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Published in the Bulletin of Experimental Treatments for AIDS September 1997 issue, by the San Francisco AIDS Foundation. |
DMP-266 and Adefovir Dipivoxil2 New AIDS Drugs Available to Patients Without Treatment Optionsby Ronald Baker, PhD As BETA goes to press, DuPont Merck and Gilead Sciences are in the final stages of discussions with the Food and Drug Administration (FDA) to make their new, experimental anti-HIV drugs available free to several thousand people with AIDS who have exhausted the benefit from most commercially available agents. A formal announcement concerning the start date and entry criteria for the DMP-266 program is scheduled for September 15. The adevofir program is expected to begin sometime in October. For information, investigator registration and patient enrollment in the DMP-266 expanded access program, physicians and patients may call 1-800-998-6854. For updates on the status of the adefovir expanded access program, physicians and patients may call 1-800-GILEAD-5. Expanded access to DMP-266 and adefovir is an important achievement, because thousands of people with AIDS are desperately awaiting access to new anti-HIV treatment options. AIDS advocates nationwide praised the 2 companies for their willingness to work cooperatively and quickly with them to design and implement expanded access programs for DMP-266 and adefovir. Community advocates participated as full partners with the 2 companies to plan these programs and to ensure that each program meets the immediate needs of people with AIDS who have only limited treatment options. These 2 independently planned and operated expanded access programs should serve as models of how AIDS drug manufacturers and community representatives can work in partnership to make promising experimental drugs available early to those in greatest need. Expanded access programs make it possible for patients with advanced AIDS who have few or no treatment options to receive experimental AIDS drugs from the manufacturer prior to FDA approval. The timely start of the DMP-266 and the adefovir expanded access programs will allow patients with few or no treatment options to adhere to the Department of Health and Human Services (DHHS) treatment guidelines (see BETA, June 1997, page 11) which recommend adding at least 2, and preferably 3, new anti-HIV drugs not previously used when changing treatment regimens. During the first 3 months of the DMP-266 expanded access program, enrollment will be restricted to 1,000 people, due to limited drug supply. Entry will be limited to people with advanced AIDS and fewer than 50 CD4 cells/mm3 who are failing or intolerant to their current treatment regimen. As drug supply increases by January 1998, both the entry criteria and the number of people enrolled will expand, according to DuPont Merck representatives. Entry criteria for the adefovir expanded access program are expected to include people with AIDS who have fewer than 50 CD4 cells/mm3 and who are unable to construct a viable combination treatment regimen based on the DHHS treatment guidelines. In addition, participants must not qualify for any adefovir clinical trials, and must have HIV viral load levels greater than 30,000 copies/mL (by RT-PCR) or greater than 15,000 copies/mL (by bDNA). Gilead Sciences expects to have adequate drug supply to accommodate 1,000 people. NOTE: Qualified individuals may enroll simultaneously in both the DMP-266 and the adefovir expanded access programs if they require access to 2 new drugs in order to construct a viable treatment regimen. The Early Promise of DMP-266DMP-266 (generic name efavirenz; trade name Sustiva) belongs to the class of anti-HIV drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTI). Forty-eight-week data from an ongoing study of 59 individuals taking DMP-266 in a double combination with the protease inhibitor indinavir (Crixivan) show that 88% achieved undetectable HIV viral load (less than 400 copies/mL). In addition, CD4 cell counts rose an average of 240 cells/mm3 in these study participants. In the control arm of the study, 42 participants took indinavir alone for 12 weeks, then added DMP-266 and d4T (Zerit). Of these individuals, 68% achieved undetectable HIV viral load and an average increase of 150 CD4 cells/mm3. These findings were presented at the 35th annual meeting of the Infectious Diseases Society of America held in San Francisco, September 13-16, 1997. Below are examples of 3- and 4-drug combinations containing DMP-266 that are now under study:
*GW 141 is an experimental protease inhibitor from Glaxo Wellcome Two Phase III studies of DMP-266 are now actively recruiting. The first is a 24-week, randomized, open-label study (#006) for individuals with no prior treatment with DMP-266, nevirapine (Viramune), delavirdine (Rescriptor), 3TC (Epivir) or any protease inhibitor drug. The second is a 24-week, randomized, double-blind study (#020) for individuals with no prior treatment with DMP-266, nevirapine, delavirdine or any protease inhibitor drug (prior 3TC use is permitted). Results of these 2 studies, expected in March 1998, will be included in the application to FDA for accelerated approval for DMP-266. For more information about these studies, including the location of study sites, call 1-800-870-8899 or 1-800-TRIALS-A. The most frequently reported adverse side effects of DMP-266 are headache, dizziness, nausea and vomiting. About 24% of individuals on the DMP-266/indinavir combination have experienced headache, rash, diarrhea, dizziness, sinusitis, nausea and flu-like symptoms. The intensity of these side effects appears to diminish over a 2-week period. Like other NNRTI and some of the protease inhibitor drugs, DMP-266 is an inducer of the cytochrome P450 enzyme sys-tem. This results in interactions with other commonly used HIV/AIDS medications. For example, DMP-266 decreases blood levels of indinavir by 35%. To achieve best results when using DMP-266 in combination with indinavir, DuPont Merck advises increasing the standard indinavir dose (800 mg every 8 hours) to 1,000 mg every 8 hours. Co-administration of DMP-266 with clarithromycin (Biaxin) reduces blood levels of the latter drug by 30%. DuPont Merck says that DMP-266 does not affect blood levels of AZT, 3TC or fluconazole (Diflucan). DMP-266 also does not appear to significantly affect blood concentrations of the protease inhibitor nelfinavir (Viracept). Interaction studies of DMP-266 with the new, improved formulation of saquinavir (Fortovase) and other drugs are ongoing. In addition to its potent anti-HIV activity, DMP-266 possesses another distinct advantage: once daily dosing is sufficient to maintain adequate blood concentrations of the drug. DMP-266 at 600 mg daily appears to be the optimal dose. Adefovir Dipivoxil: A Little Known Drug Makes its DebutAdefovir dipivoxil (also known as GS 840 or bis-POM PMEA) belongs to the nucleotide analog reverse transcriptase inhibitor class of drugs, which differs only slightly from the nucleoside analog class. Adefovir is an oral drug administered in tablet form that is currently under study for the treatment of HIV and hepatitis B virus (HBV), and as a preventive treatment for cytomegalovirus (CMV) disease. Adefovir is now in pivotal Phase III studies for HIV. Study 407, conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), is actively recruiting and seeks to enroll over 2,000 participants with fewer than 100 CD4 cells/mm3 in the U.S. A similar trial, known as Adefovir Dipovoxil for HIV or CMV (ADHOC), has begun enrolling patients in Australia and Europe. The CPCRA-sponsored study will evaluate the effect of adefovir on survival and the drug’s ability to prevent CMV disease. Patients will be randomized to adefovir or placebo, plus current anti-HIV therapy. For more information about inclusion and exclusion criteria, call 1-800-TRIALS-A. Study 408, the adefovir surrogate marker study at 35 U.S. sites, has already completed enrollment (442 patients). Study participants receive either adefovir (120 mg daily) or placebo, plus current anti-HIV therapy. In early studies, adefovir produced about a 70% reduction in HIV RNA levels among individuals who had previously used anti-HIV drugs. Although certainly not as powerful as the protease inhibitors, and perhaps not as potent as 3TC, adefovir is probably as active against HIV as most of the other nucleoside analogs. In addition, adefovir possesses 2 major advantages that potentially render the drug a very useful component of a combination anti-HIV regimen. First, adevofir is taken orally once daily, compared to most other anti-HIV agents which require 2 to 3 doses daily. Secondly, adevofir has a unique resistance profile. Even when used as monotherapy (not recommended), resistance to the drug develops very slowly. There is little to no cross-resistance with other anti-HIV drugs, and strains of HIV that are resistant to almost all nucleoside analogs and NNRTI remain susceptible to adefovir. The main adverse side effects of adefovir are nausea and diarrhea. Some patients on adefovir have experienced elevated creatinine and ALT liver enzyme levels. Although creatinine levels have returned to normal in these individuals, Gilead Sciences urges close monitoring to prevent kidney toxicity. Adefovir dose reductions may be necessary in some cases. The metabolism of adefovir depletes L-carnitine levels in the body. For this reason, Gilead Sciences recommends daily supplementation with 500 mg oral L-carnitine. Once FDA-approved for commercial marketing, adefovir will be dispensed with a supply of L-carnitine to be taken with the drug. Gilead Sciences is testing adevofir at 2 dose levels: 60 mg and 120 mg. Most studies of the drug are using the 120 mg dose. Below is a sampling of the many combination regimens under study that include adefovir:
Priorities in Anti-HIV Drug Treatment for the HomelessThe initial goal in formulating a treatment plan for homeless individuals is to stabilize their living situation, not to offer therapy, according to University of California at San Francisco (UCSF) researchers who specialize in studies of the homeless. “The first priority is to deal with essential needs such as food, shelter and treatment for mental illness or chemical dependencies,” says David Bangsberg, MD, a research fellow at SF General Hospital and the UCSF Center for AIDS Prevention Studies. Bangsberg and colleagues conclude that only after these basic needs are addressed is it appropriate to focus on specific drug treatment needs for homeless individuals who are living with HIV infection. The most pressing concerns to address in a treatment plan are prevention of Pneumocystis carinii pneumonia (PCP) and/or tuberculosis (TB), according to a commentary by the UCSF researchers in The Journal of the American Medical Association (July 2, 1997). Treatment for HIV infection should only be considered after living situation and opportunistic infection prophylaxis have been addressed, say the researchers. Once these objectives are achieved, many homeless people can deal successfully with the complicated schedules associated with 3-drug HIV therapy that includes a protease inhibitor. The UCSF research team has outlined a 6-step plan for developing a treatment program for indigent individuals. Their recommendations are as follows: “1. Patients must be informed. Clinicians have an ethical responsibility to inform patients who are competent decision-makers of their treatment options, regardless of homelessness. To fail to inform is to run the risk of withholding treatment. To make access equitable, clinicians must describe treatment options and must involve patients in decision-making. Patients need to be informed of both benefits and risks, including the dosing schedule and the risk of developing drug-resistant HIV if doses are frequently missed. 2. As much as possible, patients must be stabilized with respect to housing, contact with the healthcare system, chemical dependency and mental illness. This is more important than choosing the best antiretroviral regimen. If the patient agrees, treatment with protease inhibitors should be delayed until the patient’s life stabilizes. In our experience, most patients who are informed of these issues feel that addressing the conditions of life should take precedence over starting antiretroviral therapy. Stability is thus the initial goal, and it typically requires working as a team with social workers and others. 3. For stable patients, management depends on CD4 cell count and PPD tuberculosis skin test status. For those with CD4 cell counts of less than 200 cells/mm3, PCP prophylaxis is the first priority. For those who are PPD positive for TB, the first priority is preventive therapy with isoniazid. If patients are successful with these regimens, therapy with a protease inhibitor should be considered. 4. For those patients who are ineligible for PCP prophylaxis or isoniazid therapy, the first priority remains stabilization. If this is successful, we believe it is reasonable to put the patient who wishes to begin treatment on protease inhibitor therapy, after a detailed description of the demands of the therapy and the risk of losing future benefits if the patient is unable to adhere. If there is doubt about stability, 2 reverse transcriptase inhibitors can be recommended, with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI). After the patient stabilizes, a protease inhibitor can be started, perhaps with 2 new reverse transcriptase inhibitors. 5. For those who remain unstable, the risk of losing future benefit if the patient is nonadherent should be explained and, if the patient agrees, 2 reverse transcriptase inhibitors are recommended. 6. For those who remain unstable but insist on protease inhibitor therapy after explanation of the risks of nonadherence, we believe there is an obligation to prescribe if the patient is competent to decide and has indications for treatment. In our experience, such patients are rare. Therapy should not necessarily be provided on the first visit. The chance of success may be improved if the patient demonstrates persistence and reliability in medical follow-up. In this setting, we believe it is best to err on the side of treatment. In summary, in facing up to the use of protease inhibitors in the homeless, we are obliged to develop interventions that maximize the chance of adherence and therefore of benefit. It is ethical to withhold treatment until the patient’s life is stabilized. Prophylaxis for opportunistic infections may also take precedence over more complex therapy. The impact of drug treatment must be monitored, as well as viral resistance. If health status and survival are not improved or if transmission of resistant HIV is seen at the population level, then the use of these therapies must be reevaluated. Finally, although evaluating the risks and benefits of the new therapies is daunting, it is much better to debate the appropriate use of effective drugs than ineffective ones.” Bangsberg D and others. Protease inhibitors in the homeless. Journal of the American Medical Association 278(1):63-5. July 2, 1997. More Setbacks for Early Access to 1592Glaxo Wellcome continues to generate distressful news concerning pre-approval patient access to its new nucleoside analog drug 1592 (abacavir). In an August conference call with representatives of over a dozen community groups, the company flatly and boldly reiterated its earlier decision not to increase the size of its so-called “compassionate use” program under any circumstances. In 1997, access to the drug will be limited to only 2,900 people worldwide. Glaxo also announced in August that an expanded access program for 1592 cannot possibly begin before March 1998, and will be limited to 9,400 people worldwide. In addition to these disappointing corporate pronouncements, Glaxo apparently also has resolved to cut off substantive communication with those community groups and individuals who have publicly criticized the company for its 1592 policy. The San Francisco AIDS Foundation, Gay Men’s Health Crisis and ACT UP chapters in New York and San Francisco have been barred from participating in a forthcoming “community meeting” October 13 at Glaxo’s U.S. headquarters in Research Triangle Park, NC. These groups have been vocal in protesting the severe limitations of Glaxo’s 1592 early access programs. While the San Francisco AIDS Foundation remains open to serious dialogue with all AIDS drug manufacturers, the agency will not cease to criticize companies when they set policies or institute substandard programs that are counter to the best interests of people living with AIDS, especially those who desperately need access to new therapies. Ronald Baker, PhD, is Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation. Page last updated 1 October 1997 |
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