* Abbott's Ritonavir Wins Approval * Merck's Indinavir Recommended for Approval * Serono's Human Growth Hormone on Hold * New Indications for ddI and AZT/ddC * Review Date Set for Roche and Chiron Viral Load Test Kits
Acting with unusual swiftness, the U.S. Food and Drug Administration (FDA) granted marketing approval to ritonavir (March 1, 1996) and to indinavir (March 13, 1996), the 2 new protease inhibitor drugs from Abbott and Merck, respectively. The approval of ritonavir was announced by FDA Commissioner David Kessler, MD, less than 24 hours after the FDA Antiviral Drugs Advisory Committee recommended the drug for approval. Ritonavir is now available in pharmacies across the U.S. at an average wholesale cost of $6,500 a year.
FDA approved indinavir in record time --only 42 days after Merck filed its application for accelerated approval of the drug, making it the fastest drug approval in the FDA's history. Due to a shortage of supplies of indinavir for the next few months, Merck is implementing a temporary plan that limits distribution of the drug exclusively to Stadtlanders Pharmacy. The average wholesale yearly cost for indinavir is $4,380 ($12 a day). Beginning Monday, March 25, all prescription orders should be made through Stadtlanders. For more information, patients and physicians may call 1-800-927-8888 8:30 am - 9 pm Eastern Time beginning Monday, March 18.
* Abbott's Ritonavir (Norvir) FDA granted full (traditional) approval for ritonavir alone or in combination with other anti-HIV therapies for the treatment of advanced AIDS. The agency granted accelerated (conditional) approval for ritonavir alone or in combination with other anti-HIV therapies for the treatment of people at earlier stages of HIV disease who experience clinical or immunologic decline. The FDA-approved indications for the use of ritonavir are unusual, and reflect concerns among members of the Antiviral Drugs Advisory Committee that more information is needed about the drug's effectiveness in earlier stages of HIV disease.
Abbott Laboratories conducted a total of 9 Phase II or III studies of ritonavir. Data from these studies, in particular the 2 double-blind, randomized, multicenter, controlled Phase III studies (M-245 and M-247) show that ritonavir significantly decreases viral load and significantly increases CD4 cell counts in HIV positive individuals. M-208, an open-label, 6-month study of ritonavir in a triple combination with AZT and ddC, also demonstrates the potent anti-HIV activity of ritonavir. Preliminary results of these studies provided the principal data presented in the application for approval submitted by Abbott to FDA.
M-245 compared ritonavir to AZT (Retrovir) and to ritonavir plus AZT in 356 HIV positive individuals without prior anti-HIV therapy who had greater than 200 CD4 cells/mm3 and a baseline viral load of 15,000 copies/mL (milliliter) or greater. Participants took either 200 mg AZT 3 times/day, 600 mg ritonavir 2 times/day or a combination of AZT and ritonavir at these same doses. Results of viral load and CD4 cell count tests were assessed at 2, 4, 8, 12, 16, 20 and 24 weeks.
In this study of patients without previous anti-HIV treatment, ritonavir monotherapy produced a more profound decrease in viral load and a higher increase in CD4 cell counts than did the combination of ritonavir plus AZT or AZT monotherapy. This somewhat confounding result of M-245 (monotherapy was more effective than combination treatment) may be explained by patient non-compliance in the combination AZT/ritonavir arm, according to Abbott. The reason for non-compliance may have been due to the high incidence of gastrointestinal adverse effects (nausea and vomiting) reported by participants. This study used the notoriously bad-tasting liquid formulation of ritonavir.
M-247 was a double-blind, randomized, 2-arm, multicenter trial comparing ritonavir to placebo in 1,090 HIV positive individuals with 100 or fewer CD4 cells/mm3 who had prior anti-HIV therapy. Participants were randomly assigned to either ritonavir 600 mg twice daily or placebo, and were allowed to continue taking up to 2 FDA-approved nucleoside analog reverse transcriptase inhibitors during the study. (3TC [Epivir] was not approved at this time, and was not permitted in the study.) The double-blind phase of M-247 was to be halted when 191 people died or experienced a new AIDS-defining event beyond the first 4 weeks of the study.
When 191 cases were documented in December 1995, the study was unblinded and analyses of the data were begun. The most significant outcomes of the trial were: (1) the addition of ritonavir to existing anti-HIV therapy produced a 43% reduction in the death rate compared to the addition of placebo; and (2) ritonavir plus existing therapy reduced the risk of disease progression or death by 56% compared to placebo plus existing therapy.
DISEASE PROGRESSION OR DEATH
Ritonavir -- 86/543 (15.8%) Placebo -- 181/547 (33.1%)
Ritonavir -- 26/543 (4.8%) Placebo -- 46/547 (8.4%)
The following table summarizes the number and percentage of patients in each group who experienced the most common clinical events associated with HIV disease progression.
Table 1. MOST COMMON CATEGORIES OF DISEASE PROGRESSION
|Category ||Placebo (n=547) ||Ritonavir (n=543)|
|Death ||46 (8.4%) ||26 (4.8%)|
|Esophageal candidiasis ||40 (7.3%) ||16 (2.9%)|
|Cytomegalovirus retinitis ||20 (3.7%) ||14 (2.6%)|
|Other cytomegalovirus ||17 (3.1%) || 5 (0.9%)|
|Kaposi's sarcoma ||23 (4.2%) || 8 (1.5%)|
|PCP ||18 (3.3%) || 9 (1.7%)|
|MAI / MAC ||11 (2.0%) || 6 (1.1%)|
|HIV-related wasting || 8 (1.5%) || 2 (0.4%)|
In addition to producing these statistically significant effects on disease progression and death, ritonavir also consistently produced significant decreases in HIV RNA levels and significant increases in CD4 cell counts when compared to placebo during the observation period.
M-208 was a 6-month, multicenter, open-label study designed to evaluate the safety and effectiveness of ritonavir in combination with AZT and ddC in HIV positive individuals with 50-350 CD4 cells/mm3 without prior anti-HIV therapy. Participants first received 600 mg 2 times/day of ritonavir for 14 days, followed by the addition of AZT (200 mg 3 times/day) and ddC (0.75 mg 3 times/day). After 2 weeks of therapy, patients taking ritonavir experienced significant improvement in both viral load and CD4 counts. At 24 weeks, mean HIV RNA levels decreased from baseline by 2.46 logs. The median increase in CD4 cell count from baseline at 24 weeks was 147 cells/mm3.
In reporting the preliminary results of studies M-245, M-247 and M-208, Abbott has sought to define a strategy for maintaining suppression of HIV by combining ritonavir with nucleoside analogs. Although the results of study M-245 show the potent anti-HIV effect of ritonavir, using the drug as monotherapy eventually leads to resistant viral strains that show decreased sensitivity to ritonavir. The results of M-247 clearly demonstrate the clinical benefit of ritonavir, even among patients with advanced AIDS. Yet simply adding ritonavir to existing nucleoside analog therapy is probably not the best anti-HIV treatment strategy. Results of study M-208 show that a more powerful anti-HIV effect can be achieved by the (nearly) simultaneous administration of 3 drugs (in M-208, ritonavir, AZT and ddC) never previously used by the participants. The most formidable anti-HIV regimens may be those consisting of combinations of multiple drugs which the patient has not previously used.
Safety of Ritonavir
At the FDA hearings, Abbott characterized ritonavir as "generally well tolerated by patients." In all the ritonavir studies, the most common adverse events were related to the gastrointestinal tract and the nervous system. Nausea, vomiting and diarrhea were the most common gastrointestinal complaints. Patients tended to experience these effects within the first few days of starting the drug, according to Abbott. Nervous system adverse events consisted of circumoral (around the mouth) paresthesias (abnormal tingling or burning sensations), paresthesias elsewhere in the body and headache. As with the gastrointestinal events, these effects tended to occur during the first few days following initiation of ritonavir. Overall, circumoral paresthesias and headache were the most common adverse events.
Most participants who experienced an adverse side effect did not discontinue ritonavir. The adverse side effects that most commonly did cause discontinuation of the drug were nausea, vomiting, diarrhea and asthenia (weakness).
Ritonavir is metabolized by the cytochrome P450 oxidase system in the liver, and is possibly the most potent inhibitor of this pathway known. The P450 pathway is shared by many other drugs used in the treatment of HIV and other diseases. Abbott has categorized over 200 drugs frequently used in the treatment of HIV/AIDS with respect to their known or possible interaction with ritonavir. The company says it is in the process of publishing this list and will distribute it to physicians. Examples of drugs that should not be taken together with ritonavir due to toxicity concerns include codeine, diazepam (Valium), ketoconazole, rifabutin and piroxicam. There are many others. Physicians should obtain complete information from Abbott (or from the drug labeling) regarding which drugs are known to cause adverse interactions when taken with ritonavir.
Although inhibition of the cytochrome P450 enzyme system negatively impacts the simultaneous use of some drugs with ritonavir, this inhibition also may have an important positive consequence. Ritonavir taken with the Roche protease inhibitor saquinavir (Invirase), for example, significantly enhances plasma drug levels of saquinavir. If saquinavir levels can safely be increased in this manner, the likely result will be to increase the anti-HIV effect of saquinavir. Abbott and Roche have recently begun a study of ritonavir co-administered with the new, more bioavailable formulation of saquinavir. The first order of business will be to establish doses that can be safely tolerated, followed by a study of the effectiveness of the ritonavir/saquinavir double combination.
Resistance and Cross-Resistance
HIV has been shown to develop resistance to ritonavir, especially at suboptimal doses (below 1,200 mg/day). Laboratory tests demonstrate that ritonavir is cross-resistant to Merck's indinavir and possibly to other protease inhibitors, but not to Roche's saquinavir. Unpublished data from Roche showed that 12 of 13 patients treated with saquinavir monotherapy for 6 months exhibited no cross-resistance to ritonavir.
The issue of resistance and cross-resistance among the protease inhibitor drugs is important, and requires further study and clinical experience. It will be necessary for Abbott to give appropriate warnings about resistance and cross-resistance in the drug labeling and to develop educational materials for patients and physicians.
Clinical Chemistry Evaluations
Ritonavir may cause increases in hepatic (liver) enzymes, lipids and CPK (creatinine phosphokinase, an enzyme that may reflect toxicity to muscles). Generally, these laboratory abnormalities have not been associated with clinical abnormalities. However, since ritonavir is metabolized by the liver, hepatic enzyme tests are important for monitoring the safety of the drug. Individuals with prior or current liver disease (e.g., hepatitis) who use ritonavir should closely monitor hepatic enzyme values.
Additional Studies of Ritonavir
Abbott has recently initiated 4 additional studies: 1 for the treatment of children and 3 to evaluate various combination regimens. M-310 is assessing the safety, tolerance and anti-HIV effect of ritonavir in children with HIV infection. Thirty-six (36) to 70 children (ages 6 months to 18 years) will be enrolled.
M-313 is planned as a 12-month study to determine the safety and anti-HIV effect of a triple combination of ritonavir, 3TC and AZT in people recently infected with HIV.
NUCB-2019 is an open-label, 1-year combination study of ritonavir, 3TC and AZT in patients with no history of prior anti-HIV treatment.
M-409 will assess the tolerability and pharmacokinetic interaction of ritonavir and saquinavir in HIV negative subjects. Doses range from 200-600 mg/day for both ritonavir and saquinavir.
Abbott also plans the following studies: ritonavir/saquinavir combination; ritonavir in the treatment of Kaposi's sarcoma; ritonavir plus ddI/d4T versus ddI/d4T; and ritonavir intervention in acute opportunistic infections. Abbott has also agreed to provide "long-term follow-up safety and clinical endpoint data from M-245 and M-247 to assess the comparative clinical efficacy and safety data in patients with advanced stage disease versus patients with early stage disease."
Finally, Abbott says the company will evaluate CD4 cell and HIV RNA responses and safety among patients with greater than 100 CD4 cells/mm3 in a study comparing ritonavir/saquinavir to ritonavir.
Abbott says there is currently enough ritonavir available in the new capsule formulation to treat up to 100,000 people in the U.S. at the 1,200 mg/day dose.
The average wholesale cost of ritonavir at the FDA-approved 1,200 mg/day dose is $6,500 a year ($17.80 per day). The cost to patients will be higher, and will vary depending on the retail markup. For example, Walgreen's Pharmacy in San Francisco is charging $23.44 for the daily dose ($8,438 yearly). The Castro Village Pharmacy in San Francisco is charging $25.56 for the daily dose ($9,304 yearly).
* Indinavir (Crixivan) On March 1, the FDA Antiviral Drugs Advisory Committee recommended accelerated (conditional) approval for Merck and Company's protease inhibitor drug indinavir (Crixivan). The labeling will indicate that indinavir is approved for the treatment of HIV disease in patients for whom anti-HIV therapy is warranted. This broad indication for indinavir therapy will allow physicians to prescribe the drug to individuals at all stages of HIV infection. Commissioner Kessler said the FDA would give final approval to indinavir following an inspection of their manufacturing site.
To demonstrate the efficacy of indinavir, Merck has conducted 8 multicenter Phase II studies and has 2 ongoing Phase III trials. The indinavir trials have enrolled HIV positive individuals across the broad spectrum of HIV disease, including patients with low CD4 cell counts.
In general, Merck sought study participants with moderate to high HIV RNA levels (greater than 20,000 copies/mL), in order to evaluate the ability of indinavir to reduce viral burden. Overall, Merck designed the indinavir studies using surrogate markers (viral load and CD4 cell count) to show a potential clinical benefit. Significant increases in CD4 cell counts and significant decreases in viral load (HIV RNA copies) have been associated with a clinical benefit. An impact on viral load, in addition, may be predictive of a therapy's clinical utility. Early studies explored the effectiveness of several different doses of indinavir.
Merck eventually determined that the optimal indinavir dose is 800 mg 3 times/day. This dose was used in the Phase III trials. After selecting 2,400 mg/day as the therapeutic dose, Merck began several double-blind, randomized Phase III studies to evaluate the effectiveness of indinavir and the ability of 1 or more nucleoside analog drugs to increase its anti-HIV effects. These include studies that focus on surrogate marker results (protocols 033, 037 and 039) and clinical endpoints (protocols 028 and ACTG 320), and ongoing protocol 035.
Protocol 028 is a double-blind, randomized study among 900 patients in Brazil without prior anti-HIV therapy. Study participants have 50-250 CD4 cells/mm3 and a wide variation in viral load results (there was no entry criterion for HIV RNA values). The study is evaluating the effect of indinavir monotherapy versus AZT monotherapy versus the double combination of indinavir/AZT. CD4 cell counts and HIV RNA results are available for the first 24 weeks of treatment. CD4 cell counts are also available for up to 32 weeks in a small number of patients.
Both the indinavir and indinavir/AZT groups experienced an initial increase in median CD4 cell counts of over 100 cells/mm3. This increase has been sustained for at least 24 weeks. The AZT monotherapy group experienced only a small increase in CD4 cell count, which was not sustained at week 24. There was a statistically significant difference between the 2 indinavir groups and the AZT group in terms of CD4 cell count, but the difference between the indinavir monotherapy group and the indinavir/AZT group was not significant. Preliminary data on 82 patients at week 32 demonstrate a favorable trend for the 2 indinavir arms.
In protocol 028, the combination indinavir/AZT group experienced the greatest decrease in HIV RNA levels. The indinavir monotherapy group experienced a somewhat lesser decrease, while the AZT monotherapy group experienced the least decline in HIV RNA levels. The differences were highly statistically significant between the indinavir arms and the AZT arm in terms of HIV RNA results. About 40% of those in the 2 indinavir groups experienced decreases in HIV RNA levels to below the limit of detection (500 copies/mL) compared to 7% of those in the AZT monotherapy group.
Protocol 033 is a 52-week, double-blind study among 740 individuals with 50-500 CD4 cells/mm3. Underway in the U.S., Europe and Canada, protocol 033 has no specific
HIV RNA level entry requirement. The baseline HIV RNA level and CD4 cell count of participants are 4.34 log copies/mL and 258 cells/mm3, respectively. The study had 3 arms: indinavir monotherapy, AZT monotherapy, and indinavir plus AZT. Both indinavir groups experienced median increases in CD4 cell counts of over 90 cells/mm3. These increases were sustained for at least 24 weeks. The AZT monotherapy group showed much smaller median increases in CD4 cell count. The differences between the 2 indinavir arms and the AZT monotherapy arm in terms of CD4 cell count were highly statistically significant, while the difference between the 2 indinavir groups was not statistically significant.
The median decreases in HIV RNA values were greatest for the indinavir/AZT group, somewhat less for the indinavir monotherapy group and least for the AZT monotherapy group. These decreases were sustained for the 2 indinavir arms. The differences between the 2 indinavir groups and the AZT group in terms of HIV RNA levels were highly statistically significant, but the difference between the 2 indinavir groups was not significant.
About 40% of those in the indinavir monotherapy arm and 50% of those in the indinavir/AZT arm experienced declines in HIV RNA levels to below the limit of detection (500 copies/mL) as compared to 5% in the AZT arm.
Protocol 035 (Triple Drug Therapy)
Protocol 035 is a multicenter, double-blind, 52-week study among 96 individuals with previous AZT therapy. Study participants were randomized to one of 3 treatment arms: indinavir monotherapy (800 mg 3 times/day), AZT (200 mg 3 times/day) plus 3TC (150 mg 2 times/day) or a combination of all 3 drugs. Data are available at 20 weeks on 61 participants for CD4 cell counts and on 65 participants for HIV RNA levels. The median baseline CD4 cell count was 155 cells/mm3 and the median baseline HIV RNA value was 4.6 log copies/mL.
About 36% of individuals taking indinavir monotherapy and 91% (10/11) of patients taking the triple combination of indinavir/AZT/3TC experienced HIV RNA levels below the level of detection (500 copies/mL). Triple combination therapy reduced median HIV levels by greater than 99%. These preliminary data are impressive, particularly considering that the participants were AZT-experienced at study entry. However, the data are derived from a relatively small number of patients (22) who were on drug for 24 weeks.
Preliminary results of these studies demonstrate that indinavir monotherapy produces significantly greater increases in CD4 cell counts and greater decreases in HIV RNA levels than AZT monotherapy. In addition, indinavir/AZT appears to produce slightly greater declines in HIV RNA than indinavir monotherapy. However, use of the 3-drug combination of indinavir/AZT/3TC results in a greater proportion of patients with HIV RNA levels below the limit of detection than indinavir monotherapy or AZT/3TC combination therapy. Those on triple therapy experienced a median increase of 146 CD4 cells/mm3 compared to a median increase of 98 CD4 cells/mm3 among those on indinavir monotherapy. In patients taking AZT and 3TC, CD4 cell counts increased by a median of 22 cells/mm3.
Individuals taking indinavir (800 mg 3 times/day) as monotherapy or in combination with AZT experienced increases in CD4 cell counts of 90-100 cells/mm3 for at least 24 weeks. Those taking indinavir also experienced decreases in HIV RNA levels of greater than 1 log for 24 weeks.
The results of experiments to determine the bioavailibility of the 800 mg dose of indinavir in humans are not yet available. In animals, the bioavailability of indinavir ranges from 72% in the dog to 19% in the monkey and 24% in the rat. Merck has determined that indinavir is rapidly absorbed after oral dosing and achieves peak plasma concentrations in about 1 hour. The drug is eliminated with a half-life (time required for half of the drug to be metabolized) of about 1.8 hours.
High-fat, high-protein food intake (such as a bacon and eggs breakfast) significantly reduces the absorption of indinavir. However, it appears that low-fat, low-protein meals produce only a modest decrease in plasma concentration of the drug (2-8%). For optimal absorption, indinavir should be taken 1 hour before or 2-3 hours after eating.
Indinavir is metabolized (like ritonavir) primarily by the cytochrome P450 enzyme system in the liver. Merck researchers say that they have found no clinically significant interactions between indinavir and the following drugs commonly used in the treatment of HIV disease: AZT, 3TC, d4T, trimethoprim/sulfamethoxazole (Bactrim, Septra), clarithromycin, fluconazole or isoniazid. However, like ritonair, indinavir interacts strongly with rifabutin and with ketoconazole. Dose reduction is recommended for indinavir when co-administered with either of these 2 drugs.
There do not appear to be any clinically relevant differences in the pharmacokinetics of indinavir associated with HIV status, gender or race.
Indinavir Safety Data
Over 1,400 individuals have participated in Phase III studies where they received indinavir at a dose of 2,400 mg/day. In addition, about 200 individuals have taken indinavir at a daily dose of 2,400 mg for at least 24 weeks either alone or in combination with nucleoside analogs. About 100 of these individuals have been followed for at least 48 weeks.
Merck researchers report that indinavir has been generally well tolerated. Two adverse experiences have been identified as clearly associated with indinavir treatment: nephrolithiasis (kidney stones) and hyperbilirubinemia (high bilirubin levels in the blood). In all indinavir studies, nephrolithiasis has been defined as any episode of unexplained flank pain with or without hematuria (blood in the urine). The majority of patients who experience nephrolithiasis have remained on indinavir during and after an acute episode, according to Merck researchers.
Fifty-five (55) of more than 2,000 patients (3%) treated with indinavir have met the Merck definition of nephrolithiasis. Fifteen (15) of these 55 cases have been regarded as serious (passing a stone can be extremely painful). At least 9 of these 55 reported a past history of nephrolithiasis. Passage of a kidney stone or gravel or radiographic evidence of a stone at the time of the event occurred in about 28 cases. Forty-eight (48) of 1,976 people (2.4%) treated with indinavir at a dose of 2,400 mg/day have developed kidney stones. Merck says that nephrolithiasis has not been associated with kidney dysfunction so far. Rarely has the condition resulted in discontinuation of indinavir therapy. There is some indication that adequate fluid intake minimizes the incidence of nephrolithiasis among patients taking indinavir.
Asymptomatic hyperbilirubinemia is an adverse event determined by laboratory values that is occasionally associated with indinavir therapy. Approximately 10% of participants on indinavir have had bilirubin values greater than 2.5 mg/dL at some point in their treatment. Clinical adverse events such as jaundice have been rarely reported. The incidence of hyperbilirubinemia together with elevated serum transaminases (liver enzymes) is low, according to Merck.
There have been 12 deaths of participants enrolled in studies of indinavir. Two deaths occurred in participants on AZT monotherapy; 10 deaths were felt to be unrelated to indinavir.
Researchers have noted a number of non-serious clinical adverse events among participants in indinavir studies, both among those on indinavir monotherapy and in those who took indinavir in combination with nucleoside analogs. The most common of these experiences in the indinavir monotherapy groups were: abdominal pain (20%), asthenia/fatigue (31%), diarrhea (36%), dry skin (24%), headache (46%), insomnia (16%), lymphadenopathy (24%), nausea (34%), rash (37%) and taste abnormalities (16%). Hematologic abnormalities were infrequent with indinavir monotherapy: decreased hemoglobin (5%), hematocrit (red cell count, 6%), neutrophil count (white cell count, 9%) and platelet count (20%).
Resistance and Cross-resistance
In the early Phase I and early Phase II studies of indinavir, participants received various doses of the drug that eventually were found to be suboptimal. Resistant virus commonly appeared by week 24. Resistance to indinavir occurs in association with changes at 11 amino acid residue positions. Treatment with lower doses of indinavir (e.g., 800 mg/day) produces a less potent anti-HIV effect than that observed at higher doses and selects for viral mutants that are much less responsive to higher doses of indinavir (2,400 mg/day). Merck scientists believe that use of the 2,400 mg/day dose as initial therapy produces the strongest anti-HIV effect in more patients. In addition, the effect is sustained for a longer period at this higher dose.
HIV mutants that are resistant to indinavir are also highly resistant to Abbott's ritonavir. Many ritonavir-resistant HIV mutants are also cross-resistant to indinavir. About two-thirds of viral variants tested to date that are resistant to indinavir also show resistance to Hoffmann-La Roche's protease inhibitor saquinavir, and one-half of the tested variants exhibit high-level resistance to saquinavir, according to Merck.
NOTE: Roche scientists dispute these conclusions by Merck concerning saquinavir cross-resistance to indinavir. Further research is necessary to confirm or reject the Merck conclusions on this subject.
Implications of Cross-Resistance
Cross-resistance among the various protease inhibitors has profound implications for sequential therapy with these agents. The selection of viral resistance to indinavir in patients will produce ritonavir resistance. In addition, treatment of patients with ritonavir will likely produce indinavir-resistant virus. As a result, sequential treatment with these 2 drugs will probably not be beneficial.
The issue of sequential treatment with saquinavir and indinavir is more complicated. Merck scientists say that individuals treated first with indinavir may not benefit from subsequent treatment with saquinavir. Roche scientists disagree. Roche researchers also say that individuals treated with saquinavir do not yield variants resistant to indinavir. There are no data on patients initially treated with saquinavir followed by subsequent treatment with indinavir. More laboratory research and clinical experience are required to clarify these important issues.
The development of resistance to indinavir at the 2,400 mg/day dose is modest and may be further reduced by com-bination therapy with other anti-HIV drugs, according to Merck.
For information on how to obtain and fill an indinavir prescription, and for the patient assistance and reimbursement programs, patients and physicians may call Stadtlanders Pharmacy beginning Monday, March 18 (1-800-927-8888). Prescriptions will be filled by Stadtlanders beginning Monday, March 25.
The average wholesale cost for indinavir is $12 a day ($4,380 a year). The retail cost will be higher.
Future Studies of Indinavir
Merck is continuing 2 multicenter, double-blind, Phase III trials (protocols 028 and 033). Protocol 028 will yield additional clinical endpoint data. Merck will pursue a pediatric study, and perhaps a trial to test the drug's ability to reduce maternal transmission of HIV.
Recombinant Human Growth Hormone (Serostim)
A 15-member FDA Advisory panel voted 8 to 7 on March 1 not to recommend full approval for somatropin (Serostim), the recombinant (genetically engineered) human growth hormone from Serono Laboratories, for the treatment of wasting syndrome in AIDS. Serostim is currently available to people with AIDS-related wasting through a Treatment Investigational New Drug (IND) program (See BETA September 1994, page 10 and December 1995, page 3).
Serono presented the results of 2 Phase III trials of Serostim in support of its application for full approval. The first 12-week study demonstrated significant weight gain for patients on Serostim, and showed a marked increase in lean body mass. Patients on the drug experienced improvements in quality of life and increased strength and endurance. The second Phase III trial was designed to confirm safety, and looked only at weight gain, not body composition (i.e., lean body mass). Weight gain was shown to be statistically significant after 6 weeks of treatment with Serostim, but not at 12 weeks.
The FDA review panel was impressed by the public testimony of over a dozen patients and physicians who spoke in favor of approval for Serostim. However, some committee members felt that there were too many gaps in the data presented by Serono. For example, it is unknown whether the dose used in the 2 Phase III studies (6 mg daily) is optimal, or whether a lower dose would be just as effective. In addition, no data were presented on patients who stop therapy after 12 weeks.
Serono is now negotiating with FDA about how best to continue pursuing approval for Serostim. One possibility is for the company to apply for accelerated approval rather than full approval. The San Francisco AIDS Foundation, ACT UP/Golden Gate and other community groups support this approach. If FDA does not encourage a new application from Serono, and instead sends the company a "non-approvable" letter regarding Serostim, access to the drug through the Treatment IND will be jeopardized, and reimbursers such as Medicaid will discontinue coverage.
AZT Plus ddC
The Antiviral Drugs Advisory Committee on February 28, 1996 unanimously recommended full approval of ddC (Hivid) in combination with AZT (Retrovir) as an option for initial therapy in HIV infection. The recommendation was based on a review of 2 studies that provided clinical endpoint data to support this indication. Patients on AZT/ddC experienced slower disease progression (fewer opportunistic infections) and improved survival compared to those using AZT or ddI monotherapy. As a part of its recommendation, the committee pointed out that the benefit of the AZT/ddC combination is observed primarily in individuals without prior AZT use.
The Antiviral Drugs Advisory Committee on February 28, 1996 also unanimously recommended that ddI (Videx) be indicated as a first-line treatment for HIV infection. ddI appears to be superior to AZT in delaying disease progression and death, according to the results of 3 large studies. ACTG 152 compared ddI alone to AZT alone and to the combination of ddI/AZT in children. Results show that children receiving ddI alone or in combination with AZT developed fewer HIV-related illnesses and survived longer than those receiving AZT monotherapy.
Studying more than 5,000 patients, the European and Australian Delta trial and ACTG 175 also found that ddI alone or in combination with AZT was superior to AZT monotherapy in slowing CD4 cell decline and in delaying disease progression and death.
"The proven survival benefit of ddI shows that the drug can be considered an important component of future combinations, including those with the protease inhibitors," said Paul Volberding, MD, Director of the AIDS Program at the University of California at San Francisco/San Francisco General Hospital.
FDA Review of Viral Load Test Kits Viral load testing is a powerful new technology that is able to directly quantify the amount of HIV in the blood plasma of people who are HIV positive. Both the reliability of HIV RNA testing and its practical applications have expanded dramatically in the last year. These powerful assays already are helping to guide the course of treatment for HIV infection in a growing number of patients with HIV disease. Increasingly, researchers and physicians are relying on viral load tests to determine patients' disease stage, to predict clinical outcome and to evaluate the effectiveness of therapy for HIV infection.
Several companies produce these tests, which are not yet FDA-approved. However, both Hoffmann-La Roche (Roche Molecular Systems) and Chiron Corporation have filed recently for FDA approval of their respective HIV RNA assay kits for widespread use by physicians and researchers. The Roche test is called "quantitative competitive polymerase chain reaction" or more commonly "quantitative PCR (QC-PCR)." The Chiron product is called "branched chain DNA" or more commonly "branched DNA (bDNA)." Both tests give comparable results in measuring HIV RNA.
The FDA review of the Roche and Chiron viral load test kits will take place on March 21, 1996. If the review committee recommends approval on that date, an announcement regarding final approval should come within a couple of weeks thereafter.
HIV RNA tesing is significantly impacting the treatment of HIV disease in many ways. It has already changed the way that researchers test the effectiveness of AIDS drugs in clinical studies. Several large trials have shown that HIV load (viral load) correlates with clinical benefit (the lower the load, the better the clinical prognosis). High viral burden appears to presage disease progression and clinical decline. Within a short time, HIV RNA testing will be an FDA-approved method for demonstrating how well a particular drug (or drug regimen) is working in individual patients.
With this critically important information in hand, drug treatment can be better "individualized" for each patient. As a result, recommendations can be made about continuing, halting, changing or adding drug treatments early, before patients experience significant CD4 cell loss and clinical decline. Using HIV RNA testing in clinical trials to assess the HIV load in patients on various treatment regimens, researchers may be able to predict with reasonable certainty which drugs will work best for a particular patient or group of patients. These new assays may dramatically shorten the amount of time necessary to test drugs in patients prior to approval and marketing. One result of this would be tremendous cost savings in research and more rapid patient access to promising drugs.