclusions on CD4 efficacy are not expected until the end of this year at the earliest. If the results of Phase I trials are encouraging, Phase II trials, which would include greater numbers of patients, are expected to begin by about July, 1989. Related Research Underway In a very exciting report issued by the National Institute of Allergy and Infectious Diseases on September 22, 1988, scien- tists have developed a means of attaching a toxin to soluble CD4 that not only binds to cells actively producing HIV (those with gp120 on their surfaces) but destroys them as well. The toxin, called Pseudomonas exotoxin, is important in that now, in addition to rendering viruses harmless as they are pro- duced by the host cell, the virus-containing cell is itself des- troyed, closing off the possibility that more virus will be pro- duced and new cells infected. Since the toxin will enter and destroy only cells expressing gp120 on their surfaces, uninfected helper T cells would be spared. While scientists have demonstrated highly selective killing of HIV-infected cells in culture using this combined Pseudomonas-CD4 compound, additional laboratory work needs to be done before testing can begin on humans. This will include con- tinued testing of the effect of CD4-toxin on different types of HIV and non-HIV infected cells in culture. It is still not known whether all HIV infected cells have gp120 on their surfaces and consequently whether complete elimination of HIV from the body is possible. Summary CD4 is a very new technique that may prove to be an extremely valuable therapeutic weapon against AIDS. While human trials have begun, it is obvious that significant work lies ahead before any claims of value can be advanced in support of this substance. However, considering the unique approach and the work already completed in developing CD4, it makes sense to be hopeful about positive future developments. We will continue to report on CD4 as more information becomes available, and we can only hope, in the event of good news, that our government will move forward with haste in this area, and not with the sluggishness that has characterized AIDS research in this country during the last several years. We'll keep you posted. Stockholm: The Final Chapter This is the third installment of our report on the Stockholm conference. Numbers in parentheses correspond to abstract numbers from Stockholm. Anyone wishing to read or photocopy ori- ginal abstracts may do so by appointment at the Department of Medical Information. Treatments for KS A comprehensive article on Kaposi's Sarcoma (KS) appears in this issue. At the Stockholm conference, the major focus on KS treatments was on AZT or interferon, or a combination of both. AZT's effect on KS: The seemingly endless 24-month NIH study of AZT treatment of KS has now enrolled 273 patients. Half of participants receive placebo, and the other half receive either 250 mg AZT every 4 hours (omitting nighttime dose) or 500 mg AZT every 8 hours. An independent data safety monitoring board has, on at least four separate occasions, reviewed the data and not found differences between the recipients of placebo versus AZT, suggesting that AZT is having no appreciable effect on KS in this study. Two other studies reported on the treatment of KS with AZT; however, both were rather small. The first (#3638), a 6-month study on 20 people, used full-dose AZT and found that 30% of patients experienced disease progression, 40% had disease regres- sion, and 30% had stable disease. In another study (#3639), "nearly one-third of patients with skin KS showed regression on treatment with AZT. " Unfortunately, New York physicians treating patients with KS have not, in general, experienced such response rates with AZT alone. A German group reported (31) on a 24-week trial of AZT versus the AZT/Acyclovir combination versus placebo in treating KS. In the placebo group, disease progression was observed in 79%, whereas the rate of progression in both treatment groups was 50% -- less than placebo but not dramatically so. There were no significant differences between the AZT group and the AZT/Acyclovir group. Interferon and KS: Interferon has long been studied as a potential treatment for KS because of its anti-tumor properties. Most studies have focused on alpha-interferon, although beta-interferon is now receiving some attention. There were several studies in Stockholm of interferon and its effects on KS. Background: Previous studies of alpha-interferon on KS have used varying doses and have had mixed results. Studies which have reported the best responses (greater than 30% partial or complete responses) have used doses of 25 million units or more daily (32,33,34,35,36). Studies using lower doses have had 20% response rates or lower. A recent study (37) has shown that peo- ple with T4-cell counts of 300 or greater are much more likely to respond to alpha-interferon. Side effects of alpha-interferon include flu-like symptoms, fever, malaise, and nausea; more seri- ously, it can cause low white cell count, low red cell count, and liver abnormalities. So it seems that higher doses are more likely to be effective (although more toxic), and that patients with higher T-cell counts will more likely benefit from inter- feron. Two studies from Stockholm, using low doses of alpha- interferon, reported good results which were more or less con- sistent with the above studies. The first (#3514) was a 6-month study on 100 patients with KS. The dose used was 18 million units daily. Of those who had KS alone, 36% had "complete response." Of those who had KS with an opportunistic infection, only 16% had complete response. The second study of lower dose alpha-interferon (#3516) fol- lowed 25 patients for 7 months on a dose starting out at 10 mil- lion units daily, which was escalated until patients developed intolerance. They reported an 8% complete response and a 20% partial response. They did not differentiate between the response rates of patients with KS alone versus those who had a prior opportunistic infection. Finally, a study of higher dose alpha-interferon (#7594) in 20 patients reported a 40% response rate, but the abstract did not discuss their experience with toxicity, which likely occurred in the doses used (27-36 million units daily). AZT plus Interferon for KS: Since AZT is synergistic with interferon in the test tube, several studies have been set up looking at that combination for patients with KS. As a result of these studies, it has become apparent that the toxicity of this combination is severe. Fischl (#3133) concluded that half-dose AZT in combination with low-dose interferon (9 million units daily) had acceptable toxicity and a 56% regression after 24 weeks, an impressive figure. Krown (#3627) reported a somewhat lower response at these doses (33% regression). Both researchers agree that full-dose AZT in combination with alpha-interferon is fraught with toxicity. Clearly, more studies of this combination are needed before recommendations can be made, although most experts agree (#3628) that "patients with AIDS and KS can be treated with both AZT and alpha-interferon at doses sufficient to see both anti-tumor and anti-viral effects." We will keep abreast of these trials. Imreg-1 Imreg-1 (see article in Treatment Issues, Vol. 2 no. 4, June 1, 1988) is a substance derived from healthy white blood cells which reportedly has a beneficial effect on the immune system. The results of a study of 158 ARC and KS patients (#3048) gen- erated a lot of attention, because claims were made to the media prior to the conference that the drug was effective. The patients, who started out with between 100 and 400 T-cells, took either Imreg-1 or placebo for 6 months. No toxicity was observed. Of 96 evaluable patients, 25% of patients on placebo progressed to AIDS, while only 8% of the treated group did. 50% of patients had improvements in hypersensitivity skin testing, which may be a sign of immune enhancement. There was no evidence of increased HIV replication during the study (#3051). Although exciting, we would like to see these results corroborated before recommendations can be made. For information on ongoing studies of Imreg-1, Dr. Arthur Gottlieb can be contacted at Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112. Naltrexone Results from a group of 38 AIDS patients were reported in Stockholm (#3056). This was a double-blind placebo-controlled study (meaning that half the participants received naltrexone and half received sugar water). The results showed that there were no episodes of opportunistic infections in the treated group, while in the placebo group 26% developed infections. Although measurable immunologic parameters (such as T-cell count, T-cell function tests, etc.) did not change appreciably, one parameter, the serum alpha interferon level, generally high in AIDS patients, dropped markedly in 66% of patients. (However, we are not presently sure of the significance of alpha interferon lev- els). Nonetheless, the reduction in opportunistic infection in the treated group, coupled with the low toxicity and inexpensive price tag of naltrexone, urge us to seriously consider this therapy. Immunizations For PWAs Fall is the time of year when recommendations are made for elderly people and people with chronic diseases to receive influenza and pneumococcal vaccines. Pneumococcal pneumonia and influenza can be devastating illnesses to PWAs, and it is univer- sally recommended that immunodeficient patients receive vaccina- tions. In the part, there were serious considerations in vac- cinating a person with AIDS: whether the vaccine, by stimulating the immune system, may actually accelerate the course of HIV infection; and whether a person with AIDS could respond immuno- logically to a vaccine at all (i.e., mount an antibody response). Both of these questions have been addressed, and the available evidence is presented here. The evidence supports vaccination of all HIV-positive individuals. Pneumococcal Vaccine: In a study conducted at the University of Colorado, 32 HIV- infected individuals were vaccinated with pneumococcal vaccine. The AIDS/ARC patients did exhibit an initial rise in antibody levels, indicating that the vaccine "took", but these levels dropped to baseline within 40 weeks (38). Other studies have found suboptimal antibody responses to pneumococcal vaccine in HIV-infected patients (39,40). These limited studies do not appear to have accelerated the HIV infection, as no adverse effects or clinical deterioration have been reported (41,42). In the Multicenter AIDS Cohort Study (MACS) at the University of Pittsburgh, pneumococcal vaccine is being tested in a high-risk group of gay males without untoward reactions. The final report is not yet in. Influenza Vaccine: Similar findings have been reported with influenza vaccine. Some investigators (4) have found good antibody responses but others (3,43) have found suboptimal responses. In the MACS study, good antibody response was noted. As to the safety issue, adverse effects or clinical deterioration have not been seen with influenza vaccine (4,5,44). The MACS study confirms these find- ings. The experience gained to date has prompted the World Health Organization to issue guidelines on the immunization of HIV- infected individuals. For children, the WHO recommends continued administration of standard vaccines, with the exception that inactivated polio vaccine (IPV) be substituted for the oral polio vaccine (OPV). For HIV-infected adults, WHO makes no specific recommendations (45) but state that "data from prospective human studies have not shown any adverse effects of immunization on immune function or progression of symptoms among HIV-infected recipients of vaccines." Dr. John LaMontagne, the Influenza Program Officer of NIAID (The National Institute for Allergy and Infectious Diseases) agrees that vaccines can be given safely. He states, "It appears from the studies done by the NIAID, primarily by the MACS inves- tigators, that vaccination is useful...It would appear that because antibody responses are not as strong in HIV-infected per- sons, a decrease in vaccine efficacy might be a logical conse- quence." (46) Thus, it seems that the safety issue has been adequately studied to permit the use of vaccines in the setting of AIDS. Whether the antibody response is sufficient as to result in a lower risk of developing influenza or pneumococcal pneumonia has not been resolved, but all studies have shown at least some increase in antibody levels. Hopefully, this increase would be protective for a significant period of time. While it is generally recommended that susceptible individu- als get pneumococcal vaccine only once in their lifetime, these data suggest that PWAs receive it each winter. Influenza vac- cine is always given yearly. Despite possible limitations in the effectiveness of vac- cines in HIV-infected individuals, they should nonetheless seek whatever protection the vaccine can offer by contacting their physician. The New York City Department of Health is offering free pneumococcal and influenza immunizations to anyone who wants them. This program has been in existence for a number of years, but this year, the DOH is making a special outreach effort to seropositives, PWAs and PWARCs. People desiring these shots need not present any identification or documentation concerning their medical condition. Those who are concerned about confidentiality do not have to provide their correct name or address, but every- one must sign a consent form. Clinics will be open in all 5 bor- oughs for free shots beginning Tuesday, October 11. The program, which will be offered every fall, will continue until January or February. It would be best for people with HIV infection to have their shots as early in the season as possible. The city is also willing to provide free vaccine to doctors or clinics that see large numbers of HIV positive patients. Further information can be obtained by calling the Immunization Program Hotline at (212) 349-2664. New Studies Five New York area hospitals (St. Luke's-Roosevelt, Queens Hospital, Flushing Hospital, St. Michael's and King's Hospital) and a number of other centers throughout the country are partici- pating in trial comparing aerosolized Pentamidine with Bactrim to treat acute episodes of PCP. This trial will also be conducted at hospitals in Los Angeles, San Francisco, Chicago, Boston, San Diego, New Orleans and Cincinnati. This is a double blind, con- trolled study, randomizing patients to standard dose intravenous Bactrim or 600 mg daily of inhaled Pentamidine. Each participant must take an IV treatment and a nebulized treatment every day, of which one will be placebo. Everyone will get one of the drugs. Patients who don't respond to the treatment they are receiving will be switched to open label IV Pentamidine and, if they don't improve with Pentamidine, another experimental treatment. The study will employ the Respirgard II (Marquest) nebulizer for the aerosolized treatments. This machine has a mean particle size of 1.4 microns (considered good). Exclusion criteria include patients who are allergic to sulfa based drugs (Bactrim). Patients who have been treated for PCP or who have taken any prophylactic (preventive) treatment (aerosolized Pentamidine, Bactrim, Dapsone, Fansidar, etc.) for PCP within the previous six weeks are not eligible. Patients taking AZT or undergoing chemotherapy must interrupt those treat- ments for the three week duration of the trial. Following the trial, these therapies can be resumed. Some other antivirals may be continued, and immunomodulators are allowed as well. A minimum hospital stay of 5 days is required. This study will probably be most accessible for patients experiencing a first episode of PCP, as this population is most likely not to have taken any prophylactic treatment for 6 weeks. For further information, readers may have their physicians con- tact Rick White at (312) 390-1772. In Brief Trimetrexate: In response to heavy public pressure, the FDA recently relaxed the requirements for accessing this experimental treatment for PCP. Trimetrexate is available for early release under the FDA's Treatment-IND program. Until now, Trimetrexate was only available to people who had life-threatening reactions to standard therapies. The new guidelines still seem distress- ingly restrictive, however. Patients must have pursued both "standard" therapies (intravenous Pentamidine and Bactrim) for at least 7 days each for a total of 14 days standard therapy. (If the patient is allergic to sulfa based drugs (Bactrim), he is eligible for Trimetrexate after 7 days of IV Pentamidine.) Although it is encouraging that this highly effective drug is more easily available, it seems unreasonable to force patients to waste 2 weeks on treatments that are not working. Doctors seek- ing information on how to obtain Trimetrexate can call the AIDS Program Trimetrexate Hotline (24 hrs., 7 days) at their new number: 800-537-9978. Dextran sulfate: At least 6 cases of serious, bloody diar- rhea have been reported from patients taking 3,000 mg or more daily of Dextran sulfate. It resolved spontaneously after stop- ping the drug. We have not received any similar reports from patients taking 2,700 mg or less, but we are receiving increasing reports on "mild" stomach and intestinal problems, particularly diarrhea and gas. Patients and physicians should be aware of this, especially in evaluating possible causes of diarrhea. No further scientific data is available on Dextran's effectiveness at the present time. We have been curious for quite some time how to find an expiration date on Dextran sulfate from Japan, and have learned how to "decipher" the end-label on the KOWA MDS 300 package. The first line reads "MDS 300". The second line indicates the quan- tity of tablets in the package (500 or 1000). The next line is a manufacturing number, and the last line is the expiration date. This date is based on the Japanese calendar and requires some explanation: The number appears as a two-digit number, a decimal point, then a single-digit number. The two-digit number indicates the year of expiration, and is based on the Japanese calendar. "63" corresponds to 1988, "64" to 1989, etc. The number after the decimal point corresponds to the month of expiration. So, a product labelled "68.6" would expire in June, 1993. Bioherb, Inc. of Schaumburg, IL has claimed that it will ship 1000 Dextran sulfate tablets for $350. Although cheaper prices can be found in many buyer's clubs, it is certainly a con- venient means of access to the drug. Contact them at (312) 885- 8789. Another source of Dextran has recently come to our atten- tion: Nippon Industries of Englewood, N. J. has contracted with a Japanese pharmaceutical concern to import the drug. For further information, call Marty Ekmekjian at (210) 567-6080. Ampligen: Recently, DuPont, Inc. announced that it would pull out of an agreement with HEM Research, developer of Ampli- gen, and that they would not fund any further clinical trials. Although they would not state why, the fact that DuPont had recently done a data analysis on the ARC study led the scientific community to believe that DuPont found the drug to be ineffec- tive. The FDA, in a decision delivered on October 12, concurs that Ampligen provides no clinical benefit, and as of 5:00 PM on October 12, all clinical trials of Ampligen were halted. Ampli- gen, a substance which once held great promise for PWAs, is now a dead drug. The Pharmaceutical Manufacturers Association publishes a short, 3-page brochure called "AIDS Products in Development". Not in any way detailed, the publication may nonetheless be use- ful, as it lists just about everything, including some obscure drugs. Contact them at 1100 15th Street NW, Washington, DC 20005. (202) 835-3400. Columbia University's Gay Health Advocacy Project is spon- soring a day-long forum called "AIDS: Improving the Odds", on Saturday, Nov. 19. The event will take place in the Cathryn Bache Miller Theater at Broadway and 116th St. A number of key researchers, clinicians and activists will sit on 4 panels throughout the day, which will begin at 9:00 am and continue until 6:00 pm. The main focus will be new treatments for PWAs, PWARCs and asymptomatic seropositives. Seating is limited, and information on reservations (which are free) can be obtained by calling (212) 517-5028. Reports have been circulating about a mysterious antiviral drug called MM-1. The drug is being touted by an Egyptian rectal surgeon named Ahmed Shafik, who will provide precious little information about it. He has released results of extensive prec- linical (animal) studies and one clinical study involving 192 patients. It appears that the substance is nontoxic. The human study makes almost unbelievable claims of "cure" and fantastic clinical improvement. Dr. Shafik has never presented any results of MM-1 treatment in a scientific forum and was notably absent from the International Conference in Stockholm. He also turned down invitations from AmFAR to travel, at their expense, to the U. S. and Sweden to present his findings. Patients interested in being treated with the drug must go to Kinshasa, Zaire. An organization named Medical International Consulting Agency (MICA) is organizing trips to Zaire for treatment. The price tag? A mere $75,000, including airfare. A company representative told us that visiting foreigners will stay in special pre-fab housing, not a hospital. He knew nothing about the treatment or AIDS and could not explain why Dr. Shafik has been so secretive about MM- 1. Patients should be extremely wary of this prospect. No recognized AIDS specialists are in a position to comment on the efficacy of MM-1. Also, traveling to Zaire could expose patients to a whole host of potential infections. The cost of treatment speaks for itself. Other Resources American Foundation for AIDS Research (AmFAR) has updated their catalog of trials involving experimental drugs. The "AIDS/HIV Experimental Treatment Directory" also includes several glos- saries and information about the federal clinical trials efforts and licensing of drugs. Write to AMFAR at 40 West 57th St., New York, NY 10019, or call (212) 333-3118. "AIDS Treatment News" is a short, biweekly report which chroni- cles current developments in experimental and alternative treat- ments and deals with public policy issues. Contact John S. James at P. O. Box 411256, San Francisco, CA 94141 or call (415) 282-0110. "PWA Coalition Newsline", published "by and for people with AIDS and AIDS Related Conditions," is a grass-roots news magazine that appears monthly. The publication reports news developments deal- ing with the health crisis as well as alternative treatments. Editorials and literary contributions add another interesting dimension to this excellent source of information. Write PWA Coalition Inc., 263A West 19th St., Room 125, New York, N. Y. 10011, or call (212) 627-1810. Ask about their other publica- tion, "Surviving and Thriving with AIDS". The Universal Fellowship of Metropolitan Community Churches pub- lishes a monthly newsletter called "Alert", covering AIDS related legislation, education, research and treatment. Write to Rev. Steve Pieters, UFMCC, 5300 Santa Monica Blvd., Suite 304, Los Angeles, CA 90029. "ATIN" (AIDS Targeted Information Newsletter) performs a monthly search of hundreds of medical journals worldwide. Definitely aimed at doctors and researchers, it is the best ongoing litera- ture search available. It has an impressive cast of editors who comment on the significance of the studies cited. Published by Williams & Wilkins, P. O. Box 23291, Baltimore, MD 21203 or phone 1-800-638-6423. Project Inform publishes an excellent newsletter called "PI Per- spective" which deals with experimental treatments and focuses special attention on drug regulatory issues and public policy. Another valuable resource is their up-to-date drug hotline. Call them at 1-800-822-7422. Body Positive is a new organization established by and for HIV- antibody-positive people to exchange information, advocate research, fight discrimination, andp rovide mutual emotional sup- port. They publish a monthly newsletter called "The Body Posi- tive." Write to: 263A West 19th Street, New York, NY 10011 or call 212-633-1782. Northern Lights Alternatives ("NLA") is an organization that was created to help PWAs channel their energy in positive, healing directions. the cornerstone of NLA is a program of weekend retreats called AIDS Mastery Workshops. The main goal of these workshops is to teach NLA's central philosophy: PWAs can improve the quality of their lives through self-empowerment. NLA dissem- inates material through the telecommunications network of GayCom. Anyone with a personal computer and modem can access this ser- vice. NLA Online has launched, as of September 1987, an AIDS Bibliographic and Abstract Service (ABAS). This database gathers together over 2000 medical articles from a variety of sources. For more information about NLA and the AIDS Mastery Workshops, contact Chuck Baier or Victor Phillips at 212-877-4846. "Healing AIDS" is a monthly magazine which focuses on holostic approaches to AIDS and ARC including diet and nutrition, relaxa- tion and visualization techniques, and stress reduction. It regu- larly lists other resources. Subscriptions are $10/year for peo- ple with AIDS/ARC/low income, and $15 for others. Write: 3835 20th Street, San Francisco, CA 94114 or Phone: (415) 821-7646. The AIDS Health Project at the University of California San Fran- cisco publishs a monthly newsletter called "Focus" written "to place data and medical reports in a context that is meaningful and useful to its readers." It provides easy-to-understand prac- tical information on AIDS research. Contact UCSF AIDS Health Pro- ject, Box 0884 San Franciso CA 94143 or phone (415) 476-6430. Correction In our last issue, we mentioned that bronchoscopy is "not at all useful for diagnosing KS in the lung." In fact, this technique is probably the best technique for diagnosing pulmonary KS. Treatment Issues is GMHC's newsletter devoted to providing reli- able information on experimental AIDS therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1988 Gay Men's Health Crisis, Inc. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Barry Gingell, M. D. Managing Editor: Kevin Armington GMHC, Department of Medical Information, 129 West 20th Street, New York, NY 10011 Footnotes: 1 Friedman-Kien A et al. Kaposi's sarcoma and pneumocystis pneu- monia among homosexual men--New York City and California. MMWR 30:305-8, 1981. 2 Safai B et al. Kaposi's sarcoma: a review and recent develop- ments. Clin Bull 10:62-9, 1980. 3 Dutz W et al. Kaposi's sarcoma in infants and children. Cancer 13:684-94, 1960. 4 Stribling J et al. Kaposi's sarcoma in renal allograft patients. Cancer 42:442-6, 1978. 5 Ziegler JL et al. Kaposi's sarcoma: a comparison of classical, endemic and epidemic forms. Semin Oncol 11:47-52, 1984. 6 Drew WL et al. Cytomegalovirus and kaposi's sarcoma in young homosexual men. Lancet 2:125-7, 1982. 7 Marmor M et al. Risk factors for Kaposi's sarcoma in homosexual men. Lancet 1:1083-87, 1982. 8 Sooy C et al. Otolaryngologic manifestations of acquired immu- nodeficiency syndrome. West J Med 141:674, 1984. 9 Volberding PA et al. AIDS and other medical problems in the male homosexual: kaposi's sarcoma and the acquired immunodefi- ciency syndrome. The Med Cinics of North America, May 1986 (WB Saunders). 10 Friedman SL et al. Gastrointestinal kaposi's sarcoma in patients with the acquired immunodeficiency syndrome--endoscopic and autopsy findings. Gastroenterology 890:102-08, 1985. 11 Templeton AC et al. Prognosis in kaposi's sarcoma. J Nat. Cancer Inst 55:1301-04, 1975. 12 Krigel R et al. Epidemic kaposi's sarcoma (EKS): identifica- tion of a subset of patients with a good prognosis. Proc Am Soc Clin Oncol 4:4, 1985. 13 Sarna G et al. Oral vinzolidine as therapy for kaposi's sar- coma and carcinomas of the lung, breast, colon and rectum. Cancer Chemother Pharmacol 14:12-14, 1985. 14 Volberding PA et al. Therapy of AIDS-related kaposi's sarcoma with ICRF-159. Proc Am Soc Clin Oncol 4:4, 1985. 15 Tucker SB et al. Treatment of kaposi's sarcoma with vinblas- tine. Arch Dermatol 112:958-61, 1976. 16 Lewis BJ et al. Single agent or combination chemotherapy of kaposi's sarcoma in AIDS. Proc Am Soc Clin Oncol 2:59, 1983. 17 Mintzer DM et al. Treatment of kaposi's sarcoma and thrombo- cytopenia with vincristine in patients with the acquired immuno- deficiency syndrome. Ann Intern Med 102:200-02, 1985. 18 Laubenstein LJ et al. Treatment of epidemic kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin and vinblastine. J Clin Oncol 2:1115-20, 1984. 19 Shepherd FA et al. Combination chemotherapy and interferon in kaposi's sarcoma in AIDS. University of Toronto. 20 Volberding PA et al. AIDS and other medical problems in the male homosexual. The Med Clinics of North America, May 1986 (WB Saunders). 21 Krown SE et al. Preliminary observations on the effect of recombinant leukocyte interferon in homosexual men with kaposi's sarcoma. NEJM 308:1071-76, 1983. 22 Groopman JE et al. Recombinant alpha-2 interferon therapy of kaposi's sarcoma associated with acquired immunodeficiency syn- drome. Ann Inter Med (in press). 23 Rook AH et al. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lym- phocytes from patients with acquired immune deficiency syndrome. J Clin Invest 72:398-403, 1983. 24 Mitsuyasu R et al. Syngeneic bone marrow transplantation for patients with AIDS and kaposi's sarcoma. Blood 62 (5 suppl. 1) p. 226a, 1983. 25 Harris JW et al. Kaposi's sarcoma in AIDS: the role of radia- tion therapy. Frontiers in Rad Therp and Oncol 19:126-32, 1985. 26 Weber JN et al. HIV infection: the cellular picture. Scien- tific American p. 101, Oct., 1988. 27 Smith DH et al. Blocking of HIV-1 infectivity by a soluble secreted form of the CD4 antigen. Science 238:1704, Dec., 1987. 28 Fisher RA et al. HIV infection is blocked in vitro by recom- binant soluble CD4. Nature 331:76, Jan., 1988. 29 Clapham PR et al. Soluble CD4 neutralizes infectivity and syn- cytia of HIV-1, HIV-2 and SIV, International Conference on AIDS, Stockholm, 1988 (#2593). 30 S. Broder, J. Kahn. Personal communication. 31 Hasokat H. The potential use of zidovudine in the treatment of patients with HIV-related Kaposi's Sarcoma. Presented at IV International Conference on AIDS, Stockholm, 1988. 32 Real FX et al. Kaposi's sarcoma and the acquired immunodefi- ciency syndrome: Treatment with high and low doses of recombinant leukocyte A interferon. J Clin Onc 4(4): 544, 1986. 33 Volberding P et al. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome-related Kaposi's sarcoma. Seminar Oncol 12 (4 suppl 5):2, 1985. 34 Gelman EP et al. Human lymphoblastoid interferon treatment of Kaposis sarcoma in the acquired immune deficiency syndrome. American J Med 78:737, 1985. 35 Kovacs J et al. In Vivo Anti-Retroviral Properties of Recom- binant Alpha Interferon in AIDS with Kaposi's sarcoma and healthy HIV-Seropositive Homosexual Men. Third International Conference on AIDS, Washington, 1987, MP. 228. 36 Rozenbaum, W et al. Long term follow-up of 82 patients treated by recombinant alpha-2 interferon in AIDS related Kaposi's sarcoma. Third International Conference on AIDS, Wash- ington, 1987, TP. 229. 37 Kovacs et al. Anti-tumor and antiviral effects of Alpha Interferon in AIDS patients with Kaposi's Sarcoma: correlation with T4 count. 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, 1987, #375. 38 Janoff EN et al. Effect of Human Immunodeficiency Virus (HIV) Infection on the Longitudinal, Isotype-Specific Humoral Response to Pneumococcal Vaccine. 27th Interscience Congress on Antimi- crobial Agents and Chemotherapy, New York, 1987, #893. 39 Douglas, JM, et al. Response to pneumococcal and influenza vaccines in gay men with asymptomatic HTLV-III infection and with AIDS. 26th Interscience Congress on Antimicrobial Agents and Chemotherapy, New Orleans, 1986. 40 Ragni, MV et al. Antibody responses to immunization of patients with hemophilia with and without evidence of human immu- nodeficiency virus infection. J. Lab Clin. Med. 109: 545-9, 1987. 41 Huang K et al. Antibody response after influenza and pneumo- coccal immunization in HIV infected homosexual men. JAMA 157: 2047-50, 1987. 42 Rhoads JL et al. Response to vaccination in HIV seropositive subjects. Third International Conference on AIDS. Washington, June, 1987, WP. 110. 43 Nelson KE et al. The influence of HIV infection on antibody responses to influenza vaccines. Ann Int Med 109:383, 1988. 44 Nelson KE. The influence of HIV infection on antibody responses to influenza vaccines. Third International Conference on AIDS. Washington, June, 1987, WP. 116. 45 von Reyn CF et al. Human Immunodeficiency Virus Infection and Routine Childhood Immunisation. Lancet, September 9, 1987, 669- 72. 46 John LaMontagne, personal communication. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display