|February 2000||Bruce H. Woolley, Pharm.D.,||Editor Vol. 7, No. 2|
|Kenneth J. Hunt, Associate Editor|
The HIV Treatment Pipeline
Medical science has made tremendous progress in the battle against HIV. There remain, however, a number of concerns regarding the anti-retrovirals that are currently available. New drugs are necessary to overcome significant problems with cross-resistance, high pill burden, complex dosing schedules, and potential long-term toxicity. Fortunately, many new drugs are on the way. Many of the following drugs have improved resistance profiles, simplified dosing schedules, and fewer side effects.
Adefovir Dipivoxil (ADV, Preveon, PMEA) -a reverse transcriptase inhibitor (RTI) that has been in expanded access for some time and is now in phase III clinical trials for the treatment of HIV and hepatitis B (HBV). Hoped to be an effective treatment in combinations therapy
PMPA (Tenofovir DF) -an acyclic nucleotide analogue similar to ADV. It is in advanced clinical studies and appears to be relatively potent and well-tolerated. The likely dose (300 mg) will be given once a day.
FTC (Emtricitabine) - similar to 3TC but is more potent and is likely to be taken once a day. It has activity against HIV and HBV and is synergistic with the other NRTIs. Currently in phase II/III development.
F-ddA (Lodenosine) - a fluorinated purine nucleoside RTI now in phase II trials. It has little cross-resistance with other RTIs and appears safe and well-tolerated.
dOTC (BCH-10652) - a hetero-substituted nucleoside analogue in phase I/II trials. It has low-grade cross-resistance with ZDV and 3TC. It appears to be well tolerated, with a good safety profile and little mitochondrial toxicity, and relatively potent.
DPC 961, 963, 082, and 083 are second-generation NNRTIs that remain effective against HIV strains with certain mutations. DPC 961 is the furthest along in development is. The drug has many of the advantages of efavirenz (EFV) while overcoming some of its problems.
Emivirine (EMV, MKC-442, Coactinon) is an NNRTI now in phase II trials. EMV is taken twice daily and is generally well tolerated. The main adverse events of EMV are nausea, dizziness, headache, and rash. It is relatively potent in triple-combination therapy. Unfortunately, this drug has questionable potency.
Calanolide A - a novel NNRTI originally derived from tropical plants of the genus Calophyllum. It has activity against HIV with certain mutations, though many are too resistant
Other NNRTIs in development include loviride,[46,47] tivirapine, and HBY 097.
ABT-378/r (ABT-378/ritonavir) - a PI combination in phase III trials, with the ritonavir (RTV) being used to increase ABT-378 levels. It has low cross-resistance with other PIs. The likely dose will be 400 mg of ABT-378 with 100 mg of RTV (in three capsules) every 12 hours.
Tipranavir (TPV, PNU-140690) - a nonpeptidic PI. It has some efficacy against virus resistant to the current PIs. It is probable that TPV will be combined with some dose of RTV when it is used.
BMS 232632 is an azapeptide PI that is more potent than, and only partially cross-resistant with, the currently approved PIs. This drug is currently in phase II testing.
DMP-450 is an acyclic urea PI that is in phase I testing. It is potent against HIV-1 and HIV-2 and is relatively inexpensive to produce.
T-20 is a peptide that blocks gp41-mediated fusion and thereby prevents viral entry into the cell. It is given by subcutaneous injection twice a day. Long-term results and further studies should help establish the usefulness of T-20 as adjunctive therapy.
Interleukin-2 (IL-2) has been successfully used as adjunctive therapy to HAART to increase overall and naive CD4+ cells, without exerting a significant effect on viral load.[61,62].
Remune is a GP 120-depleted HIV vaccine. Several studies regarding Remune are continuing, but the results reported thus far have been discouraging.
GM-CSF (Leukine) has previously been reported to augment the immune system and decrease viral load in HIV-infected patients treated with HAART. A recent study appears to support these reports in advanced patients. The drug is in phase II clinical trials.
Mycophenolic acid (MPA, Cellcept) reversibly inhibits inosine monophosphate dehydrogenase, which limits the de novo synthesis of guanosine monophosphate and inhibits lymphocyte proliferation. MPA is currently used in organ transplant patients.
PRO 542 (CD4-IgG2) is a fusion protein comprising a human immunoglobulin. The drug was able to neutralize HIV in vitro and provided in vivo protection against HIV in a mouse model. It is currently in phase I trials and was well tolerated in HIV-infected patients given a single infusion.
Thanks to Boyle, Brian A. The AIDS Reader 9(8):519-529, 1999. For the complete review of HIV therapy pipeline, visit http://pharmacotherapy.medscape.com/16443.rhtml
FDA Health Advisory- Prescribing Flu Drugs
The FDA recently published a Public Health Advisory for health care practitioners to remind them of important therapeutic considerations when treating patients with influenza-like symptoms. The FDA warns that physicians should consider whether to use one of the four drugs currently approved for antiviral therapy in uncomplicated influenza. Amantadine (symmetrelÒ /Endo) and rimantadine (flumadineÒ /Forest) have been available for some years in the United States for illness due to influenza A. Recent approval of zanamivir (RelenzaÒ /GlaxoWellcome) and oseltamivir (TamifluÒ /Roche), two new drugs with activity against influenza A and B, has increased interest in the role of specific antiviral drugs for this disease.
While health care professionals and consumers are becoming familiar with the treatment options, the FDA provides several considerations for health care professionals treating flu patients:
The FDA recommends that patients become familiar with the complete prescribing information when considering flu drugs. The labeling for all four flu drugs includes summaries of adverse events observed during clinical trials, as well as post-marketing experience for the two drugs with a longer marketing history. As with all drugs, FDA encourages health care professionals to report any serious adverse event associated with the use of antiviral drugs for influenza to the FDA's MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178), or to the pharmaceutical manufacturers:
Relenza (zanamivir), GlaxoWellcome,
Tamiflu (oseltamivir), Roche, 1-800-526-6367
Symmetrel (amantadine; also available in generic forms), Endo, 1-800-462-3636
Information from FDA Public Health Advisory, Center for Drug Evaluation and Research. www.fda.gov.
Escalation in HMO Failures in 1999
Sixteen Health Maintenance Organizations failed in 1999. This number increased from nine the prior year, according to the latest report by a national rating service. The Weiss Ratings service reported that the two most vulnerable sectors in the U.S. economy are banks and HMOs. Another HMO, Harvard Pilgrim Health Care of Massachusetts, went under on January 4 of this year; the Massachusetts Insurance Administration seized control of Harvard Pilgrim they disclosed greater-than-anticipated losses.
According to Weiss, most companies in the HMO industry are still losing money on their operations. They reported eight bank failures in 1999, compared with three in the previous year. Insurance company failures rose 5% in 1999
Thanks to Reuters Medical News, http://managedcare.medscape.com/
Protection Against Internet Drugs
Use of the Internet to buy medical products is growing rapidly. Many consumers currently benefit from the convenience and privacy of this new option. Unfortunately, the safe use of the Internet by both consumers and businesses is now being threatened by fraudulent or disreputable Internet pharmacies that sell products illegally.
There are several safeguards invoked to protect consumers against unsafe use of drugs, including the requirement that drugs be dispensed only for valid prescriptions and that new prescriptions be issued only after a physical exam. The Internet makes it easy to bypass these safeguards. Unethical doctors can illegally prescribe pills online to consumers they have never met in states where they are not authorized to work. Unscrupulous, unlicensed pharmacies can ship pills across state lines. The federal governments authority to prosecute these organizations is limited and penalties are currently inadequate.
The White House recently announced that President Clinton is proposing a new initiative to protect consumers from the illegal sale of pharmaceuticals over the Internet. The initiative, which will be included in this year's budget, would:
The President's 2001 budget will include $10 million to fund these and other activities. This effort should prove to slow down the illegal prescription and sale of drugs over the Internet, protecting the consumer from unsafe and fraudulent activities.
White House Press Release, Office of the Press Secretary Dec 28,1999. Full release at www.fda.gov/cder
The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations