[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 8 September, 1993 Gay Men's Health Crisis: Treatment Issues > Reports From Berlin: Opportunistic Infections Overview > Coagulation Substitutes and CD4 Decline in Hemophilia > Combination Therapy and Early AZT: New Data > Treatment Briefs >> Switching from AP to TMP/SMX >> Splenectomy for Thrombocytopenia >> Viral Strains, Progression, and AZT >> Treatment Information for Prisoners >> Pregnancy Hormone Studied For KS >> DHEA Study Results >> Two Foscarnet Reports >> CRIA Begins Aspirin Study >> Other New Trials in New York City >> Treatment Issues On-Line ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Reports From Berlin: Opportunistic Infections Overview by Gabriel Torres, M.D. Opportunistic infections remain the most common cause of morbidity and death in persons with HIV disease. The expanding knowledge base on the management and prevention of opportunistic infections was evident at the Berlin conference; many presentations dealt with refinements in treatment and prophylaxis strategies, rather than epidemiological observations. Epidemiology Update Dr. M. Flepp from the University Hospital in Zurich reported trends in the incidence of opportunistic infections (OIs) in a Swiss cohort of over 6,000 men and women with HIV who experienced an OI during 1985-91 and who had CD4 counts performed within two months of diagnosis.[1] Persons treated with zidovudine (AZT) developed OIs at lower CD4 cell levels compared with those who did not receive AZT. Since 1986 there has been a dramatic decline in the incidence of PCP, Candida esophagitis, herpes, Kaposi's sarcoma, and dementia, yet there has been an increase in CMV, MAI, and lymphoma. Extracerebral Toxoplasmosis and Diagnosis Two presentations by French researchers demonstrated that toxoplasmosis can occur outside the brain (extracerebral) in a disseminated form, with parasites found in the eyes, lungs, blood, bone marrow, muscles, bladder, and heart. In one series, only 42 percent of cases had cerebral involvement.[2] Another report examined toxoplasmosis in the lungs.[3] Pulmonary toxoplasmosis presented most commonly when CD4 counts were less than 100 and was associated with fever, cough, shortness of breath, and septic shock in 12.5 percent. Fourteen percent had negative toxoplasma titers. Diagnosis was made by bronchoalveolar lavage (BAL) in most cases; others had parasites detected in the blood or other sites. In the cases with septic shock, serum LDH was elevated over 1,000. In 29 percent, extracerebral toxoplasmosis was the cause of death. Various poster presentations described new methods for diagnosis of toxoplasmosis including PCR, dot blot hybridization, in vitro production of toxoplasma antibodies, CSF culture on THP-1 cells, and direct immunofluoresence using anti-P30 monoclonal antibodies in human embryo lung fibroblasts. New treatment strategies for toxoplasmosis A small study from Texas showed that tetracycline derivatives (in particular, doxycycline or minocycline) alone or in combination with pyrimethamine were effective in seven patients with toxoplamosis.[4] A larger multicenter study showed that atovaquone at a dose of 750mg four times daily was associated with clinical and radiological responses in patients with toxoplasmosis who were intolerant or failing standard therapy.[5] Response to atovaquone and survival in this study were related to plasma concentrations of the drug. Toxoplasmosis Prophylaxis Various studies demonstrated that trimethoprim/sulfmethoxazole (T/S) is an effective prophylaxis for toxoplasmosis. In the ALPHA study, a European study which compared two doses of ddI, those receiving T/S developed toxoplasmosis at a significantly lower rate than those receiving aerosolized pentamidine (AP).[6] In this large trial, 68 percent of participants had positive toxoplasma serologies. Only one case of toxoplasmosis occurred in the group receiving T/S compared with 30 cases among those receiving AP. A large Italian study of 528 patients randomized to receive either aerosolized pentamidine or dapsone/pyrimethamine showed that toxoplasmosis developed more frequently in those on AP (24 cases) compared with those on D/P (two cases) after a median follow-up of 335 days.[7] Cryptosporidiosis Several studies were presented which evaluated the use of paromomycin or letrazuril for the treatment of cryptosporidial diarrhea. In one study from France, 24 patients with cryptosporidial diarrhea were treated with two grams of paromomycin for four weeks, followed by one gram per day for maintenance. After a mean follow-up period of seven months, a clinical response was observed in 22, with a mean weight gain of 2.7 kg. All responders had clearance of the parasite from the stool and/or intestinal biopsies. Six patients relapsed under maintenance therapy; four recovered after the dose of paromomycin was increased to two grams per day.[8] In a Canadian study, fifteen patients with cryptosporidiosis were treated with letrazuril in escalating doses of 50 to 100mg orally for up to six weeks.[9] Of fourteen evaluable patients, seven responded. Of the responders, five had a complete response (defined as eradication of the parasite from the stool and symptomatic improvement) and two had partial responses (defined as symptomatic improvement but persistence of the parasite in the stool.) Half of the patients developed a drug-related rash. In a second Canadian letrazuril study, 4 percent of 24 patients had a complete response and 50 percent had a partial clinical response at a dose of 50 mg per day.[10] Half of patients relapsed 1.6 months after starting letrazuril; thus the investigators conclude that the effect of letrazuril was incomplete and transient. A presentation made by French researchers described the natural history of cryptosporidiosis in 37 patients.[11] Forty-six percent of the patients had spontaneous resolution of the infection. Fifty-four percent of patients had worsening of disease with chronic diarrhea in 15 percent and death in 14 percent. A relationship of biliary involvement to poor prognosis was noted. Biliary involvement was defined as dilatation or thickening of the bile ducts on abdominal CT scans or sonograms. Microsporidiosis Microsporidiosis was found in the respiratory tract of several patients studied by the Centers for Disease Control in the United States.[12] The microsporidia Encephalitozoan hellem was cultured in vitro from two patients and in several it was visually detected from sputum or BAL specimens using electron microscopy or fluorescent antibody staining. Other extraintestinal sites of microsporidiosis reported include the eye, the urinary tract, and the gall bladder. Nasal and ocular microsporidiosis can be diagnosed by scraping the conjunctival or nasal mucosa and staining with the Weber chromatrope stain or Gram stain.[13] Mycobacterium-avium complex (MAC) MAC infections received considerable attention at the Berlin conference. A symposium of leading MAC experts highlighted that MAC was rapidly becoming one of the leading infections in persons with advanced HIV disease in the United States, occurring in 15 to 24 percent of patients with AIDS. One presentation noted that laboratory measurements of resistance can be useful in the management of MAC infections. In one study of clarithromycin to treat MAC bacteremia, 90 percent of responders had MAC isolates which were sensitive to the drug at a minimum inhibitory concentration (MIC) of less than 2.0ug/ml compared with MICs greater than 32ug/ml in those who relapsed. An observational study of 467 patients enrolled in CPCRA trials showed that the incidence of MAC increases as CD4 counts decrease. The development of MAC increased the risk of death by 2.3 times. Use of ethambutol or clarithromycin decreased the risk of death by 30 percent, better than other drugs, which decreased the risk by only 12 percent.[14] Another study looked at the effect of commonly prescribed drug regimens on survival in patients followed in a primary care clinic in New Orleans. The study found that no treatment regimens improved survival.[15] A poster showed that high-dose rifabutin (600mg/day) can be used to treat MAC bacteremia even in patients who break through rifabutin prophylaxis. The regimen of rifabutin, clofazimine, and ethambutol was more effective than ethambutol and clofazimine in this study group.[16] An ongoing Canadian trial compares rifampin, ethambutol, ciprofloxacin, and clofazamine with rifabutin, ethambutol, and clarithromycin given orally for sixteen weeks. Patients in the study have been stratified by prior rifabutin prophylaxis use. Seventy patients have been enrolled yet the study remains blinded.[17] There was little new information on MAC prophylaxis. Various posters showed that clarithromycin at doses of 250 to 1000mg/day was effective in preventing MAC infections in small groups of patients, yet these studies were uncontrolled and had relatively short lengths of follow-up. In addition to MAC, another atypical mycobacterium, Mycobacterium genavense, has been found to cause disease in persons with AIDS in many European countries, Australia, and the United States. Patients with this infection had very low CD4 counts (an average of fifteen) and presented with massive weight loss, diarrhea, hepatomegaly, and abdominal pain. Two-thirds of the patients died within one year, despite treatment for mycobacteria.[18] Tuberculosis One-third of the population of the world is infected with tuberculosis and 8 million cases of active disease occur every year, accounting for 3 million deaths. Four to five million persons worldwide are co-infected with tuberculosis and HIV, 75 to 80 percent of whom are in Africa. In 1990, three percent of TB cases globally were HIV-related; by the year 2000, ten percent are estimated to be HIV-related. Tuberculosis infection causes immune activation and can increase the rate of progression to AIDS. Patients with higher CD4 counts can develop TB, which is usually localized to the lungs and commonly smear-positive. As the CD4 count declines the presentation of TB may change, with more disseminated disease, miliary lung involvement, negative sputum smears, atypical chest x ray patterns, and false negative anergy tests. Reinfection has been demonstrated to occur in HIV-infected patients resulting in relapse after adequate treatment. Several studies of tuberculosis among African patients with HIV infection were presented at the conference. In one large study from Rwanda, 89 percent of patients with tuberculosis were found to be HIV-positive. Features which distinguished HIV-positive patients with TB included more extrapulmonary involvement, disease in the middle and lower lobes of the lung, and anergy to PPD skin testing.[19] In another study from Cote d'Ivoire, HIV-positive patients with extrapulmonary TB were found to have lower CD4 counts than those with pulmonary TB.[20] Another double-blind placebo-controlled study demonstrated that isoniazid can reduce the rate of development of active tuberculosis by 50 percent - from 5.3/100 person-years to 2.3/100 person-years.[21] One study of supervised, intermittent short-course therapy with thrice weekly isoniazid, rifampin, ethambutol and pyrazinamide proved to be highly successful.[22] The study was performed in Haiti and included 117 HIV-positive and 310 HIV-negative patients with tuberculosis. Eighty-two percent of the HIV-positive and 91 percent of the HIV-negative TB patients completed more than 80 percent of the therapy, yet the death rate among the HIV-positives was higher (9 percent) than in the HIV-negatives (1 percent). Proven cures (negative AFB smears and cultures and radiologic resolution of disease) were more common among the HIV-negative patients. Relapses were equally common in both groups. Among the HIV- positives, those who died had a lower CD4 count than those who survived eighteen months. Several presentations described outbreaks of multi-drug-resistant TB in the United States, mostly in New York City, New Jersey, and Florida. In New York in 1991, 7 percent of newly diagnosed TB cases and 30 percent of previously treated TB patients were resistant to isoniazid and rifampin. One outbreak among 38 patients in a NY hospital revealed a short incubation period of 1.5 to six months and survival of only nineteen weeks.[23] Survival was better among those who received within two weeks at least two drugs to which the organism was susceptible. Another study of susceptibilities of TB isolates in a different NY hospital found that only six and seven drug regimens would confer greater than 90 percent effectiveness as initial regimens.[24] Cytomegalovirus Various studies investigating new treatment strategies for cytomegalovirus retinitis were presented. One compared two dose regimens of foscarnet (90mg/kg twice daily versus 60mg/kg three times daily) for induction therapy among 87 Italian patients with CMV retinitis.[25] Both dosage regimens were equally effective in arresting CMV and side effect profiles were similar. In another comparative study, patients with CMV gastrointestinal disease were randomized to either ganciclovir or foscarnet.[26] Endoscopic and symptomatic improvements were similar in both groups, though the toxicities were different. A pilot study of SDZ MSL 109, a human monoclonal anti-CMV antibody, given in combination with either ganciclovir or foscarnet for maintenance therapy of CMV retinitis, proved to be safe and well-tolerated.[27] The time to retinitis progression was longer than had been seen in patients who received monotherapy with foscarnet or ganciclovir. A phase I trial of HPMPC, a new anti-CMV agent being investigated by Gilead Sciences at the National Institutes of Health and in San Francisco, showed that the drug led to renal toxicity at a dose of 5mg/kg twice daily.[28] Urine cultures of two patients who received this dose showed transient clearance of the virus. Fungal Infections Fungal infections received considerable attention at the conference and some useful clinical information was made available to clinicians to bring back to their patients. Trials using itraconazole, the new azole marketed as Sporonox, were presented which show it is a useful alternative to the other azoles, such as fluconazole, and may have some advantages. One trial from Rwanda compared itraconazole (200mg per day) with amphotericin B (0.75mg/kg/day) for primary therapy of cryptococcal meningitis.[29] Ninety-two patients with newly diagnosed cryptococcal meningitis were randomized to either regimen for six weeks. Survival at eight weeks was similar with both drugs, yet amphotericin B was more effective in clearing cryptoccoccus from the cerebrospinal fluid. A study of a cyclodextrin solution formulation of itraconazole (100 or 200mg twice daily) showed that it was effective in two-thirds of persons with oral or esophageal candidiasis refractory to treatment with fluconazole, ketoconazole or itraconazole capsules.[30] Dr. Marcus Conant reported at a satellite symposium on fungal diseases that itraconazole is effective for onychomycosis (finger- and toenail infections by dermatophytes) with pulse doses of 100mg twice daily for seven days, one week per month. He also reported success in treating eosinophilic folliculitis, a condition caused by the fungus Pityrosporum ovale, with 200mg twice daily of the drug. Another study evaluated the use of high doses of fluconazole alone or in combination with flucytosine for cryptococcal meningitis.[31] Doses of fluconazole used were 800mg, 1200mg or 1600mg/day with or without flucytosine 150mg/kg/day. Response rates were 71 to 80 percent in the flucytosine-containing regimens compared to 25 to 38 percent in the fluconazole alone groups. Another study from UCLA examined the use of in vitro susceptibility assays to determine whether cryptococcus has developed fluconazole resistance. This assay can be used to determine which patients should receive amphotericin for primary therapy of cryptococcal meningitis. A small study of fluconazole (50mg three times weekly) versus intense monitoring for candidiasis in women showed that 35 percent of those receiving intense monitoring developed candidal infections compared to 6 percent of those receiving fluconazole.[32] Multiple poster presentations also described the rising incidence of fluconazole-resistant candidiasis in advanced HIV-positive patients maintained on long-term fluconazole therapy. Resistant strains of Candida albicans and the emergence of less sensitive Candida strains such as C. krusei, C. tropicalis and C. glabrata were commonly observed. Another fungal infection which received considerable attention was Aspergillus fumigatus, a fungus found to cause pulmonary disease, sinusitis, external and middle ear disease, and brain and muscle abscesses in patients with AIDS. Predisposing factors for invasive aspergillosis may include neutropenia, previous pulmonary disease (especially PCP), use of antibiotics, marijuana use, and corticosteroids.[33] Pulmonary disease may manifest as thin walled cavities in the upper lobes, nodules, or lower lobe infiltrates. Treatment is with amphotericin B or itraconazole. In one open study of itraconazole (400mg per day), 28 percent had complete responses by the end of the treatment. Penicillium marneffei is a new fungal infection which has rapidly become one of the major opportunistic infections in southeast Asia, especially in Thailand, China, Hong Kong, and Vietnam. In Thailand alone, 140 cases have been diagnosed thus far. Patients typically present with fever, anemia, weight loss, skin lesions, cough, lymphadenopathy, hepatomegaly, or papules on the palate. The skin rash usually involves the face, ears, upper trunk, and arms and may have a necrotic umbilication. The fungus may be isolated from blood, skin or bone marrow biopsy cultures. Untreated, mortality is 100 percent, whereas 75 percent respond to amphotericin B or itraconazole within two to three weeks. 1 Flepp M, et al. Abstract WS-B01-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 2 May TH, et al. Abstract WS-B13-1. Ninth International AIDS Conference, Berlin. June 6-11, 1993. 3 Rabaud C, et al. Abstract WS-B14-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 4 Blockman KW, et al. Abstract PO-B10-1427. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 5 Torres R, et al. Abstract PO-B10-1453. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 6 Tournerie C, et al. Abstract WS-B13-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 7 Opravil M, et al. Abstract PO-B10-1429. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 8 Bissuel F, et al. Abstract WS-B13-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 9 Harris M, et al. Abstract WS-B13-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 10 Walach C, et al. Abstract PO-B10-1472. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 11 Gerard L, et al. Abstract WS-B13-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 12 Schwartz DA, et al. Abstract WS-B14-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 13 Schwartz DA, et al. Abstract PO-B10-1440. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 14 Church T, et al. Abstract WS-B10-6 Ninth International AIDS Conference. Berlin. June 6-11, 1993. 15 Bucher G, et al. Abstract WS-B10-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 16 Sullam P, et al. Abstract PO-B07-1238. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 17 Shafran SD, et al. Abstract WS-B10-5. Ninth International AIDS Conference. Berlin June 6-11, 1993. 18 Pechere M, et al. Abstract WS-B10-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 19 Batungwanayo J, et al. Abstract WS-B09-1. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 20 Ackah A, et al. Abstract WS-B09-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 21 Wadhawan D, et al. Abstract PO-B07-1114. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 22 Holt E, et al. Abstract WS-B09-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 23 Edlin BR, et al. Abstract WS-B09-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 24 Rose DN, et al. Abstract WS-B09-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 25 Carosi G, et al. Abstract WS-B11-3. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 26 Blanshard C, et al. Abstract WS-B11-4. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 27 Tolpin M, et al. Abstract WS-B11-2. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 28 Polis M, et al. Abstract WS-B11-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 29 Taelman H, et al. Abstract WS-B12-3. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 30 Cartledge JD, et al. Abstract Ws-B12-2. Ninth International AIDS Conference. Berlin. June 6-11,1993. 31 Milefchik E, et al. Abstract WS-B12-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 32 Fiore TR, et al. Abstract PO-B09-1369. Ninth International AIDS Conference. Berlin. June 6-11, 1993. 33 Tumbarello M, et al. Abstract PO-B09-1382. Ninth International AIDS Conference. Berlin. June 6-11, 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Coagulation Substitutes and CD4 Decline in Hemophilia by Naomi Pfeiffer and Greg Haas Impurities in clotting factor substitutes used by persons with hemophilia to replace their missing factor VIII may hasten CD4 decline in those with HIV, according to a preliminary report released at the Ninth International Conference on AIDS in Berlin. The multicenter study, presented by Dr. Stephanie Seremetis of Mt. Sinai Medical Center in New York City, showed that purer concentrates were associated with slower declines in CD4 counts in HIV-positive persons with hemophilia.[1] According to Dr. Seremetis, the findings were a "surprise" to the researchers themselves. In her presentation, she stated that the study results "should persuade the experts to rethink current treatment of these patients with standard intermediate-purity products." At least 80 percent of the persons with hemophilia in the United States who repeatedly infused factor VIII concentrates between 1978 and 1985 became infected with HIV. During that period, the internal bleeding which occurs in persons with hemophilia was treated with pooled blood products that contained impurities, including HIV. In 1985, heat-treated intermediate-purity factor concentrates became generally available. These products were free of HIV but contained other viruses and proteins. In 1989, a new generation of high-purity concentrates was approved by the FDA. These products are purified using monoclonal antibodies and contain substantially fewer contaminants. In December 1992, the FDA aproved a second type of high-purity product which is manufactured through recombinant technology. The higher-purity products are significantly more expensive than the earlier concentrates. Previous studies have indicated that impurities present in intermediate-purity concentrates can suppress lymphocyte function in both HIV-positive and HIV-negative persons with hemophilia and can activate HIV in latently infected cells. Earlier evidence convinced British health authorities to switch to the monoclonal antibody-derived factor VIII concentrates for their HIV-positive population, according to Seremetis. Other countries are weighing the move despite the higher costs. However, some U.S. hematologists are not convinced that the switch is worth the expense and do not prescribe higher-purity concentrates for their clients. In the randomized, controlled trial of factor VIII products, 60 HIV- positive patients with severe hemophilia were given either an intermediate-purity or high-purity concentrate. After three years, 35 patients remained in the study. Twenty of these were in the high- purity arm and fifteen were in the intermediate-purity arm. Those in the high-purity arm maintained stable CD4 counts (mean 416 at baseline, 393 after three years), while the fifteen on the intermediate-purity arm experienced a significant drop (mean 378 at baseline, 190 after three years). According to the researchers, the difference in CD4 levels was so dramatic that the trial was stopped after three years. However, at the time the trial was stopped, there was no difference in AIDS-defining events (one in each arm). Dr. Seremetis noted that the study was the longest and largest of its kind and that the CD4 difference was independent of antiretroviral therapy. She suggested that repeated infusions of intermediate-purity concentrates may impair cell-mediated immunity. No one has suggested that high-purity factor VIII concentrates have either immune-restoring or antiviral capabilities. Rather, the study lends preliminary support to the view that reducing the quantity of foreign proteins that the immune system encounters may slow its deterioration. 1 Seremetis S, et al. Abstract PO-B42-2495. Ninth International AIDS Conference. Berlin. June 6-11, 1993. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Combination Therapy and Early AZT: New Data by Derek Link Data from three large efficacy studies of various nucleoside analog treatment strategies were released this summer. These data shed some light on combination therapy and early AZT use in asymptomatics. Combination AZT/ddC: ACTG 155 ACTG 155 was designed to assess the safety and efficacy of combination therapy with AZT and ddC compared with ddC monotherapy or continued AZT monotherapy in patients with at least six months of prior AZT use. The study was randomized and double- blinded. Patients enrolled were either symptomatic with under 300 CD4 cells or asymptomatic with under 200 CD4 cells. Primary endpoints in the study were time until occurrence of an AIDS- defining event or death. Secondary endpoints included survival, CD4 cell count changes, reduction in p24 antigen levels, weight gain, and change in Karnofsky score. The study had three arms: AZT 200mg tid (three times daily), ddC 0.75mg tid, or AZT 200mg tid plus ddC 0.75 tid. Patients were randomized 2:2:3 respectively - which means that more patients were intentionally randomized into the combination arm. In March 1992, the study investigators amended the protocol to allow patients who reached an endpoint the option of receiving open-label AZT/ddC combination therapy. The study accrued 1,001 patients, 991 of whom are included in the analysis: 283 received AZT, 285 received ddC, and 423 received combination therapy. The median follow-up time in the study was 17.1 months. There were no differences in baseline characteristics among randomization groups. The median age of study participants was 37. The study population was 90 percent male and 82 percent white. Sixteen percent had a history of IV drug use, and 83 percent entered the study with symptomatic disease. The median length of prior AZT use was eighteen months. The median baseline CD4 count was 119. Twenty-eight percent of patients entered with detectable p24 antigen. Study investigators stratified patients by disease status, length of prior AZT, and type of PCP prophylaxis. In November 1992, the study investigators decided to examine three patient subgroups based on their baseline CD4 counts: those with under 50 CD4 cells, those with 50 to 150 CD4 cells, and those with 150 to 300 CD4 cells. Thirty- eight percent (388 patients) withdrew from the study after a median of 7.9 months. The two most common reasons cited for withdrawal were the desire to take another antiretroviral (33 percent) or patient request (27 percent). Overall, the probability of suffering a severe side effect within twelve months was 44 percent for the AZT group, 40 percent for the ddC group, and 49 percent in the combination group. Severe toxicities were uncommon in the 150 to 300 CD4 group. Peripheral neuropathy was more common in the ddC and combination groups (22 and 23 percent respectively) than the AZT alone group (13 percent); peripheral neuropathy occurred most frequently in the under 50 CD4 group. In patients with 50 to 150 CD4 cells, stomatitis (ulcers in the mouth) was more common in the ddC group (8 percent) than the other two treatment groups (AZT 1 percent, combination 2 percent). In patients with under 50 CD4 cells, neutropenia was more common in the AZT and combination groups (41 and 35 percent respectively) than the ddC alone group (18 percent). There were no differences among the three treatment arms in disease progression or death. The probability of remaining free of new AIDS-defining events or death by twelve months was 70 percent for the AZT arm, 67 percent for the ddC arm, and 73 percent for the combination group. These differences were not statistically significant. In addition, there were no significant differences by any stratification category. When efficacy data are examined by CD4 cell subgroup, several points emerge. Most endpoints occurred in the under 50 CD4 cell group. There were no significant differences among any treatment arms in the under 50, or 50 to 150 CD4 cell groups. In the 150 to 300 CD4 cell group, the twelve-month probability of remaining event- free was 86 percent for the AZT group, 88 percent for the ddC group, and 95 percent for the combination group. In this patient subgroup, combination therapy was superior to AZT monotherapy but not to ddC monotherapy. ACTG 155 has not yet been published in a peer-reviewed publication; therefore, conclusions drawn from the data may well change. However, researchers have discussed the study at several conferences, including the Ninth International AIDS Conference in Berlin and the NIH State of Art Panel on Antiretroviral Therapy last June. While Dr. Margaret Fischl, the study's principal investigator, stated at the NIH meeting that "155 is, in some ways, a negative study," she also emphasizes that the subgroup analysis of patients with 150 to 300 CD4 cells indicates benefit with the combination in patients with higher pretreatment CD4 counts who received prolonged AZT treatment. Early AZT: Long Term Follow-up of ACTG 019 ACTG 019 was the seminal study of early AZT treatment in asymptomatics. The study began in July 1987 and randomized patients at all CD4 cell levels to receive AZT 500mg daily, AZT 1500mg daily, or placebo. In August 1989, study investigators terminated the under 500 CD4 cell group of ACTG 019 due to a dramatic reduction in the rate of progression to AIDS or death in the AZT arms after 19 months. At that time, the study investigators offered all patients AZT and followed them to assess the long-term safety and efficacy of the drug. ACTG 019 was the basis for the original government recommendation that all asymptomatic patients with under 500 CD4 cells start AZT. Dr. Paul Volberding presented the long-term follow-up data from this study at the Berlin AIDS Conference. The data include 1565 patients (1338 in the original report plus 227 randomized after May 1989) followed for approximately 2.6 years: 493 patients were randomized to the placebo group, 542 to the AZT 500mg group, and 530 to the 1500mg AZT group. The study lost a significant number of patients to follow-up: 131 in the placebo group, 123 in the 500mg AZT group, and 129 in the 1500mg AZT group. Overall, 232 patients reached a primary endpoint. The study investigators analyzed the data in four ways. Patient outcome by original treatment group was analyzed. Overall, there were no differences in survival in any group up to 2.6 years. The investigators then analyzed time to progression after initiation of open-label AZT use in all patients. Overall, there was no difference in progression among the three arms. However, the study investigators note that they did not plan this analysis from randomization and thus it is statistically imbalanced. The investigators also analyzed those randomized to the placebo group. Starting AZT significantly reduced the risk of progression in the placebo group, but this effect waned over time. By one to two years, AZT's benefit disappeared. The study investigators broke the data down into two CD4 cell subgroups: above 300 cells, and below 300. The investigators said they chose these groups arbitrarily because an equal number of events occurred in each. [However, the investigators also said that a 250 CD4 cell cutoff produced similar results, although these data were not described.] Overall, there was no survival advantage to AZT in either CD4 cell subgroup. Patients in the above 300 CD4 cell group had delayed progression to AIDS or death compared to the below 300 group. Furthermore, the duration of AZT's benefit appeared longer in the above 300 group. The investigators assert that AZT appeared effective for no more than 1.5 years in the under 300 group. In the above 300 group, AZT's benefit appeared to extend beyond 1.5 years, although the investigators do not know how long the effect continues. Although these data have not yet been published, study investigators distributed a summary of the most important findings. The authors conclude there is a "consistent pattern of a statistically significant but transient beneficial effect of AZT on the time to AIDS and death." Despite the noted transient benefit, the investigators caution, "There was no evidence that AZT prolonged survival overall or in any CD4 strata." Earlier AZT: The BW 020 European-Australian Study BW 020, a Burroughs Wellcome-funded study of early AZT in asymptomatic patients with 750 to 400 CD4 cells, was recently published in the New England Journal of Medicine.[1] This randomized, placebo-controlled, double-blinded study began in 1988 and enrolled 993 patients in Australia and nine European nations. Patients received AZT 500mg bid (twice a day) or placebo for a median time of 94 weeks. Primary endpoints in the study were progression to AIDS or severe ARC (also called CDC Group IV C-1), progression to CDC group IV C-2 disease (symptoms, such as recurrent oral candidiasis, recurrent oral hairy leukoplakia, disseminated herpes zoster, and persistent diarrhea, that are indicative of a damaged immune system but not severe enough to be included in Group C-1), or two CD4 counts below 350. Additionally, the investigators developed a new category - early HIV clinical disease - which includes symptoms that, in the investigators' opinion, are indicative of early progressive HIV infection, yet do not meet the criteria for CDC group IV C-2. These symptoms include milder oral candidiasis, milder oral leukoplakia, and localized herpes zoster infection. Overall, the study confirmed the safety of early AZT therapy. Reported toxicities were mild and their frequency low. Patient noncompliance was the most frequent reason for dose modifications - 14 percent in the placebo group, 18 percent in the AZT group. Hematological side effects caused a dose modification in 3 percent of placebo patients and 7 percent of AZT patients. Two percent of placebo patients and 6 percent of AZT patients reported nausea which resulted in dose modification. One percent of placebo patients and 3 percent of AZT patients reported headaches which resulted in dose modification. Other toxicities which occurred more frequently in the AZT group, but did not result in dose modifications, included: nausea, headache, asthenia (weakness), and anorexia. The study investigators analyzed the data in several ways. Firstly, a combined analysis of disease progression was defined as progression to clinical endpoints (including progression to AIDS, ARC, or CDC Group IV C-2 diseases) plus CD4 cells dropping below 350. AZT significantly reduced disease progression compared to placebo. One hundred twenty-nine placebo patients reached this endpoint compared with 76 AZT patients. Secondly, progression to AIDS was analyzed in the study. Ten placebo patients and six AZT patients progressed to AIDS during the study. This difference was not statistically significant. Thirdly, progression to CDC Group IV disease, which includes progression to AIDS and CDC Group IV C-2 symptoms, was analyzed. Twenty-two placebo patients and eleven AZT patients progressed to CDC group IV disease. This difference was statistically significant. The probability of progression to CDC Group IV disease at two years was 6 percent in the placebo group and 3 percent in the AZT group. Fourthly, AZT significantly reduced progression to CD4 cell levels below 350 in study participants. Seventy AZT patients dropped to below 350 CD4 cells compared with 113 placebo patients. Overall, progression to CD4 levels below 350 was reduced by 40 percent in AZT patients. Finally, AZT significantly reduced the risk of developing clinical HIV disease as defined by the study investigators. Clinical HIV disease includes all patients who progressed to AIDS, CDC Group IV C-2 disease, and early HIV symptoms. At two years, AZT patients had a 9 percent risk of progression to clinical HIV disease compared with 15 percent in the placebo group. On the crucial question of the duration of AZT's benefit, the study investigators assert that the "immunological effects of [AZT] therapy were clearly evident at 2.5 years and may extend for at least three years." The investigators conclude that data from several studies suggest that the duration of AZT's benefit is longer in patients with higher pretreatment CD4 counts. They state that "all these factors argue for early intervention with AZT in order to obtain the most prolonged benefit and allow patients to maintain a good quality of life." Since BW 020 is the first study which shows a benefit to early AZT use in patients over 500 CD4 cells, its significance should not be underestimated. In fact, Burroughs Wellcome intends to use this study to support an expanded indication of AZT for patients over 500 CD4 cells in the United Kingdom, according to a recent report in Scrip, a respected, international pharmaceutical industry newsletter. However, methodological questions with the study limit its immediate application to clinical care. Since this study used a new set of endpoints, the ability of these endpoints to predict ultimate clinical outcome must be established before firm conclusions can be made. Additionally, the published report leaves an important element of the study's statistical analysis unclear: was the study, and progression to AIDS in particular, analyzed as intention-to-treat? Intention-to-treat is a method of statistical analysis considered by the FDA and most leading statisticians to be the gold standard for efficacy studies. It will likely be some time before the statistical and methodological questions with this study are resolved. Conclusions These three, long-awaited clinical studies provide some important preliminary information on several crucial questions, such as the clinical efficacy of AZT/ddC combination therapy and the duration of early AZT's effect. However, the clinical application of these new findings is not immediately clear. ACTG 155 failed to define a clear role for AZT/ddC combination in the clinical management of patients who have received previous prolonged AZT monotherapy. Yet this treatment strategy was conditionally approved based on positive surrogate marker data from AZT-naive patients. Therefore, when and in whom should combination therapy be initiated? Answers to these questions must await the completion of ACTG 175 and other on- going studies of combination treatment in naive patients. Unfortunately, results from ACTG 175 are not expected until at least 1995. Similarly, the long term follow-up of ACTG 019 and BW 020 both demonstrate that, while AZT's effect diminishes over time, it's benefits may be longer in patients with higher pretreatment CD4 cell levels. However, both studies failed to demonstrate a positive effect of long-term early AZT on progression to AIDS or death. Therefore, the crucial question faced by all perscribing physicians and patients - when to start AZT treatment - remains ambiguous from these data. Much larger studies, which enroll perhaps tens of thousands of patients, will likely be needed to resolve this question. FDA Committee to Review ddC The FDA's Antiviral Advisory Committee will meet to review ddC monotherapy and combination therapy September 20, according to an announcement in the Federal Register August 26. Hoffmann LaRoche, the New Jersey-based affiliate of the Swiss drug company which manufactures ddC, will present new data from several studies, including CPCRA 002, a study comparing ddI with ddC in advanced AIDS patients, in a second attempt to obtain approval of ddC monotherapy. Hoffmann LaRoche first sought approval for ddC monotherapy at an Antiviral Advisory Committee meeting in April 1992 based on data from ACTG 114 and ACTG 119, two studies which compared AZT to ddC. At that time, the Committee recommended against approval of ddC monotherapy due to inadequate data supporting efficacy. Presently, ddC is conditionally approved for use only in combination with AZT in patients with previous AZT experience. AZT/ddC combination therapy was the first treatment conditionally approved by the FDA. Conditional approval is a new regulatory mechanism which allows drugs to be marketed before their efficacy has been established. In exchange for early marketing rights, the sponsoring drug company must perform studies, determined by the FDA, which demonstrate the clinical efficacy of the drug. If subsequent studies show that the conditionally-approved drug does not produce a clinical benefit, the FDA may withdraw the drug from the market. In light of ddC's conditional approval, the Advisory Committee will also examine new data, particularly ACTG 155, on AZT/ddC combination therapy. Documents obtained by Treatment Issues through a Freedom of Information Act request with the FDA describe the conditions of ddC's approval. Hoffmann LaRoche must present data which confirm that improvements in surrogate markers demonstrated with AZT/ddC combination therapy, such as increased CD4 cells, correlate with clinical efficacy. "Clinical endpoint data from ACTG 155 should provide primary information for the combination of surrogate markers," according to the documents. Other studies, including ACTG 175, a study of combination versus monotherapy nucleoside treatment as first line-therapy in asymptomatic patients, CPCRA 007, a study of combination therapy in advanced AIDS patients, and CPCRA 015, a large study of early versus late nucleoside treatment, "should also provide confirmatory data on clinical endpoints." While ACTG 175 and CPCRA 007 are ongoing, CPCRA 015 has not yet started and may never begin due to logistical problems. Hoffmann LaRoche must also present data from other clinical studies to fulfill the conditional approval. According to the documents, the company must work towards the "finalization of the analysis and report of BW 27,433-28" (a Burroughs Wellcome study used for ddC's approval), pursue "alternative dosing regimens" of AZT/ddC combination therapy, and conduct a "large simple trial" of ddC. Hoffmann LaRoche must submit further toxicological and pharmacological data on the drug combination as well. In addition, the Advisory Committee will review data on the toxic effects, such as liver toxicities and peripheral neuropathy, of various nucleoside analogs on September 21. 1 Cooper DA, et al. New England Journal of Medicine. 1993. 329: 297- 303. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Treatment Briefs by David Gold Switching from AP to TMP/SMX ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A study, reported in The Journal of Infectious Diseases (1993; 168: 314-7), found that two-thirds of 130 HIV-positive patients taking aerosolized pentamidine (AP) could be successfully switched to Bactrim or Septra (TMP/SMX) without allergic reactions or hematological toxicity. TMP/SMX is the most effective preventive treatment for Pneumocystis carinii pneumonia (PCP), a common, life-threatening infection in people with HIV. TMP/SMX is also less expensive and easier to administer than AP. Those who could not be switched developed fever and rash within the first two weeks, which resolved when the drug was discontinued. Significantly, patients with CD4 cell counts under 200 did not tolerate the crossover as well as those with higher CD4 cell counts. Fifty-seven percent of the lower CD4 group developed skin reactions to TMP/SMX compared with 27 percent in the higher CD4 group. Splenectomy for Thrombocytopenia ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Splenectomy (surgical removal of the spleen) is a common therapeutic intervention for patients with AIDS or ARC who have thrombocytopenia (low platelet counts). A study reported in AIDS (1993;7: 1063-7) of 22 HIV-positive patients who had their spleens surgically removed secondary to thrombocytopenia showed that the surgical procedure led to reversal of the blood disorder in most patients, including those with MAI, lymphoma, and Kaposi's sarcoma. Previous studies had shown that patients with MAI die soon after splenectomies, yet this did not occur in the study. Two patients developed pneumococcal infections after the splenectomy, but they had not received Pneumovax, the pneumococcal vaccine, prior to the operation. None of the patients had an acceleration of their HIV illness after the splenectomy and all but one of the patients had a complete or partial response in their platelet counts. Viral Strains, Progression, and AZT ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A team of Dutch researchers report in The Journal of Infectious Diseases (1993;168:733-6) a viral substudy from a randomized, double-blinded, placebo-controlled trial of AZT. The researchers found that the presence of certain HIV strains - syncytium-inducing (SI) or non-syncytium-inducing (NSI) variants - affected disease progression and the efficacy of AZT. Syncytia are groups of originally separate cells which clump together to form a single mass. The formation of syncytia in CD4 cells causes cell dysfunction and eventual cell death in laboratory experiments. Researchers do not yet know if syncytia form in vivo. The researchers found that patients who entered the study with SI variants at baseline progressed rapidly to AIDS and death despite AZT treatment. An equal percentage of placebo and AZT patients with SI variants at baseline progressed to AIDS by two years. In contrast, patients who entered with NSI variants at baseline progressed more slowly and received benefit from AZT. No patient treated with AZT who remained NSI throughout the study progressed to AIDS by two years. Thirty-eight percent of placebo patients who remained NSI throughout the study progressed to AIDS by two years. The researchers noted that SI variants can develop in NSI patients through an unknown mechanism. In fact, AZT treatment did not prevent the emergence of SI variants. The researchers observed, "In this small study, conversion to SI phenotype even tended to occur more rapidly in the AZT-treated group." Six AZT-treated patients converted from NSI to SI during the study period compared with two placebo patients. Assays to determine SI/NSI variants require sophisticated laboratory equipment found only in specialized research centers. Commercially available tests of SI/NSI variants are unlikely to become available in the foreseeable future. However, several research teams are now investigating this phenomenon. More information on the significance of these viral variants for clinical research and care should be forthcoming. Treatment Information for Prisoners ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ AmFAR runs a program which provides AIDS/HIV treatment information, including complimentary copies of Treatment Issues, to prison libraries across the country. Joe Guimento at AmFAR coordinates the program. Call him at 212/682-7440 for more information. Pregnancy Hormone Studied For KS ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Human Chorionic Gonadotropin (HCG), an approved treatment for inducing fertility in women, cryptorchidism (the failure of the testicles to descend), and male hypogonadism (inadequate gonad function), has been proposed as a KS treatment based on an anecdotal report of spontaneous resolution of KS lesions in a pregnant Belgian woman and unpublished animal data from Robert Gallo at the National Cancer Institute. Sharon Lee, a Kansas physician who is affiliated with San Francisco's Project Inform, will perform a study of HCG on six of her male KS patients. The study will examine 5000 units of HCG three times a week for up to six months. In addition to HCG's effect on KS lesions, the study will also examine any possible penile or testicular changes in the men. DHEA Study Results ^^^^^^^^^^^^^^^^^^ DHEA (dehydroepiandrosterone) is a testosterone precursor with unknown physiological significance which may have immunomodulatory effects, according to several laboratory studies. DHEA has been proposed as an alternative approach to treating HIV and is available through buyers' clubs in New York and San Francisco. An open-label, dose-ranging study of the drug in 31 asymptomatic people with 250 to 600 CD4 cells was reported in the Journal of AIDS (1993; 6(5): 459-465). Doses ranged from 750mg/day to 2250mg/day. No side effects were observed. CD4 counts did not improve in study participants. Neither p24 antigen nor B-2 microglobulin levels decreased. The authors state that a randomized clinical trial of this agent is now necessary to evaluate efficacy. Two Foscarnet Reports ^^^^^^^^^^^^^^^^^^^^^^ Foscarnet may be the drug of choice for CMV encephalitis, a research team from the National Cancer Institute reports in Antimicrobial Agents and Chemotherapy (1993; 37(5): 1010-14). Foscarnet crosses the blood brain barrier and can be detected at therapeutic levels in cerebrospinal fluid after a single dose. However, the clinical efficacy of foscarnet for CMV or herpes encephalitis is still unresolved. In addition, a small randomized study of 32 AIDS patients with CMV retinitis suggests that higher maintenance doses of foscarnet may be superior to lower doses. The study, published in The Journal of Infectious Diseases (1993; 168: 444-448), found a daily dose of 120mg/kg significantly extended survival time and prolonged the time to retinitis progression compared with lower maintenance doses of the drug (60 or 90mg/kg/day). Median survival was 157 days for the 90mg dose compared with 336 days with the 120mg dose. Kidney toxicities, a well-known side effect of foscarnet, were slightly more common at the 120mg dose; other adverse effects did not occur more frequently. CRIA Begins Aspirin Study ^^^^^^^^^^^^^^^^^^^^^^^^^ The Community Research Initiative on AIDS (CRIA), a New York- based community AIDS research group, has announced a clinical trial of aspirin for HIV disease. Dr. Donald Kotler of St. Lukes Hospital, the study's principal investigator, will test aspirin's ability to reduce HIV-related inflammation. Certain inflammatory mechanisms, such as increased levels of inflammatory cytokines, may increase HIV replication. The placebo-controlled trial is open to asymptomatic HIV-positive people with 50-350 CD4 cells. Call 212/924-3934 for more information. Other New Trials in New York City ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Two new trials for CMV retinitis have opened at New York Hospital. One study compares intravitreal ganciclovir implants (small pellets of drug sewn into the eye which release drug directly to the infected area) with standard intravenous ganciclovir therapy. The other study compares three treatment regimens for CMV retinitis: high-dose ganciclovir versus high-dose foscarnet versus the combination of both. Call 212/639-7237 for more information on these studies. New York University has started a trial of recombinant human growth factor (r-HGF) for HIV-related wasting syndrome. Call 212/561- 3906 for more information. Finally, a study at St. Vincent's Hospital (212/790-7625), and Memorial/Sloan Kettering (212/639-7163), will compare liposomal doxorubicin (Doxil) with adriamycin, bleomycin, and vincristine (ABV), a common Kaposi's arcoma treatment regimen, for advanced KS. Treatment Issues On-Line ^^^^^^^^^^^^^^^^^^^^^^^^ Treatment Issues is now available on three on-line computer bulletin boards: The BACKROOM, 718/951-8256 modem, 718/951- 8998 voice; NAPWA Link, 703/998-3144 modem, 202/898-0414 voice; and PRC BBS 217/525-3469 modem, 217/525-3456 voice. Treatment Issues is committed to expanding further its on-line availability over the coming months.