Treatment Issues Vol. 11, no. 2

-It UMR 2 AY 17a GAY EN' HE LTH RISS ' S U E NE SLE TE O LUP ME1 NUMB ASTERPEBR1 S Protease Inhibitors: Resistance, Resistance, Resistance by Dave Gilden, with John Falkenberg and Gabriel Torres, M.D. Nothing at the Retrovirus Conference changed the fact that all the HIV drugs now available or in advanced development operate by interfering with either HIV's reverse transcriptase or protease enzymes. Protease inhibitors are potent drugs in their own right, and combining them with reverse transcription inhibitors makes for a synergistic "one-two punch" against the virus. In examining the various combinations described below, bear in mind that it is very difficult to obtain greater than a 99% (2 log) average reduction in HIV viral load over the first month or two, or more than 99.7% (2.5 logs) over the first six months. The reasons for this lie in both the drugs' mode of action and the dynamics of HIV infection. All the present drugs stop the infection of new cells. None can kill or inhibit infected cells in any way, nor do they affect the HIV-driven metabolic processes within them. Since 99% of the new virus comes from actively producing cells with a short lifespan on average, viral load can drop quickly only by that percentage. Further, limits in the sensitivity of viral load assays (commonly considered to be 400 to 500, sometimes 200, HIV RNA copies/ml of plasma-or 20 to 50 copies/ml for the new ultrasensitive tests) reduce the observable viral load reductions. It is impossible with these tests to tell directly how close to zero a person's viral load has fallen. Similarly, the dynamics of CD4 cell proliferation tend to limit the average initial rises in CD4 counts to 100 to 150 cells/mm3 of blood. The differences between combinations are most observable in the long-term viral load endpoints and the stability of those endpoints. The present HIV drugs are plagued by resistance. These drugs are very specific in their action, which helps to protect the body from side effects but also makes it possible for HIV to slightly alter its enzyme structures and render the drugs ineffective. Combinations of drugs require HIV to mutate at more points in its genes before it can resist all the drugs and rebound to previous viral loads. Besides a drug regimen's immediate impact on viral load, the ease with which resistance can develop is a crucial factor in determining durability of response. Reports at the conference proposed various ways to use protease inhibitor-containing combinations to build a sufficiently high "genetic barrier" against HIV breakthrough. Creating this barrier is easier in people with no prior treatment. Those with advanced disease and/or long treatment history present a more difficult problem. Their circumstances, including high viral loads, mean that the HIV within them likely has already spawned many mutants at least partially resistant to various drugs. Plus, large residual HIV levels after initiating therapy are a breeding ground for more resistance. C) LC) LO) LO) Table 1: AZT/3TC/Indinavir in Advanced AIDS baseline group size size at 24 weeks median baseline viral load median viral load change at 24 weeks* percent with viral load below detection* median baseline CD4 median CD4 change at 24 weeks Indinavir alone 107 81 94,000 -0.15 log (-28.6%) 2% 17 +65 AZT/3TC 105 60 94,200 Triple Combo 108 85 76,400 -0.20 log -2.19 log (-36.7%) (-99.4%) 0% 14 0 65% 15 +84 *Lower limit of viral load assay = 500. HAART Therapy in Advanced Disease Nonetheless, potent HAART (for highly active antiretroviral therapy) combination therapies can be of benefit even to people with advanced AIDS and with extensive past exposure to anti-HIV therapy. This was confirmed by two studies at the Retrovirus Conference. In one (Merck protocol 039-abstract LB7), 320 volunteers with CD4 cell counts of less than 50 received either AZT/3TC/indinavir, indinavir alone or just AZT/3TC. All participants had at least six

t ISSUES C months of AZT but had never before taken a protease inhibitor or 3TC. The results are summarized in Table 1. The 65 CD4 count rise at 24 weeks from indinavir monotherapy is surprising given the regimen's poor antiviral performance. The reason may be that for the first two weeks, the viral load drop from indinavir alone equaled the reduction achieved with the triple therapy, about 1.3 logs (95.0%). The median viral load in the triple therapy arm kept gradually falling at least until week 16, when it essentially stabilized. In those on indinavir alone, the median viral load rebounded after the second week, and by week 16 was only about 0.1 log (20.7%) below baseline. (The AZT/3TC arm's median viral load was stable from week 2 to week 24.) As for the CD4 counts, the two indinavir containing arms rose in parallel Nellinavir has shown through the twelfth week after which the monotherapy arm declined slightly while itself to be a respectable those on triple therapy continued their rise. Other indinavir trials, too, have seen a long protease inhibitor, but lag between viral load rebound and fall of i od tCD4 count back to baseline in those on indiit is odd that the navir monotherapy. That process can take optimum dose is still over a year. (Trial 039 is now continuing beyond 24 weeks with everyone on open controversial. Further, label triple combination therapy.) Another trial looking at people in it is premature to judge advanced disease was a pilot study conWill. ducted in Vancouver, British Colombia how nelfinavir Will (abstract 234). This trial followed 21 heavily be affected by pretreated patients who were failing or C Coss- intolerant to their nucleoside analog theraresistance. py and seemed to have run out of options in this drug class. The 21, who were all naive to indinavir and nevirapine, received those two drugs in combination with 3TC. Baseline CD4 count averaged only 28 (everyone was under 50), and average baseline viral load was 135,000 HIV RNA copies/ml of plasma. This combination of a potent protease inhibitor, a rather well tolerated non-nucleoside reverse transcriptase inhibitor and a relatively benign nucleoside analog had a surprisingly positive effect as salvage therapy. In the 12 participants who had reached 20 weeks of therapy, CD4 counts were up 100 above baseline and continuing to rise, and viral load had fallen more than 1,000-fold (99.9%). However, so far only two of the 12 had undetectable viral loads using the new ultrasensitive PCR assay. Seven (58%) were undetectable by the standard PCR test that goes down only to 500 copies/ml. Three of the participants have dropped out, two due to nausea or vomiting and one because of skin rash. Other indinavir news included the latest results from protocol 035, a trial of AZT/3TC/ f e br Ua r V199 7 indinavir versus AZT/3TC versus indinavir alone in 97 adults with at least six months of prior AZT therapy. Follow-up is now out to 68 weeks in two-thirds of the group. This trial included a population that was a little less advanced than the two above: a baseline median CD4 count of 142 (one eligibility requirement was a CD4 count between 50 and 400) and a baseline median viral load of 43,000. Participants also had to have had at least six months of prior AZT treatment. The actual average past exposure to AZT was 30 months, with 80% of the participants carrying AZT-resistant HIV (by genetic analysis). The group was therefore somewhat representative of a real population with advanced diseased, in whom HIV has developed resistance to AZT during past treatment. Trial participants assigned to receive AZT/3TC/indinavir from the beginning have exhibited stable viral load reductions, a median of 2 logs (99%) or greater, out to a year or a year and a quarter so far. Of those on treatment for 68 weeks, 18 of 21 (86%) still have plasma viral loads below the test limit of 500 HIV RNA copies/ml and 10 of 14 (71%) checked with an ultrasensitive assay are also below 50 copies/ml. Nelfinavir: What about Cross-Resistance? Agouron Pharmaceuticals' protease inhibitor nelfinavir (brand name Viracept) is now up for FDA licensing review. Although rumors of its imminent approval are rampant, the company's "conservative" prediction is FDA approval by June of this year. Meanwhile, Agouron researchers presented a number of reports at the Retrovirus conference, including information on the compound's efficacy when combined with AZT/3TC or d4T. In contrast to the indinavir studies above, the AZT/3TC/nelfinavir trial (Agouron protocol 511) included only people with less than one month prior AZT and no other past treatment. Their CD4 counts could be any number, and in many cases were below ten. The d4T trial (Agouron protocol 506) included both treatment-naive and -experienced people (90 naive and 218 experienced with an average of 27 months prior therapy). The trial required that their CD4 counts exceed 50. Table 2 summarizes the data from these two trials. It is risky to compare the studies' data, especially given the two populations' different treatment histories. Still, the triple therapy seems superior to the double d4T/nelfinavir combination, both in terms of viral load and CD4 cell response and in the stability of that response: viral load in the d4T/nelfinavir cohorts reached a peak decline of about 1.5 logs (96.8%) and then started gradually rebounding. The viral load

treatment Table 2: Two Nelfinavir Trials AZT/3TC ~ Nelfinavir d4T ~ Nelfinavir AZT/3TC + Nelf + Nelf d4T + Nelf + Nelf 500 mg 750 mg 500 mg 750 mg TID* TID* TID* TID* baseline group size 101 97 99 109 97 101 size at 24 weeks 73 68 74 54 75 76 baseline viral load 170,000 150,500 134,400 120,000 150,700 155,100 mean viral load change -1.4 logs -2.0 logs -2.0 logs -0.7 logs -1.0 logs -1.1 logs at 24 weeks' (-96.0%) (-99.0%) (-99.0%) (-80.0%) (-90.2%) (-92.3%) percent with viral load below detection' 18 65 81 4 20 20 baseline CD4 count 276 307 283 279 291 268 CD4 change at 24 weeks +100 +160 +155 +51 +106 +103 *TID = three times a day. 'Lower limit of viral load assay = 500. (Using an assay with a lower limit pegged at 100 HIV RNA copies/ml yielded viral load drops at 24 weeks of 1.4 logs (96.0%), 2.3 logs (99.5%) and 2.5 logs (99.7%) for AZT/3TC, AZT/3TC/500 mg nelfinavir and AZT/3TC/750 mg nelfinavir, respectively.) curves of those on AZT/3TC/nelfinavir were flat to slightly downward from week eight onward. Most of the trial results show no significant difference in response to the 750 mg and 500 mg doses, and Agouron's application for FDA approval stated that the standard nelfinavir dose should be 500 mg thrice daily. Notice, though, that in the AZT/3TC/nelfinavir trial, 81% of those receiving 750 mg had undetectable viral loads, whereas only 65% of those receiving 500 mg reached this level. As a result of this statistically significant difference, some HIV specialists are disputing Agouron's proposed dose, asking that the 750 mg dose be specified instead since there is a sign that it better suppresses HIV. This higher dose would provide more insurance against the emergence of drug resistance and HIV rebound. Countering this argument is nelfinavir's tendency to cause diarrhea. In the triple combination trial, those on 750 mg nelfinavir had a 54% greater incidence of developing diarrhea (12 of 96 at the lower dose versus 19 of 99 volunteers at the higher). Aside from controversies over the dose, there has been considerable discussion about nelfinavir's resistance profile. Agouron has presented data to indicate that if nelfinavir is the first protease inhibitor taken, it can profitably be succeeded by others if nelfinavir resistance emerges. There have also been claims that the converse is true-that people who fail on other protease inhibitors due to drug resistance can still get benefit from nelfinavir. Should nelfinavir prove to have a unique resistance profile that obviates cross-resistance, it would be a very valuable addition to the anti- HIV armamentarium indeed. Such hopes are premature at best, as the available data is scant and ambiguous. Cross-resistance between nelfinavir and other protease inhibitors first came up a year ago, during the FDA hearings on approving Abbott Laboratories' ritonavir. During its presentation the company presented a graph indicating that HIV that had mutated to protect itself from ritonavir could also resist nelfinavir to a certain extent. Agouron countered last spring with its own lab culture studies purportedly indicating that a unique, single mutation at codon 30 on the protease gene is HIV's response to exposure to nelfinavir. (This mutation switches amino acid 30 on the HIV protease enzyme so that nelfinavir has difficulty binding to the molecule.) Codon 30 mutant HIV is still fully sensitive to other protease inhibitors. However, the same nelfinavir test tube experiments found that when HIV is cultured a little further in the presence of increasing concentrations of nelfinavir, a second mutation appears that grants HIV further immunity to nelfinavir. This is the same codon 84 mutation that reduces HIV's sensitivity to ritonavir, although it is not seen that often in HIV isolated from humans taking ritonavir. (There are other, more common sets of mutations not involving codon 84 that also make HIV unsusceptable to ritonavir). At the Retrovirus Conference, Amy Patick, Ph.D., Agouron's drug resistance expert, present vol 11 no2

* ISSUES C ed the results of several studies that she has con* ducted (abstract 10). The HIV isolates involved all came from participants in either the combination studies described above or earlier monotherapy studies. In the nelfinavir monotherapy trials, 36 of 54 (56%) participants analyzed had HIV with the protease codon 30 mutation by week 16. By contrast, only three of 49 (6%) of the people on AZT/3TC/nelfinavir had this mutant HIV. Sixteen such individuals who were maintained on nelfinavir for another 28 weeks (44 weeks on nelfinavir in all) had no detectable codon 84 mutation, but other, supplementary mutations did tend to accumulate. Six viral clones isolated from five people with the 30 mutation were five to 93 -fold less susceptible to nelfinavir than wild type virus (the range in resistance probably arises from the supplementary mutations). All of these isolates were fully susceptible to other proABT-378 seems to tease inhibitors. But, the question remains, if someone's HIV is resistant to nelfinavir, will their resistance by its HIV more rapidly become resistant to other protease inhibitors to which that sheer potency- person might be switched? One specific cause of concern: the supplementary at least in the lab. mutations at codons 36, 46 and 71 are frequently seen from exposure to other protease inhibitors as well as to nelfinavir. Their presence could facilitate the development of resistance to protease inhibitors that follow nelfinavir. And what about nelfinavir as a second-line protease inhibitor? People on one of the currently approved compounds would like to know that they can switch to nelfinavir if they start failing their present therapy. Dr. Patick presented an analysis of 23 HIV isolates obtained from people failing on indinavir, ritonavir or saquinavir. Fourteen (61%) of these isolates were still susceptible to nelfinavir in culture. The catch is that the protease inhibitor resistant HIV that had only one identified mutation was still sensitive to nelfinavir (with one mild eight-fold exception), but the virus found with two mutations (most at codon 90 plus either 82 or 84) was seven- to 75-fold resistant. Indeed, multiple mutations are more common than single ones after prolonged protease inhibitor therapy. These data led Dr. Patick to conclude (however tentatively), "Nelfinavir failures are treatable by other protease inhibitors. Failures on other protease inhibitors with one mutation are treat able with nelfinavir, but more than one mutation is a problem-so there is a need to switch early." Emilio Emini, M.D., who led the effort to develop indinavir at Merck would exercise greater caution about nelfinavir as either first- or t eb r u ar Y I1 second-line therapy: "You cannot say that if you start on protease inhibitor A and become resistant, the virus will still be susceptible to B, C or D," he declared. "You will get varying degrees of cross-resistance up to 100%. It all depends on the mutations generated. You don't get just one mutation. You alter the genetic background in ways that you can't see [in lab tests] because the mutations are present at too low a level. And it is from this background of minor mutations that resistance to new drugs appears." Nelfinavir has shown itself to be a respectable protease inhibitor, but it is odd that at this late stage, with the drug before the FDA, the optimum dose is still controversial. Further, it is premature to judge how nelfinavir will be affected by cross-resistance. Certainly it is intemperate to draw conclusions on optimum protease inhibitor sequencing on the basis of 23 isolates. Further information on nelfinavir's place as follow-on protease inhibitor in the case of treatment failure may be available in the near future: Agouron is tracking the viral load response in a group of protease inhibitor treatment failures now enrolled in the nelfinavir expanded access programs. And lest anyone think that there is no money to made from AIDS drugs: Agouron's stock price has skyrocketed from the high twenties to the mid-nineties in the past year, almost entirely on the perceived strength of nelfinavir. Abbott Labs Tries Again Abbott Laboratories in the meantime surprised the conference by unveiling its new protease inhibitor ABT-378 with much fanfare (abstracts 14 and 206-213). This compound has remained hidden from public view for some time (see Treatment Issues, May, 1996, page 5). It is highly active against HIV, about three or four times more so than Abbott's original protease inhibitor, ritonavir. The structure of ABT-378 also circumvents some of the drug-resistance mutations that afflict other protease inhibitors. For example, its activity is hardly impaired by a protease gene mutation at codon 82 that confers considerable resistance to both ritonavir and indinavir. In general, though, ABT-378 seems to overwhelm drug resistance by its sheer potency. In combination with small amounts of ritonavir, which blocks the relatively rapid breakdown of ABT-378 by the liver, it is easy to obtain drug levels that are 50 times the levels that are effective against wild type (non-drug resistant) HIV and ten to 20 times higher than HIV with a single mutation like that at codon 82. It is nevertheless possible to generate HIV that is not inhibited by ABT-378 and is considerably less sensitive to other protease inhibitors as well. One mutant

treatment COD created in the laboratory by exposing HIV to increasingly high concentrations of ABT-378 had five mutations and was 338 times less sensitive to ABT-378. It also was about 20 times less sensitive to ritonavir and indinavir. Four of the five mutations also appear during analogous culture tests of Glaxo Wellcome's experimental protease inhibitor 141W94. ABT-378 is an interesting new compound, but it does not represent a radical break with the earlier protease inhibitors. Its structure, mechanism of action and resistance mutations are comparable to those of other members of its class. A big remaining question is how feasible it is to achieve levels within humans that overwhelm any resistance on HIV's part. There are as yet no human trials to evaluate what drug levels can be attained in reality, either with ABT-378 alone or in combination with ritonavir. No information as to the new compound's toxicity is available, either. The data Abbott presented at the Retrovirus Conference at best come from rat studies, and much of the figures are derived from testtube cell cultures or even straightforward chemical analyses in cell-free solutions. Combining Protease Inhibitors Although human trials of ABT-378 plus ritonavir have not yet occurred, a trial of saquinavir plus ritonavir has been continuing since last spring (unpublished presentation in session 84 by John Mellors, M.D.). The reason for combining ritonavir with saquinavir is similar to combining ritonavir with ABT-378. In both cases, ritonavir, which inhibits one of the enzyme pathways in the liver, greatly increases and stabilizes blood levels of a compound that otherwise would be rapidly metabolized. The quantities required for saquinavir are much larger than those suggested for ABT-378 and are large enough to have an anti-HIV effect of their own. This reinforcement helps to delay breakthrough of drug-resistant HIV, the more so because the two agents trigger divergent mutational patterns. Results from the ritonavir/saquinavir trial are now in hand for 20 to 24 weeks of treatment. This trial includes four arms: 400 mg ritonavir twice daily plus 400 mg saquinavir twice daily; 600 mg ritonavir twice daily with either 400 or 600 mg saquinavir twice daily; and 400 mg three times a day of both ritonavir and saquinavir. Initial viral load averaged about 30,000 and average initial CD4 was about 300. (The trial enrolled 141 participants, all protease inhibitor naive.) For all four arms, median viral load reductions go below the limits of the viral load assay (here considered as 200 copies/ml) at four to eight weeks and stay there. This represents at least a 2 log (99%) medi an drop. At week 20 or 24, 60% to 85% of people on the different trial regimens had no detectable viral load. CD4 counts were up 75 to 125. There was no statistically significant difference in the effect of the various regimens, although by week 20 the group receiving ritonavir and saquinavir at 600 mg twice daily was lower than the other three in percent with undetectable viral load and in CD4 cell count rise. (This group may be less compliant due to more side effects and a more complicated dosing schedule.) Seven participants have been allowed to add d4T/3TC after their viral loads failed to become undetectable. Six of these seven are now undetectable, following four to 16 weeks of four-drug therapy. Another trial reported at the Retrovirus Conference (abstract 254) tried a similar four-drug approach in 32 people with refractory HIV. The participants had persistent viral loads above 5,000 copies or evidence of disease progression despite four months on two nucleoside analogs and one protease inhibitor. They received ritonavir (600 mg twice a day), saquinavir if (400 mg twice a day) and two nucleoside analogs. The week 16 results were as fol- inh lows: viral load down 2.2 logs (99.4% reduction from a baseline mean of 72,500 do copies/ml), with 93% of participants having in undetectable viral load (below 400 copies/ml), CD4 count up an average of 72 cri (from a baseline average 79). M Ritonavir/saquinavir by itself frequently Mi fails to elicit a good response in advanced patients (see Treatment Issues, December, 1996, page 4). Throwing two more drugs into the mix may be helpful for many of these cases, assuming that a patient can absorb and tolerate extra drugs, that his or her HIV remains sensitive to these drugs, and that his or her body is still able to support at least the minimum functioning needed for survival... There are many factors that might eventually or immediately interfere, although in these two small groups, at least, treatment was initially successful for most individuals. Should Abbott have lost interest in the ritonavir/saquinavir combination due to the arrival of ABT-378, the Hoffmann La Roche protease inhibitor may have found a new partner: nelfinavir. In a preliminary trial of 13 people on saquinavir plus nelfinavir (abstract 371), nelf inavir slowed liver metabolism of saquinavir to the extent that total exposure to the latter was raised five-fold (compared to a 20-fold average increase with ritonavir). Coin bination therapy included 750 mg of nelfinavir thrice daily (note the dose) plus 800 mg three a two-protease ibitor combination esn't work, throwing two reverse transptase inhibitors ght help. vol 11 no 2

v ISSUES I (U times a day of the new, more absorbable version of saquinavir (the "soft gel capsule" containing saquinavir formulated with special lipids which quadruple the proportion of saquinavir absorbed by the intestines). At 12 weeks, viral loads were down 2.0 logs (99%), with eight of 13 participants (62%) at undetectable levels (below 500 copies/ml). CD4 counts were up by 105. There are 12 possible double protease inhibitor combinations just counting the three protease inhibitors on the market and nelfinavir. Many of these may be feasible combinations in terms of tolerability, drug-drug metabolic interactions and lack of cross-resistance. Bear in mind that ritonavir works with saquinavir and possibly ABT-378 above all because of ritonavir's particular metabolic properties. By blocking the hepatic breakdown of the other protease inhibitors, ritonavir raises them to highly potent levels. Conversely, there may be interference between protease inhibitors because they compete for the same binding sites on the protease enzyme. By getting in each other's way, two protease inhibitors would have a combined effect less than the sum of their individual effects (this is termed antagonism), never mind the hoped for synergy, which occurs when the combined effects are greater than the sum of the individual ones. At the Retrovirus Conference, Merck and Roche researchers reported preliminary results indicating that indinavir administered concurrently with saquinavir raises the latter's blood levels five to eight times (abstract 608), similar to what nelfinavir does. But a team from Harvard Medical School determined that in lab culture at least, the interactive effects of indinavir and saquinavir are antagonistic, except at low doses in wild type virus (abstracts 11 and 188). ~III:--100

GAY EN' HE LTH RISS l s NE SLE TE O LUXP ME VALANUMBTER 45 API S9 Roche Brings New Formulation of Saquinavir To FDA by Jill Cadman On May 12, Hoffmann-La Roche announced that it was applying to the FDA for approval of the long awaited "soft gelatin capsule" formulation of saquinavir. The soft gel capsule contains the protease inhibitor saquinavir blended with a proprietary lipid mixture that raises intestinal absorption of the compound to 12% of the total drug available, three times the abysmally low 4% observed with the hard capsule. The recommended dose of the new version is 1,200 mg three times a day (TID), compared to 600 mg TID for the hard capsules. Taking this much will require 18 saquinavir soft gel capsules per day and provide eight to ten times the drug exposure of the current formulation. The eight-week dose-ranging study (NV15107) that identified 1,200 mg TID as the preferred dose recorded a respectable, though hardly record-breaking, 1.43 log (96.3%) drop in viral load among 22 volunteers on saquinavir monotherapy. The safety study (NV15182) showed few adverse side effects with the new formulation, but caution should be advised for those with a history of liver disease. In addition to the safety data, the FDA has recently requested a head-to-head activity study comparing the two formulations to prove that the soft gel is an enhancement over the hard capsule. Sixteenweek activity data from this study (NV15355) should be available by mid-summer and will be submitted to the FDA during the review process. Roche expects to receive the FDA's go-ahead to market the improved saquinavir by the end of this year. Community activists have raised concerns about the continuation of Roche's aggressive marketing campaign which is advertising saquinavir as "a protease inhibitor you can live with." The hard capsules are administered at 600 mg TID, a suboptimal dose that may breed resistance to both the new formulation and other protease inhibitors by failing to have much impact on HIV replication. At a community meeting in May, activists asked Roche to pull the campaign until the soft gel capsules are available. Tammy Lewis, Product Director for saquinavir, conceded that the best way to use the current formulation is in combination with the protease inhibitor ritonavir, which raises blood levels of saquinavir ten-fold by blocking the drug's metabolism in the liver. But the saquinavir/ritonavir combination has not been reviewed, much less approved, by the FDA, and Roche is prohibited from promoting it. Roche is now pursuing approval of an expanded indication of saquinavir for use in combination with other protease inhibitors. Approval is not likely within the next 12 months The "protease inhibitor and would probably be limited to.0 specific drug combinations initially you can live with Is (in particular, 400 mg saquinavir plus beingreplaced. 400 mg ritonavir), rather than a g broad saquinavir/other protease inhibitor indication. Discussions have already taken place between Roche, Abbott and the FDA regarding registration trials in Europe for saquinavir/ ritonavir. Another long-standing community complaint is the current price of saquinavir. At $5800 per year wholesale, the hard capsule saquinavir is at least as expensive as the other protease inhibitors even if it is the weakest. Ms. Lewis says it is "premature" to comment on the pricing of the soft gel capsule. Especially at the preferred 1,200 mg TID dose, the soft gel could prove much more costly than the present version. rC=rz C=rla C= v o no

w ISSUES C I w w E w FDA Approves Nelfinavir On March 14, the U.S. Food and Drug Administration granted Agouron's protease inhibitor nelfinavir (brand name: Viracept) clearance for distribution through the agency's accelerated approval procedure. Nelfinavir is the fourth protease inhibitor to be approved for adults and the first to be approved for children. The FDA-approved indication gives broad guidelines for usage, simply stating, "for the treatment of HIV infection when antiretroviral therapy is warranted." The adult dosage is 750 mg three times a day. The pediatric formulation is available in an oral powder and doses are determined by weight for children two to 13 years old. For optimal absorption, it is best to take nelfinavir with a meal or a light snack. Nelfinavir has considerable stability in the body, which allows patients some leeway in scheduling their doses. Agouron spokeswoman Joy Schmitt commented, "In all of our clinical trials as well as our expanded access programs, we've always simply stated TID dosing [three times daily]. It's been as loosely structured as that. There hasn't been a need to put a timing on it, though obviously there needs to be common sense on how an individual would take the drug." The most common reported side effect is mild to moderate diarrhea, which according to the package insert can usually be controlled with non-prescription drugs. Although the FDA did not require that nelfinavir be used along with other antiviral therapy, the package insert recommends combining it with nucleoside analogs. There has been much speculation on the utility of using nelfinavir as first-line treatment. This is because HIV that develops nelfinavir resistance may not be cross-resistant to the other current protease inhibitors, which could be used as follow-up drugs. But such a conclusion is based on HIV isolates taken from just five patients during nelfinavir therapy, according to the official package insert. The isolates demonstrated emerging resistance to nelfinavir but did not exhibit decreased susceptibility to the other protease inhibitors in lab cultures. For those people who have become resistant to other protease inhibitors and need to switch treatments, nelfinavir could be an option. However, the package insert notes that six of seven HlV isolates that had developed reduced sensitivity to ritonavir during therapy with that protease inhibitor also showed decreased sensitivity to nelfinavir. For more information on the nelfinavir resistance question, see Treatment Issues, February, 1997, pages 6-8. Nelfinavir is 29% more expensive than Merck's indinavir (Crixivan), with a wholesale cost of $5650 for a year's supply. Although the New York State AIDS Drug Assistance Program included nelfinavir on its list of covered drugs even before FDA approval, widespread inclusion of nelfinavir in Medicaid and ADAP formularies will further stretch scarce public health resources. There is a nelfinavir patient assistance program reachable at 888/777-6637. The program will first attempt to find outside means of reimbursement but can provide the drug free of charge if necessary. Agouron will also provide nelfinavir free of charge to uninsured children in the U.S.. Ritonavir Approved for Children The FDA also granted approval for a pediatric ritonavir formulation on March 14. In so doing, the agency increased the number of protease inhibitors available for children from zero to two in one day (see above for nelfinavir). Dosing recommendations are based on safety data collected from ongoing studies of children aged two to 16. The safety of ritonavir in children under two has not been established. When taking ritonavir, children unfortunately suffer from the same long list of side effects and drug-drug interactions as adults do. The evaluation of ritonavir's antiviral effect in children is still in progress. An interim report at this winter's Fourth Conference on Retroviruses and Opportunistic Infections (abstract 722) indicated that ritonavir's antiviral activity in children was similar to that in adults. More Pharmacies to Carry Crixivan Since indinavir (Crixivan) entered the market in March, 1996, its manufacturer, Merck & Co., has given the mail-order Stadtlander's Pharmacy exclusive distribution rights in order to manage the limited supplies available. This was to be a temporary situation until Merck was able to bring new production facilities on line later that year. After many delays, Merck will finally expand the distribution program to include other pharmacies as of May 1, 1997. But sales will still be limited to participating pharmacies, and people must still enroll in a cumbersome distribution program. We are not yet at the point when a person can walk into a pharmacy with a script for this protease inhibitor and expect to have it filled immediately. march 1997 N

Any pharmacy or provider interested in dispensing indinavir can register with Merck. Participating pharmacies will report certain identifying patient information so Merck can continue to monitor and control distribution. This is referred to as "enrolling" patients and is being handled through a subsidiary of Merck called PAID Prescriptions. The participating pharmacy will only receive a month's supply of indinavir for each enrolled patient after transmitting the pertinent information to PAID (via fax, phone or computer network). Pharmacies must also confirm with PAID each month that the patient needs to refill an order before the medication will be shipped (PAID will fax a reminder to the pharmacist). It is therefore very important to make sure the pharmacist requests the refill in advance so that it will be ready to be picked up when needed. According to a Merck spokesperson, indinavir will not be going into normal distribution in the foreseeable future. Merck states that special measures are still necessary in order to insure all patients have uninterrupted access to the drug. Although production has increased, supplies must still be closely monitored due to demand in nations where indinavir is newly approved. (Indinavir has been approved in 49 countries to date, the most recent being Albania). Those patients already enrolled and receiving indinavir through Stadtlander's may continue to do so by simply filling out the monthly refill cards as usual. No one is under any obligation to continue using Stadtlander's, and those who wish to switch will be able to mark a box on the April refill card to that effect. These people should then enroll with another pharmacy and make sure there will be no problems with insurance coverage. A new paper prescription will be required in most cases by the new pharmacy, but doctors will not have to call to enroll patients, as was the case in the past. New patients just beginning indinavir can sign up with their participating pharmacy of choice. Note that there may be a two or three day delay between enrolling and receiving indinavir for the first time. Anyone who needs help enrolling in the distribution program, locating a participating pharmacy, or obtaining financial assistance should call 888/CRIXIVAN. Viral Load Patient Assistance Programs Both Chiron and Roche have set up patient assistance programs (PAP) to ensure there is access to viral load tests for those who have no current means of payment. The number to call for information (in English or Spanish) for the Roche program for PCR tests is 888/TEST-PCR. The PAP representative will first determine whether the caller is eligible for coverage through an insurance company and will assist in negotiating with that carrier. If third-party reimbursement cannot be arranged and the applicant is qualified, Roche will send the applicant's doctor a voucher for a free test, along with the address of the laboratory designated to perform the test. There is supposed to be a two week turnaround time from initial call to approval for those who qualify. Eligible patients are entitled to a maximum of five free tests per calendar year and must go through a simplified recertification process for each additional test. The number to call for information on Chiron's bDNA PAP is 800/775-7533. This is the reimbursement hotline, which assists people in finding payment methods and working out problems with claims (prior to April 15, 1997 inquiries about the PAP can be directed to 888/HIV-LOAD) The bDNA test is still not FDA-approved, but, according to a survey done by Chiron, most claims are being paid for by private insurers, Medicaid or ADAP. For those who have no means of payment, Chiron is working with certain local hospitals and clinics that serve indigent or uninsured patients to provide free tests on site. This means that a person must register with a participating medical facility in order to have access to the program. Facilities are being targeted in large urban areas with several sites already on line in San Francisco, Los Angeles, Boston and Chicago and others planned in cities with large populations of people living with AIDS. The program is not available to those outside the immediate geographic area. One final note for those who had PCR tests performed last summer under Roche's free introductory program and never received the results due to a massive logjam at the labs involved: Roche is still offering two complimentary replacement tests (see Treatment Issues, November, 1996, page 12). Physicians can request coupons for patients in this situation until the end of June. The coupons are valid for six months from date of issue and can be unofficially transferred to any patient. Doctors can also call the PAP number, 888/TEST-PCR, to obtain the coupons. treatment =00 V3 V3 rl-_ C== C=Z C.a v o I 10 no 5

glossary Alternative Names for Common Medications Common HIV/AIDS-Related Generic Name Brand Name Abbreviation Description Application Distributor acyclovir Zovirax ACV Nucleoside Analog Herpes Glaxo Wellcome albendazole Albenza Antibiotic Microsporidiosis SmithKline Beecham amphotericin B Fungizone IV AmB Antifungal Fungal Infections Apothecon Fungizone oral Bristol-Myers Squibb atovaquone Mepron Antiprotozoal PCP Glaxo Wellcome azithromycin Zithromax Antibiotic MAC/Bacterial Infections Pfizer cidofovir Vistide HPMPC Nucleotide Analog CMV Gilead Sciences ciprofloxacin Cipro Antibiotic MAC/Bacterial Infections Miles clarithromycin Biaxin Antibiotic MAC Abbott clindamycin Cleocin Antibiotic PCP/Toxoplasmosis Pharmacia & Upjohn clotrimazole Lotrimin CLO Antifungal Candida Schering-Plough Mycelex Bayer dapsone Dapsone USP Antibiotic PCP Jacobus daunorubicin, liposomal Dauno-Xome Lipsome-encapsulated KS NeXstar Cancer Chemotherapy delavirdine Rescriptor DLV Non-nucleoside Reverse HIV Pharmacia & Upjohn Transcriptase Inhibitor (NNRTI) didanosine, Videx ddl Nucleoside Analog HIV Bristol-Myers Squibb dideoxyinosine doxorubicin, liposomal DOX-SL Lipsome-encapsulated KS Sequus Cancer Chemotherapy dronabinol Marinol THC Appetite Stimulant Wasting Roxane erythropoietin Epogen EPO Growth Factor Anemia Amgen Procrit Ortho Biotech ethambutol Myambutol Antibiotic MAC/TB Lederle famciclovir Famvir Nucleoside Analog Prodrug Herpes SmithKline Beecham fluconazole Diflucan FLU Antifungal Candida/Cryptococcal Pfizer Meningitis flucytosine Ancobon 5-FC Antifungal Candida/Cryptococcal Hoffmann-La Roche Meningitis foscarnet Foscavir Nucleoside Analog CMV/Acyclovir-resistant Astra Herpes ganciclovir Cytovene DHPG Nucleoside Analog CMV Hoffmann-La Roche ganciclovir implant Vitrasert Intraocular implant CMV Chiron Vision granulocyte colony Neupogen G-CSF Growth Factor Neutropenia Amgen stimulating factor (filgrastim) granulocyte-macrophage Leukine GM-CSF Growth Factor Neutropenia Immunex colony stimulating factor Prokine Schering-Plough (sargramostim) hydroxyurea Hydrea Host factor inhibitor HIV SmithKline Beecham immune globulin Gamimune N IVIG Passive Immunotherapy ITP, Bacterial Infections in Children Bayer 4l:_:u ne 10 Gammagard Gammar Polygam S/D Venoglobulin WinRho SO Baxter * Centeon American Red Cross Alpha Therapeutic NABI

Generic Name indinavir Brand Name Crixivan Common Abbreviation IDV Description Protease Inhibitor HIV/AIDS-Related Application HIV treatment ISSUES Distributor Merck interferon alpha-2 interleukin-2 isoniazid itraconazole ketoconazole lamivudine megestrol acetate Intron A Roferon-A Proleukin Nydrazid Sporanox Nizoral Epivir Megace IFNoc IL-2 INH ITR 3TC Immune modulator Immune modulator Antibiotic Antifungal Antifungal Nucleoside Analog Hormonal Appetite Stimulant KS HIV TB Fungal Infections Candida/Histoplasmosis HIV Wasting Schering-Plough Hoffmann-La Roche Chiron Apothecon Janssen Janssen Glaxo Wellcome Bristol-Myers Squibb metronidazole nandrolone decanoate nelfinavir nevirapine nitazoxanide nystatin octreotide acetate oxandralone paclitaxel paromomycin pentamidine pentamidine, aerosolized pyrimethamine recombinant human growth hormone rifabutin Flagyl Deca Durabolin Viracept Antibiotic Anabolic Steroid Protease Inhibitor Ambiasis Wasting HIV Searle Organon Teknica Agouron NFV Viramune NVP NTZ Mycostatin Sandostatin Oxandrin Taxol Humatin Pentam NebuPent Daraprim Serostim Mycobutin Non-nucleoside Reverse Transcritpase Inhibitor (NNRTI) Antiprotozoal Antifungal Digestive Hormone Analog Anabolic Steroid Anticancer Antibiotic Antiprotozoal Antiprotozoal Antiprotozoal Hormone HIV Cryptosporidiosis Candida Diarrhea Wasting KS Amoebiasis/Cryptosporidiosis PCP PCP Toxoplasmosis Wasting Unimed Bristol-Myers Squibb Sandoz Bio-Technology General Bristol-Myers Squibb Parke-Davis Fujisawa Fujisawa Glaxo Wellcome Serono Adria Laboratories Boehringer Ingelheim rHGH Antibiotic MAC rifampin Rifadin Rimactane ritonavir Norvir saquinavir Invirase stavudine Zerit sulfadiazine Sulfadiazine Tablets USP thalidomide Synovir trimethoprim/ Bactrim sulfamethoxazole Septra trimetrexate NeuTrexin valaciclovir Valtrex zalcitabine Hivid Antibiotic TB/MAC RTV SQV d4T Protease Inhibitor Protease Inhibitor Nucleoside Analog Antiprotozoal Anti-inflammatory/TNF Inhibitor TMP/SMX Antibiotic HIV HIV HIV Toxoplasmosis Aphthous Ulcers/Wasting PCP/Toxoplasmosis PCP Herpes HIV Marion Merrell Dow Novartis Abbott Hoff mann-La Roche Bristol-Myers Squibb Eon Celgene Hoffmann-La Roche Glaxo Wellcome US Bioscience Glaxo Wellcome Hoffman-La Roche Antibiotic Acyclovir Prodrug Nucleoside Anaolg ddC zidovudine Retrovir AZT, ZDV Nucleoside Analog HIV Glaxo Wellcome Ic ju n e10

w ISSUES C Principles and Guidelines for the Treatment of HIV Infection July 1997 The Office of AIDS Research of the National Institutes of Health (NIH) and the Department of Health and Human Services made public the Principles and Guidelines for the Treatment of HIV Infection. These publications are the result of the work of two panels called to formulate both the principles that should guide the treatment of HIV infection and the guidelines for the practical application of such principles. The two panels attempted to answer the most important questions regarding antiretroviral therapies; 1. When to start treatment. 2. What combination of drugs to use. 3. Who should start therapy. 4. Advantages and disadvantages of starting early therapy. Principles for the Treatment of HIV Infection (Summary) 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual. 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T-cell destruction, while CD4+ T-cell counts indicate the extent of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4+ T-cell counts is necessary to determine the risk of disease progression in an HIV-infected individual and to determine when to initiate or modify antiretroviral treatment regimens. 3. As rates of disease progression differ among individuals, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4+ T-cell counts. 4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy. 5. The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been treated previously. 6. Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages. 7. The available effective antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints. 8. Women should receive optimal antiretroviral therapy regardless of pregnancy status. 9. The same principles of antiretroviral therapy apply to both HIV-infected children and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations. 10. Persons with acute primary HIV infections should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays. 11. HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should be counseled to avoid sexual and drug-use behaviors that are associated with transmission or acquisition of HIV and other infectious pathogens.

treatment Guidelines for Treatment The panel on charge of formulating the guidelines for the treatment of HIV infection, dealt with the following issues: * The use of viral load and T-cell count tests. * When to start treatment and with what. * Treatment for advanced HIV infection. * When to stop treatment. * When and how to change treatment. * Treatment for acute HIV infection. * Treatment during pregnancy. Before starting anti-retroviral therapy, every one should have a complete blood test done, including a chemical profile. The test should include a T-cell count and viral load count. The recommendations about whether or not to start treatment are based on the clinical status of the patient and on the laboratory tests. Indications for the Initiation of Antiretroviral Therapy Clinical Category CD4 + T-Cell Count and Viral Load Recommendation Symptomatic (AIDS, thrush, Any value Treat unexplained fever) Less than 500/mm3 CD4 or Asymptomatic more than 20,000 copies of Treatment should be offered HIV RNA by PCR More than 500/mm3 CD4 and Some experts would offer Asymptomatic less than 20,000 copies treatment while others would of HIV RNA by PCR delay therapy and observe Indications for the Initiation of Antiretroviral Therapy Once the decision to start antiretroviral therapy has been made, the panel recommends that the best way to use the currently available drugs is in a combination of at least three agents. Although the possible combinations are numerous, the panel also established categories according to the shown efficacy of each combination, taking into account potential side effects and the interactions between the different drugs. Preferred Combinations One Protease Inhibitor & Two Nucleoside Analog. AZT + ddl Indinavir (Crixivan) d4T + ddl Nelfinavir (Viracept) AZT +ddC Ritonavir (Norvir) d4T + 3TC AZT + 3TC Alternate Combinations 1 Non-Nucleoside + 2 Nucleoside Analog. (Nevira pine) (From the colurm above) Or Saquinavir (Invirase) + 2 Nucleosidos Analog. A combination of just two drugs (e.g. two nucleosides) is not considered optimal. The use of just one drug (monotherapy), regardless of how strong, is not recommended at all.

* ISSUES C Principios y Directrices para el Tratameinto 16 de la Infeccion con VIH -Julio 1997 La Oficina de Investigaciones del SIDA de los Institutos Nacionales de la Salud (NIH por sus siglas en ingles) y el Departamento de Salud y Servicios Humanos acaban de publicar los principios y directrices para el tratamiento de la infecci6n de VIH con las terapias antiretrovirales disponibles hasta el momento. Esta publicaci6n es el resultado del trabajo de dos paneles convocados, uno para formular los principios que deben guiar el tratamiento y otro para formular las directrices del mismo. Ambos paneles se ocuparon de darle respuesta a los interrogantes ms importantes en cuanto a las terapias antiretrovirales: 1. Cuando empezar tratamiento. 2. Que combinaci6n de drogas usar. 3. Quienes deben comenzar tratamiento. 4. Ventajas y desventajas de comenzar tratamiento temprano. Principios para la Terapia de la Infeccion con VIH El panel defini6 11 principios que deben ser la base para cualquier estrategia de tratamiento antiretroviral para VIH. Estos principios se basaron en: a) El entendimiento de la relaci6n entre la replicaci6n viral y la progresion de la infecci6n, b) La capacidad que tienen las drogas disponibles actualmente de suprimir la replicaci6n viral por un tiempo prolongado, c) La capacidad de estas drogas para evitar la aparici6n de virus resistente a las drogas y d) La relaci6n entre los cambios en la carga viral y la mejorfa clinica. Resumen de los Principios 1. La replicaci6n permanente del VIH conduce al dailo del sistema inmunol6gico y, casi inevitablemente, a la progresi6n hacia el SIDA. 2. Los nivels del virus (niveles de ARN de VIH en el plasma) en la sangre indican la magnitud de la replicacion viral y estan relacionados con la destrucci6n de celulas T4 mientras que el conteo de las celulas T4 indica hasta que punto se ha dafiado el sistema inmunol6gico. 3. Debido a que la progresi6n de la enfermedad difiere de persona a persona, las decisiones sobre tratamiento deben ser individualizadas, basadas en los niveles de riesgo indicados por los niveles de la carga viral y conteos de celulas T-4. 4. El objetivo de cualquier terapia antiviral es la maxima supresi6n posible de la replicaci6n del VIH para evitar la aparici6n de VIH resistente a las drogas. 5. La mejor manera de alcanzar la supresi6n duradera de la replicaci6n viral es la iniciaci6n simultanea de combinaciones de drogas anti-VIH efectivas a las cuales el paciente no haya sido expuesto previamente. 6. Cada droga en la combinaci6n debe ser usada de acuerdo al horario y dosis 6ptimas. 7. El niimero de drogas antivirales es limitado y la resistencia causada de medicamento a medicamento (resistencia cruzada) es posible y ha sido documentada, por lo que cualquier cambio de terapia aumenta las limitaciones futuras. 8. Las mujeres deben recibir terapia antiviral 6ptima sin importar su estado de gravidez. 9. Los mismos principios de terapias antiretrovirales se aplican a niflos y adultos pero el tratamiento de niilos envuelve consideraciones farmacol6gicas, virol6gicas e inmunol6gicas idnicas. 10. Pesonas con infecci6n aguda (inicial) deben ser tratadas con terapia antiretroviral combinada para suprimir la replicaci6n viral a niveles por debajo del limite de detecci6n. 11. Todas aquellas personas VJH positivas, incluso aquellas con cargas virales por debajo del lmite de detecci6n, deben considerse infecciosas y por ende deben ser aconsejadas acerca de la transmisi6n del VIH a trav6s del sexo y actividades relacionadas con el uso de drogas.

treatment C-, Directrices para el Tratamiento El panel encargado de formular las directrices sobre tratamiento se ocup6 de algunos temas principales: * El uso de pruebas de laboratorio para carga viral y conteo de celulas T-4. * Cuindo empezar tratamiento yu con que. * Terapia en infecci6n aguda (inicial). * Cuaindo parar el tratamiento. * Cuindo y hacia cuail tratameinto cambiar * Terapia para infecci6n avanzada con VIH. * Tratamiento durante el embarazo. Antes de empezar terapia antiretroviral, todas las personas deben hacerse un examen de sangre completo, incluyendo un perfil quimico. Dicho examen debe incluir un conteo de celulas T-4 (o CD4) y una carga viral. Las recomedaciones sobre si empezar tratamiento se basan en el estado clinico de la persona y en los resultados de laboratorio. Tabla para el Inicio de Terapia Antiretroviral Categoria Clinica Conteo de T-4 y Carga Viral Recomendacion Sintomatico (SIDA, candida oral, Cualquier valor Dar tratamiento fiebre inexplicada, desgaste) Menos de 500/mm3T-4o Se debe ofrecer Asintomatico mas de 20.000 copias de tratamiento virus PCR Mas de 500/mm3 T-4 y Algunos expertos ofrecen Asintomatico menos de 20.000 copias tratamiento mientras que de virus PCR otros esperan y observan Una vez se haya decidido empezar la terapia antiretroviral, el panel estableci6 que la mejor forma de usar los once medicamentos disponibles en la actualidad, es en combinaci6n de por lo menos tres agentes. A pesar de que las combinaciones posibles son numerosas, el panel tambien estableci6 categoras de acuerdo a la eficacia demostrada por cada combinaci6n teniendo tambien en cuenta los efectos secundarios potenciales y las interacciones entre diferentes medicamentos. Combinaciones Preferidas Un Inhibidor de Proteasa y Dos Nucleosidos Analog. AZT + ddl Indinavir (Crixivan) d4T + ddl Nelfinavir (Viracept) AZT +ddC Ritonavir (Norvir) d4T + 3TC AZT + 3TC Combinaciones Secundarios 1 No-N ucleosido + 2 Nucleosidos Analog. (Nevirapine) (De Ia columna anterior) 0 Saquinavir (Invirase) + 2 Nucleosidos Analog. Las combinaciones con dos medicamentos solamente (v.g. dos nucleosidos) no se recomienda mucho y el uso de un solo medicamento, sin importar que tan fuerte sea, no se recomienda en lo absoluto.

ISSUES C Cu a) h Amount enclosed: 1 $35 Individuals * $70 Physicians/Institutions 1 $70 International * $_ Sliding Scale (HIV-positive and/or low income: please send what you can afford) 1 I have included an additional tax-deductible contribution of $_ Please check one: U New Subscription 11 Renewal Subscription L0 Please send a full set of back issues (we suggest a donation of $25). Please make checks payable to GMHC. Charge it. 11 Mastercard 11 Visa LI AMEX Card # Expiration date: /_ /_ NAME ORGANIZATION ADDRESS treatment ISSUES EDITOR Dave Gilden ASSOCIATE EDITOR Jill Cadman MEDICAL CONSULTANT Gabriel Torres, M.D. ART DIRECTOR Adam Zachary Fredericks TECHNICAL & MARKETING COORDINATOR Chuck Sock PROOFREADERS Carole Lemens Susan McCreight Ellie Tweedy Carol Vizzier VOLUNTEER SUPPORT STAFF Edward Friedel Helen Kane Lenore Rey Eva Zysman Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Please note new mailing address and e-mail address: GMHC Treatment Issues 119 West 24th Street, New York, NY 10011 Fax: [phone] e-mail: [email protected] @1997 Gay Men's Health Crisis, Inc. CITY STATE ZIP A copy of GMHCs latest financial report with the Department of State may be obtained by writing to NYS Department of State, Office of Charities Registration, Albany, NY 12231, or to GMHC. I