Review of 1998

This article highlights some of the more significant and interesting news concerning antiviral agents reported in 1998 issues (Volume 11) of the Antiviral Agents Bulletin. Various indexes (e.g., Organization, Agent, and Virus/Disease) of 1998 news articles are also included in this issue. In 1998, the Bulletin published over 380 news articles. HIV-infection remains the predominant target for antiviral therapeutics and vaccine development activities, with about one-half of 1998 Bulletin articles concerning HIV-infection. However, more significant advances, including the approval of new therapeutics, promising reports of efficacy and novel agents entering and progressing in clinical trials, occurred with other viral diseases.

In terms of health care delivery and product approvals (U.S.), substantial progress was reported last year with therapeutics and vaccines for viral diseases for which few or no treatment/prophylactic options were previously available, including chronic hepatitis B and C, and pediatric respiratory syncytial virus and rotavirus infections. Lamivudine (Epivir-HBV) became the first oral drug and the first alternative to alpha interferon for treatment of chronic hepatitis B. Rebetron Combination Therapy (interferon plus ribavirin) received approval for use in chronic hepatitis C patients previously treated with interferon and subsequently for first-line therapy. The first rotavirus vaccine (RotaShield) received approval. A prophylactic respiratory syncytial virus monoclonal antibody (Synagis) became the first monoclonal antibody approved for treatment of an infectious disease. The first solvent-detergent, virus-inactivated blood plasma product (PLAS+SD) received approval. The first antisense drug to receive approval, fomivirsen sodium (Vitravene), joined other drugs approved for treatment of cytomegalovirus retinitis. In the HIV area, several new drugs with mechanisms similar to available drugs entered the market, offering simpler compliance (less frequent dosing) and other improvements. Otherwise, several previously approved antiviral therapeutics and vaccines were approved for new or expanded indications.

Encouraging Developments and Trends

• A rotavirus vaccine (RotaShield) from Wyeth-Ayerst Labs. was approved for prevention of rotavirus gastroenteritis in infants, becoming the first rotavirus vaccine.
  
• Lamivudine (Epivir-HBV) from Glaxo Wellcome Inc. was approved for treatment of chronic hepatitis B, becoming the first oral treatment for chronic hepatitis B.
  
• Fomivirsen sodium (Vitravene) from Isis Pharmaceuticals, Inc. and CIBA Vision Corp. was approved for second-line treatment of cytomegalovirus retinitis in AIDS patients, becoming the first antisense drug approved for any indication.
  
• A humanized respiratory syncytial virus (RSV) monoclonal antibody (Synagis) from MedImmune, Inc. was approved for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients, becoming the first monoclonal antibody product to receive approval for an infectious disease.
  
• Efavirenz (Sustiva), a non-nucleoside HIV reverse transcriptase inhibitor, from DuPont Pharmaceuticals Co. was approved, becoming the first once-daily HIV drug.
  
• Abacavir sulfate (Ziagen), a nucleoside analog, from Glaxo Wellcome Inc. was approved for treatment of HIV-infection in adults and children.
  
• Rebetron Combination Therapy, interferon alfa-2b (Intron A) plus ribavirin (Rebetrol), from Schering-Plough Corp. was approved for treatment of chronic hepatitis C, first in patients having relapsed following alpha interferon therapy and subsequently for first-line treatment.
  
• Pooled Plasma, Solvent/Detergent Treated (PLAS+SD) from V.I. Technologies, Inc. and the American Red Cross was approved, becoming the first virus inactivated blood plasma product in the U.S.
  
• Indinavir sulfate (Crixivan), an HIV protease inhibitor, from Merck & Co. received full approval from FDA based on improvements in clinical endpoints.
  
• Interferon alfa-2b (Intron A) from Schering-Plough Corp. received supplemental approval for pediatric treatment of chronic hepatitis B.
  
• Famciclovir (Famvir) from SmithKline Beecham Corp. received supplemental approval for recurrent herpes simplex virus infections in HIV-infected patients.
  
• Influenza vaccine (Fluogen) from King Pharmaceuticals, Inc., formerly from Warner-Lambert Co., was approved.
  
• A pediatric oral formulation of nevirapine (Viramune) from Boehringer Ingelheim Pharmaceuticals, Inc. received supplemental approval for treatment of HIV-infection. Nevirapine also received supplemental approval for use with HIV protease inhibitors.
  
• Cytomegalovirus immune globulin (CytoGam) from MedImmune, Inc. received supplemental approval for prophylaxis of cytomegalovirus disease associated with transplantation of the kidney, lung, liver, pancreas and heart.
  
• Hepatitis B vaccine (Engerix-B) from SmithKline Beecham Corp. received supplemental approval for use in persons with chronic hepatitis C virus infection.
  
• Meditech Pharmaceuticals, Inc. is introducing an over-the-counter topical version of MTCH-24 (docusate sodium) for the treatment of oral herpes.
  
• Several diagnostic products received approval including a rapid influenza diagnostic (FLU OIA) and the first urine HIV-1 Western Blot test.

• Amprenavir (Agenerase), an HIV protease inhibitor, from Glaxo Wellcome Co. showed efficacy in Phase III trials.
  
• A live intranasal influenza virus vaccine (FluMist) from Aviron, Inc. showed prophylactic efficacy in children and adults in Phase III trials.
  
• Zanamivir (Relenza), a neuraminidase inhibitor, from Biota Holdings Ltd. and Glaxo Wellcome showed efficacy for treatment of influenza in Phase III trials.
  
• GS 4104, a neuraminidase inhibitor, from Hoffmann-La Roche Inc. and Gilead Sciences, Inc. showed efficacy for treatment of influenza in Phase III trials.
  
• Interleukin-2 (Proleukin) from Chiron Corp. in combination regimens improved the immune state of patients with advanced HIV/AIDS and reduced the number of resting CD4+ T-cells harboring HIV.
  
• Topical 10% n-docosanol (Lidakol) cream from Lidak Pharmaceuticals showed efficacy in a Phase III trial for treatment of recurrent oral-facial herpes.
  
• Several anti-HIV drugs in combination regimens continued to show efficacy (undetectable HIV plasma viral load) after two or more years.
  
• A placebo-controlled trial in Thailand showed that a short course of treatment with AZT (Retrovir) from Glaxo Wellcome reduces transmission of HIV from infected mothers to newborns by about 50%.
  
• Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine) from Immunex Corp. plus antiretroviral drug therapy showed promise for treatment of advanced HIV-infection.
  
• T-20 (pentafuside) from Trimeris Inc. showed promise for treatment of HIV-infection.
  
• DISC HSV-2 vaccine, a genital herpes immunotherapeutic vaccine, from Cantab Pharmaceuticals, PLC and Glaxo Wellcome Ltd. showed promise in early trials.
  
• An HIV ribozyme gene therapy from Ribozyme Pharmaceuticals, Inc. and Chiron Corp. showed promise.
  
• A prophylactic prime-boost HIV vaccine regimen using canarypox virus vector HIV vaccine (ALVAC-gp160) from Pasteur-Merieux Connaught plus HIV gp120 vaccine from Chiron Corp., induced immune responses.
  
• S-59 psoralen photoinactivation of plasma, red blood cells and platelets from Cerus Corp. and Baxter Healthcare Corp. showed promising results.
  
• Gene therapy-modified CD4+ and CD8+ T-cells from Cell Genesys, Inc. survived in vivo for over ten weeks, the first report of the prolonged survival in patients of immune cells genetically engineered to be HIV-specific.
  
• Thymosin alpha 1 from SciClone Pharmaceuticals, Inc. continued to show efficacy for treatment of chronic hepatitis B and entered pivotal Phase III trials.
  
• Valacyclovir (Valtrex) from Glaxo Wellcome Inc. was shown comparably effective to acyclovir for reducing viral shedding in asymptomatic genital herpes.
  
• Oral acyclovir (Zovirax) from Glaxo Wellcome Co. was shown to suppress recurrences of ocular herpes.
  
• Various two-drug combinations, including double protease inhibitors and combinations including a non-nucleoside reverse transcriptase inhibitor, showed promise for treatment of HIV-infection.
  
• An immunotherapeutic HIV vaccine (Remune) from Immune Response Corp. plus combination drug therapy showed promise for treatment of HIV-infection.
  
• Indinavir sulfate (Crixivan) from Merck & Co. showed comparable efficacy against HIV in men and women.
  
• Adefovir dipivoxil (Preveon), a reverse transcriptase inhibitor, from Gilead Sciences, Inc. showed promise for treatment of chronic hepatitis B and HIV-infection.
  
• Genvir, oral controlled-release acyclovir, from Flamel Technologies showed efficacy comparable to (or better than) acyclovir for acute genital herpes.
  
• Hepatitis B immune globulin (H-BIG) from Nabi plus Epivir-HBV showed indications of efficacy for prevention of hepatitis B virus infection in liver transplants.
  
• Combinations of hydroxyurea (Hydrea) from Bristol-Myers Squibb Co. and nucleoside analogs showed promise for treatment of HIV-infection.
  
• Cesarean sections were shown to reduce the risk for transmission of HIV from infected mothers to their newborn infants by about 50%.
  
• Adefovir dipivoxil (Preveon) from Gilead Sciences, Inc. continued to show promise, demonstrating durable decreases in HIV plasma viral load after 48 weeks.
  
• PNU-140690, a non-peptidic HIV protease inhibitor, from Pharmacia & Upjohn showed potential for treatment of HIV-infection.
  
• Monophosphoryl lipid A (MPL) adjuvant from Ribi ImmunoChem Research Inc. with hepatitis B vaccine from SmithKline Beecham Biologicals improved immune responses in vaccine-unresponsive patients.
  
• The successful induction of HIV-1 specific cytotoxic T-lymphocyte responses using a DNA vaccine in HIV-infected patients was reported.
  
• PEGylated-40K interferon alfa-2a (Pegasys) from Hoffmann-La Roche Inc. showed promise for treatment of chronic hepatitis C virus infection.
  
• An intranasal, cell-cultured influenza vaccine from BioChem Pharma showed promise in an early trial.
  
• A new 5% formulation of hepatitis B immune globulin (H-BIG) for intravenous administration from Nabi showed efficacy and safety.
  
• MTH-68/B, a live bursal disease virus vaccine, from the United Cancer Research Institute showed promise for treatment of acute hepatitis B and C virus infections.
  
• FTC from Triangle Pharmaceuticals, Inc. showed promise for treatment of chronic hepatitis B and HIV.
  
• A rotavirus vaccine from AVANT Immunotherapeutics, Inc. showed promise in infants.
  
• Passive immune therapy using HIV immune globulin from asymptomatic HIV-infected patients was reported to be effective for treatment of HIV-infection.
  
• Simian virus 40 (SV40) contaminated poliovirus vaccines used in the U.S. between 1955-1963 were shown not to be associated with an increase in cancer rates.
  
• Famciclovir (Famvir) from SmithKline Beecham Corp. showed efficacy for treatment of orofacial herpes after laser skin resurfacing (laser peel) cosmetic surgery.
  
• Lodenosine (F-ddA), a nucleoside analog, from U.S. Bioscience, Inc. showed promise for HIV-infection.
  
• MEDI-501, a human papillomavirus vaccine, from MedImmune, Inc. and SmithKline Beecham Corp. was shown to be safe and induce antibodies.
  
• Increased histamine in the blood improved responses to interferon therapy in patients with chronic hepatitis C.
  
• Maxamine, a histamine type-2 receptor agonist, from Maxim Pharmaceuticals, Inc. showed promise for treatment of chronic hepatitis C virus.
  
• Reticulose, a peptide-nucleic acid formulation, from Advanced Viral Research Corp. showed efficacy for treatment of HIV-infection in a Phase III trial.
  
• Cidofovir (Vistide) from Gilead Sciences, Inc. plus cytosine arabinoside successfully treated a case of progressive multifocal leukoencephalopathy (PML), the first successful treatment of PML (attributed to JC virus).
  
• Low-dose oral interferon-alpha from Pharma Pacific Management Pty. Ltd. showed indications of efficacy for treatment of pediatric measles.
  
• Palivizumab (Synagis), a respiratory syncytial virus (RSV) monoclonal antibody, from MedImmune, Inc. showed promise for treatment and prevention of RSV disease in adult stem cell transplant recipients.
  
• Several HIV drugs were shown to cross the blood-brain barrier; and HIV protease inhibitors combined with nucleoside analogs were reported to prevent or even reverse the progression of HIV encephalopathy.
  
• Twice-daily saquinavir (Fortovase) from Hoffmann-La Roche Inc. demonstrated activity comparable to three-times daily administration, the current regimen.
  
• Gene therapy from Cell Genesys, Inc. decreased levels of HIV in gastrointestinal lymphoid tissue in patients in whom drugs failed to eradicate HIV in the blood.
  
• bis(POC)PMPA, an oral PMPA prodrug, from Gilead Sciences, Inc. showed promise for HIV-infection.
  
• Chemokines were shown to apparently be responsible for allowing some hemophilia patients to remain free of HIV-infection, despite having received repeated infusions of HIV-contaminated blood products.
  
• An HIV immunotherapeutic vaccine (Remune) from Immune Response Corp. demonstrated HIV subtype cross reactive immune responses.
  
• It was reported that the immune system can control HIV-infection if acute infection is promptly treated with aggressive combination drug therapy.
  
• L-carnitine, a nutritional supplement, increased T-cell counts in HIV-infected patients.
  
• A trial demonstrated that transgenic foods (edible vaccines) can induce specific pathogen-associated immune responses in humans.
  

• VaxGen, Inc. started the first large-scale, Phase III clinical trials with a prophylactic HIV vaccine, AIDSVAX.
  
• HE2000, a Òcellular energy regulatorÓ from Hollis-Eden Pharmaceuticals, Inc. entered trials for HIV-infection.
  
• VX-497, an inhibitor of inosine monophosphate dehydrogenase, from Vertex Pharmaceuticals Inc. is in trials for treatment of chronic hepatitis C.
  
• The National Cancer Institute began trials with an HIV multideterminant cluster peptide vaccine.
  
• AG7088, an inhibitor of rhinovirus 3C protease, from Agouron Pharmaceuticals entered clinical trials.
  
• Valacyclovir (Valtrex) from Glaxo Wellcome is in a Phase III trial for reducing genital herpes transmission.
  
• AMD3100 from AnorMED, Inc. entered trials for treatment of HIV-infection.
  
• WF10, a 1:10 dilution of tetrachlorodecaoxygen, entered Phase III trials for treatment of HIV-infection.
  
• An immunotherapeutic HIV vaccine (Remune) from Immune Response Corp., plus interleukin-2 (Proleukin) from Chiron Corp. and antiretroviral drugs is in trials for immune reconstitution in HIV-infected patients.
  
• The Inter-Company Collaboration (ICC) for AIDS Drug Development started a new trial with various combination regimens.
  
• ISIS 13312, a second-generation antisense oligonucleotide, from Isis Pharmaceuticals, Inc. (Carlsbad, CA) entered trials for cytomegalovirus retinitis.
  
• A human hepatitis B virus monoclonal antibody (OST 577; Ostavir) from Protein Design Labs, Inc. entered Phase II trials for treatment of chronic hepatitis B.
  
• VIR201, an immunotherapeutic avipox virus vector HIV vaccine, from Virax Holdings Ltd. entered trials for treatment of HIV-infection.
  
• MKC-442, an HIV non-nucleoside reverse transcriptase inhibitor, from Triangle Pharmaceuticals, Inc. is in trials for treatment of HIV-infection.
  
• DDI (Videx) from Bristol-Myers Squibb Co. is in Phase III trials for once-daily treatment of HIV-infection.
  
• HGP-30W, a prophylactic HIV p17 peptide vaccine designed for use in lesser-developed countries, from CEL-SCI Corp. entered Phase II studies.
  
• PRO 2000 topical microbicidal/spermicidal gel from Procept, Inc. entered trials for prevention of sexually transmitted diseases, including HIV and genital herpes.
  
• (+)-Calanolide A, a botanical drug for treatment of HIV-infection, from Sarawak MediChem Pharmaceuticals, Inc. is in trials for treatment of HIV-infection.
  
• Trials have started in Thailand using a recombinant HIV-1 strain E gp120 prophylactic vaccine with MF59 adjuvant from Chiron Corp.
  
• Ampligen from HemispheRx Biopharma, Inc. entered Phase III trials for treatment of chronic fatigue syndrome.
  
• Reticulose, a peptide nucleic acid formulation, from Advanced Viral Research Corp. entered a Phase III trial for treatment of genital warts in HIV patients.
  
• BCH-10652, a nucleoside analog, from BioChem Pharma Inc. entered trials for HIV-infection.
  
• Topical leukocyte interferon (Alferon N Gel) from Interferon Sciences, Inc. entered Phase II clinical trials for treatment of intravaginal warts.
  
• A live Salmonella typhi vector prophylactic HIV vaccine from the Univ. of Maryland entered clinical trials.
  
• Trials began with mucosal administration of ALVAC-HIV vCP205, a live canarypox virus vector prophylactic HIV vaccine, from Pasteur Merieux Connaught and use of granulocyte-macrophage colony stimulating factor (GM-CSF) as a vaccine adjuvant.
  
• Maxamine from Maxim Pharmaceuticals, Inc. plus alpha interferon entered Phase II trials for treatment of chronic hepatitis C.
  
• A multivalent vaccinia virus vector HIV vaccine from St. Jude ChildrenÕs Research Hospital designed to stimulate immunity against HIV isolates from various parts of the world entered clinical trials.
  
• PEN203, a Papirine compound, from Pentose Pharmaceuticals, Inc. is in trials for treatment of human papillomavirus-associated warts.
  
• TXU (anti-CD7)-pokeweed antiviral protein (TXU-PAP) from the Hughes Institute is in trials for HIV.
  
• S-1153, an HIV non-nucleoside reverse transcriptase inhibitor, from Shionogi & Co., Ltd. entered Phase I trials for treatment of HIV-infection.
  
• A hepatitis C virus vaccine from Chiron Corp. entered Phase I trials.
  

• Studies confirmed that KaposiÕs sarcoma-associated herpesvirus (KSHV; human herpesvirus-8) is the cause of KaposiÕs sarcoma in HIV-infected patients.
  
• Cytotoxic T lymphocytes isolated from patients infected with one HIV-1 clade were also active in vitro against other clades of HIV-1, suggesting that HIV vaccines may induce cross-clade protective immune responses.
  
• PRO 2000 Gel, a topical microbicidal/spermicidal gel, from Procept, Inc. provided complete protection against vaginal herpes in mice.
  
• An ebola virus gene therapy-type plasmid vaccine showed efficacy in mice and guinea pigs.
  
• Investigators from NIH reported the first efficacy in primates with an antisense gene therapy approach for treatment of a retroviral infection; and a new model for the study of HIV pathogenesis in live tissues was reported.
  
• Cidofovir (Vistide) from Gilead Sciences, Inc. demonstrated efficacy for treatment of monkeypox, the first drug to show efficacy against a primate orthopoxvirus.
  
• Aphios Corp. is developing immunotherapeutic HIV vaccines using HIV inactivated by SuperFluids CFI (critical fluids inactivation) technology.
  
• A DNA vaccine showed complete protection in nonhuman primates against rabies.
  
• A new virus, transfusion-transmitted virus, was shown to be common worldwide but not pathogenic in humans.
  
• HveC was shown to mediate entry of a number of alpha herpesviruses into human cells.
  
• MDI-P, a solution produced by the electrolysis of saline, from Medical Discoveries, Inc. showed potent in vitro activity against HIV.
  
• Aryl phosphate derivatives of bromo-methoxy-azidothymidine (bromo-methoxy AZT) from the Hughes Institute showed potent spermicidal and anti-HIV activity.
  
• AMD3100 and other bicyclams from AnorMED, Inc. were highly potent inhibitors of HIV-1 and HIV-2.
  
• Thrombospondin, a protein in saliva, was shown to inhibit HIV in vitro.
  
• Nabi 3700.001, a ring expanded nucleoside analog, from Nabi showed potent inhibition of hepatitis B virus.
  
• Hepatitis C virus immune globulin (Nabi-Civacir) from Nabi showed indications of efficacy in chimpanzees.
  
• The Hughes Institute is developing dual-function, (antiviral and contraceptive) vaginal products to reduce the risk for females of contracting HIV-infection.
  
• Several companies reported progress in development of drugs and vaccines for the new ÒHong Kong fluÓ or Òbird fluÓ strain of influenza A. This strain did not become epidemic/pandemic as some had feared.
  
• University of Wisconsin School of Veterinary Medicine investigators identified a molecular mechanism involved in the virulence of influenza A virus.
  
• Unknown constituent(s) of human chorionic gonadotropin (hCG) were reported to be active in vitro against KaposiÕs sarcoma and HIV.
  
• DAPD, a nucleoside reverse transcriptase inhibitor active against HIV and hepatitis B virus, from Triangle Pharmaceuticals, Inc. showed a unique resistance pattern and synergy with other nucleosides.
  
• D-D4FC showed potent activity against HIV both in vitro and in animal testing.
  
• OraVax, Inc. is developing a live yellow fever virus vector Japanese encephalitis vaccine.
  
• Peptimmune, Inc. is developing Peptimer peptide vaccines, including an immunotherapeutic HIV vaccine.
  
• CNI-H1194, a Nuclear Importation Inhibitor, and cyclophilin A (CyPA) antibodies are being developed by Cytokine Networks Inc. for treatment of HIV-infection.
  
• Vertex Pharmaceuticals Inc. resolved the three-dimensional atomic structure of hepatitis C virus helicase.
  
• Interleukin-1beta from Cistron Biotechnology, Inc. plus influenza A vaccine encapsulated in Novosomes (liposomes) from Novavax, Inc. boosted responses to the influenza vaccine in animal studies.
  
• The Dana-Farber Cancer Inst. reported new structural models of HIV gp120.
  

• Average monthly costs in a managed care setting were lower for HIV-infected patients maintaining undetectable viral loads compared to those with detectable viral load.
  
• Average monthly HIV-related treatment costs in managed care settings stabilized over the three-year period 1995 to 1997.
  
• The International AIDS Vaccine Initiative (IAVI) issued two grants totaling $9.1 million to fund development of novel HIV vaccines by two organizations, including price concessions to maximize vaccine availability in lesser developed countries.
  
• Glaxo Wellcome offered substantial discounts for purchase of AZT (Retrovir) by developing countries for the reduction of maternal transmission of HIV-infection.
  
• Nearly all states quickly adopted efavirenz, a new HIV drug more expensive than others in its class, into their AIDS Drug Assistance Program (ADAP) formularies.
  
• Lamivudine (Epivir-HIV) was the largest-selling HIV therapeutic with sales approaching $1 billion annually (before its approval for chronic hepatitis B).
  
• U.S. sales of D4T (Zerit) from Bristol-Myers Squibb Co. surpassed those of AZT, becoming the most commonly prescribed anti-HIV thymidine nucleoside analog.
  
• The most popular single anti-HIV regimen was the triple drug combination D4T (Zerit) from Bristol-Myers Squibb Co. plus lamivudine (Epivir-HIV) from Glaxo Wellcome Inc. plus indinavir (Crixivan) from Merck & Co.
  
• Measles vaccination is showing success in the U.S. with a record low number of cases (138) reported in 1997.
  
• The American Academy of Pediatrics issued new recommendations for pediatric polio vaccination.
  
• HemispheRx Biopharma, Inc. developed a Òready-to-useÓ liquid formulation of Ampligen.
  
• U.S. influenza vaccination rates were up, with 65% of older adults vaccinated for the 1997-1998 flu season.
  
• Chiron Diagnostics released its more sensitive (50 copies/ml lower limit) Quantiplex HIV-1 RNA 3.0 assay.
  
• The U.S. Supreme Court ruled that the Americans with Disabilities Act covers persons with HIV-infection.
  
• Hepatico, a blend of herbs, from Alta Natural Herbs & Supplements Ltd. will be marketed as a nutraceutical for treatment of hepatitis A, B and C.
  

Discouraging News

• Initial regulatory submissions by Aviron, Inc. for approval of its live attenuated intranasal influenza vaccine (FluMist) were not acceptable to FDA.
  
• Bristol-Myers Squibb Co. halted development of sorivudine (Usevir; BV-araU) for treatment of herpes zoster due to safety and liability concerns. The company also canceled its license with Lidak Pharmaceuticals Inc. for marketing of topical n-docosanol (Lidakol) cream for treatment of oral herpes.
  
• VIMRx Pharmaceuticals Inc. halted development of synthetic hypericin (VIMRxyn) for treatment of HIV-infection, chronic hepatitis C and sterilization of blood for transfusion (but development for skin warts continues).
  
• Abbott Laboratories experienced manufacturing difficulties with the capsule formulation of its HIV protease inhibitor, Norvir (ritonavir).
  
• Interferon Sciences, Inc. was advised by the FDA that its Phase III trial with leukocyte interferon (Alferon N Injection) for treatment of HIV-infection was insufficient to support approval.
  
• Interferon Sciences, Inc. reported that a trial comparing Alferon N Injection to Intron A from Schering-Plough found it to have equivalent, not superior, efficacy for treatment of chronic hepatitis C.
  
• Warner-Lambert Co. discontinued development of CI-1012, an HIV zinc finger inhibitor drug.
  
• An intranasal influenza virus vaccine with chitosan mucosal adjuvant from Medeva PLC and Peptide Therapeutics Group PLC failed to show efficacy in a Phase I trial.
  
• LifeTECH Corp. halted development of ozone for sterilization of blood and blood products.
  
• Chiron Corp. and Green Cross Corp. suspended trials with HIV-IT (V), an immunotherapeutic HIV retroviral vector gene therapy vaccine.
  
• Boehringer Mannheim returned all rights for hepatitis B (OST 577) and cytomegalovirus (Protovir) humanized monoclonal antibodies to Protein Design Labs, Inc. and terminated a Phase II study with OST 577.
  

• HIV infection of T-cells was shown to almost invariably rebound from undetectable/low to substantial levels after discontinuation of aggressive drug therapy. Patients having achieved low HIV plasma viral loads using highly potent combination induction regimens generally experience a resurgence in viral load after switching to a maintenance regimen containing fewer drugs.
  
• HIV was reported to develop resistance to essentially all currently marketed antiretroviral drugs, and drug-resistant HIV was reported to be transmissible.
  
• Low adherence to treatment regimens was reported to be common among HIV-infected patients.
  
• A survey showed that about 25% of persons in the U.S. starting treatment for HIV are prescribed therapy inconsistent with the current treatment guidelines.
  
• Progression of HIV-infection, in terms of viral load, was different in female vs. male injection drug users, suggesting that women may need more aggressive treatments.
  
• Merck & Co., Inc. discontinued trials with twice-daily indinavir (Crixivan; a protease inhibitor) plus reverse transcriptase inhibitors.
  
• Contrary to prior reports, acyclovir (Zovirax) from Glaxo Wellcome Inc. did not improve survival in AIDS patients.
  
• Abacavir (Ziagen) from Glaxo Wellcome Inc. was reported to induce potentially severe hypersensitivity reactions in a small percentage of HIV-infected patients.
  
• A large proportion of HIV-infected patients who develop AIDS show a rapid collapse in T-cell homeostasis 18-30 months before the onset of clinical symptoms.
  
• HIV antigen-pulsed (exposed) dendritic cells were reported ineffective for treatment of HIV-infection.
  
• Pfizer Inc. failed to renew its collaboration with Immusol, Inc. for development of ribozyme gene therapies for treatment of HIV-infection.
  
• Cytarabine (Cytosar-U) from Pharmacia & Upjohn was reported ineffective for treatment of progressive multifocal leukoencephalopathy in AIDS patients.
  
• Ranitidine (Zantac), a popular anti-ulcer drug, from Glaxo Wellcome Inc. was shown to lack significant efficacy for treatment of early HIV-infection.
  

• A wide gap persists between treatment of HIV-infection in developed countries, exemplified by relatively costly combination drug therapy, and treatment in lesser developed countries, where most HIV-infected persons often receive no drugs or any other medical treatment.
  
• The cost for treating all HIV-infected adults worldwide with conventional triple combination drug therapy was estimated at $36.5 billion.
  
• A live attenuated SIV vaccine was pathogenic in 100% of infant macaques vaccinated orally or intravenously, a setback for development of live HIV vaccines.
  
• Contrary to the belief that CD8+ T-cells are resistant to HIV-infection, CD8+ T-cells were shown to express CD4 receptors, making them susceptible to HIV-infection.
  
• Various U.S organizations started promoting the importance of chronic hepatitis C virus (HCV) infection in the U.S., referring to it as Òthe next epidemic.Ó
  
• South Africa halted funding for purchases and provision of AZT by government-supported programs for prevention of maternal transmission of HIV-infection.
  
• Activists and others protested the prices set by DuPont Pharmaceuticals Co. for recently approved Efavirenz (Sustiva) for treatment of HIV-infection
  
• Activists and others protested the cost of Rebetron Combination Therapy from Schering-Plough, with addition of ribavirin to interferon alpha-2b (Intron A) adding about $1,000/month to the cost of treatment, and the exclusive bundling of ribavirin with Intron A preventing off-label use of ribavirin with other therapeutics.
  
• Common colds, usually caused by rhinoviruses, were shown to frequently be caused by other viruses, complicating development of therapeutics and vaccines for the common cold.

Corporate and Federal Activities

• Pharmacia & Upjohn and Chiron Corp. formed a collaboration for the discovery and development of drugs for treatment of hepatitis C virus infection.
  
• The Immune Response Corp. and Agouron Pharmaceuticals, Inc. formed a collaboration for development of Remune, an HIV immunotherapeutic vaccine.
  
• SmithKline Beecham Biologicals linked with BioChem Pharma Inc. for development and marketing of intranasal cell-cultured influenza virus vaccines; with MedImmune, Inc. for human papillomavirus vaccines for prevention of cervical cancer and genital warts; and with AVANT Immunotherapeutics for oral rotavirus vaccines.
  
• Glaxo Wellcome PLC linked with PowderJect Pharmaceuticals PLC for development of DNA-based vaccines using needleless delivery systems and received exclusive rights to PowderJectÕs prophylactic hepatitis B virus vaccine and options for ten other DNA vaccines.
  
• 3M Pharmaceuticals linked with Vanguard Medica for development of an analog of the topical drug imiquimod (Aldara) as an oral drug for chronic hepatitis C.
  
• Johnson & Johnson linked with BioCryst Pharmaceuticals, Inc. for development of oral influenza virus neuraminidase inhibitors.
  
• OraVax, Inc. and Pasteur Merieux Connaught linked to develop a dengue virus vaccine and PMC has an option to license a Japanese encephalitis virus vaccine.
  
• V.I. Technologies, Inc. linked with the American Red Cross for marketing of virus inactivated blood plasma (PLAS+SD) and received a $50 million order.
  
• Agouron Pharmaceuticals Inc. linked with BioStar Inc. for development of a rhinovirus infection diagnostic.
  
• Lidak Pharmaceuticals Inc. selected CONDEA Chemie GmbH to manufacture n-docosanol (Lidakol), the active ingredient in 10% n-docosanol cream.
  
• Bio-Technology General Corp. linked with the Swiss Serum and Vaccine Institute for development and marketing of a third-generation recombinant hepatitis B vaccine.
  
• Viragen, Inc. obtained exclusive access to nearly all of the U.S. supply of human leukocytes for production of leukocyte alpha interferon.
  
• Schering-Plough Corp. linked with Immune Response Corp. to develop gene therapy products for the treatment of hepatitis B and C, and other diseases.
  
• Genzyme Transgenics Corp. and Interferon Sciences, Inc. linked to develop transgenic alpha interferon products.
  
• Hoffmann-La Roche Ltd. linked with Progenics Pharmaceuticals, Inc. for development of HIV therapeutics which target recently identified HIV cell fusion co-receptors.
  
• Merck & Co. linked with Isis Pharmaceuticals, Inc. for discovery of drugs for treatment of hepatitis C.
  
• Pasteur Merieux Connaught linked with Cistron Biotechnology, Inc. for development of interleukin-1 beta (IL-1b) as a vaccine adjuvant.
  
• The Virco Group linked with Laboratory Corporation of America Holdings to market tests for HIV resistance to antiretroviral drugs.
  
• CSL Ltd. linked with Aviron, Inc. for development and marketing of live intranasal influenza virus vaccine (FluMist) in Australia and other South Pacific countries.
  
• Tripos, Inc. and Sepracor Inc. linked for discovery and development of drugs active against drug resistant HIV.
  
• Progenics Pharmaceuticals, Inc. linked with Pharmacopeia, Inc. for discovery of drugs that block the attachment of HIV to CD4.
  
• Nabi concluded a Collaborative Research and Development Agreement with the Centers for Disease Control and Prevention for primate efficacy testing of Nabi-Civacir, a hepatitis C immune globulin preparation.
  
• ArQule, Inc and Sepracor Inc. linked for discovery and development of drugs targeting resistant strains of HIV and hepatitis B virus.
  
• Pall Corp. linked with V.I. Technologies, Inc. for joint development of inactivation technology for red blood cells and platelets.
  
• Cantab Pharmaceuticals PLC linked with the Chemo Sero Therapeutic Research Institute for development of DISC VSV, a prophylactic varicella-zoster virus vaccine.
  
• Theratechnologies Inc. linked with Genetix Pharmaceuticals for use of its HIV Vpr technology in gene therapy applications; and linked with Chiron Corp. to jointly test this technology for treatment of HIV-infection.
  
• Schering-Plough Corp. extended its strategic alliance with Corvas International, Inc. for development of orally bioavailable hepatitis C virus serine protease inhibitors.
  
• DuPont Pharmaceuticals Co. linked with Signal Pharmaceuticals, Inc. for development of drugs that inhibit gene regulating targets within hepatitis C virus and HIV.
  
• Genelabs Technologies, Inc. contracted with three companies (Tripos, Inc., MDS Panlabs, and SRI International) for combinatorial chemistry services for development of nucleic acid-binding antiviral compounds.
  
• Pasteur Merieux Connaught extended its agreement with Corixa Corp. for study of Leishmania elongation Initiation Factor (LeIF) as a vaccine adjuvant.
  Acquisitions, mergers and divestments included:
  
• Rhone-Poulenc SA and Hoechst AG are merging their life sciences activities into a new company, Aventis.
  
• DuPont Co. acquired the 50% share held by Merck & Co. in their DuPont Merck Pharmaceutical Co. joint venture, forming DuPont Pharmaceuticals Co.
  
• OraVax, Inc. and Peptide Therapeutics Group PLC entered into an agreement to merge.
  
• The Virus Research Institute merged with T Cell Sciences, Inc. to form AVANT Immunotherapeutics, Inc.
  
• Wyeth-Ayerst Laboratories, American Home Products Corp., acquired Apollon, Inc., a company specializing in GENEVAX Òfacilitated DNA injectionÓ vaccines.
  
• King Pharmaceuticals, Inc. acquired products from Warner-Lambert Co. including Fluogen, the companyÕs influenza virus vaccine, and vidarabine (Vira-A), used for treatment of certain herpes simplex virus infections.
  
• Astra AG and Zeneca Group are merging to form AstraZeneca.
  
• American Home Products Corp. and Monsanto Co. canceled a planned merger.
  
• Aquila Biopharmaceuticals, Inc. acquired VacTex, Inc.
  
• Amarillo Biosciences Inc. sold 70% of its Vanguard Biosciences Inc. veterinary health subsidiary to Agritek Bio Ingredients Corp., including rights for animal use of low-dose oral interferon.
  
• Chiron Corp. sold Chiron Diagnostics Corp. to the Bayer Group, including branched chain DNA (bDNA) products used for measuring HIV plasma viral load.
  
• Chiron Corp. completed acquisition of the interest held by Hoechst AG in Chiron Behring GmbH & Co.
  
• Chiron Corp. and Hoechst Marion Roussel Ltd. formed a joint venture, Chiron Behring Vaccines Private Ltd., for rabies vaccine manufacture and marketing in India.
  
• LeukoSite, Inc. and Warner-Lambert Co. extended their collaboration for the discovery and development of chemokine-targeted drugs for treatment of HIV-infection.
  

• The National Institute of Allergy and Infectious Diseases is assisting VaxGen, Inc. with its Phase III trials of AIDSVAX, a prophylactic HIV vaccine.
  
• The FDA issued a letter to manufacturers of viral vaccine products informing them of new testing guidelines.
  
• NIAID awarded a $9.4 million contract to BBI Biotech Research Laboratories to provide testing to support HIV vaccine trials.
  
• Fortovase, an HIV protease inhibitor, from Hoffmann-La Roche Inc., was accepted as a ÒpreferredÓ treatment in the U.S. Department of Health and Human ServicesÕ guidelines for treatment of HIV-infection.
  
• The United Kingdom announced requirements for removal of leukocytes from all blood and blood products derived from whole blood, joining other countries where leukodepletion by filtration is already a requirement.
  
• The FDA approved Paxene (paclitaxel) from NaPro BioTherapeutics Inc. and Ivax Corp. for KaposiÕs sarcoma, but the drug cannot be marketed due to orphan drug exclusivity granted to Taxol from Bristol-Myers Squibb Co.
  

Patents and Technology Transfer

• Isis Pharmaceuticals, Inc. purchased the antisense-related intellectual properties of Gilead Sciences, Inc.; and CpG ImmunoPharmaceuticals, Inc. received an exclusive license to Isis patents concerning use of phosphorothioate oligonucleotides (S-oligos) for immune stimulation.
  
• Triangle Pharmaceuticals, Inc. licensed rights (except in Korea) to L-FMAU, particularly for hepatitis B, from Bukwang Pharmaceuticals Ind. Co., Ltd.
  
• Tranzyme Pharmaceuticals Inc. exclusively licensed lentivirus vectors from the UAB Research Foundation for HIV drug sensitivity testing and gene therapy.
  
• SmithKline Beecham Corp. expanded its agreement with Genelabs Technologies, Inc. for marketing rights for hepatitis E virus vaccines.
  
• MedImmune, Inc. concluded an agreement with Chiron Corp. for use of MF59 vaccine adjuvant with its parvovirus B19 vaccine.
  
• Glaxo Wellcome Inc. linked with Hoechst Marion Roussel (and its partner, Bayer AG) to evaluate HBY 097 and other quinoxaline HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs).
  
• Agouron Pharmaceuticals, Inc. licensed rights to S-1153, an HIV non-nucleoside reverse transcriptase inhibitor, from Shionogi & Co., Ltd. and rights to JE-2147 (KNI-764), an HIV protease inhibitor, from Japan Energy Corp.
  
• Pasteur Merieux Connaught licensed vaccine carrier technology from BTG International Inc.
  
• Endorex Corp. optioned use of hepatitis B virus peptide immunogens in oral vaccines from BTG.
  
• Tanox Biosystems, Inc. licensed use of antibody humanization patents from Protein Design Labs, Inc.
  
• Schering-Plough Corp. acquired from ICN Pharmaceuticals, Inc. rights to co-market oral ribavirin for treatment of hepatitis C virus infection in the European Union.
  
• AVANT Immunotherapeutics licensed use of Therapore Òimmunotherapy deliveryÓ technology for hepatitis B and C and HIV vaccines from Harvard University.
  
• BioChem Pharma Inc. obtained rights to candidate hepatitis B drugs from Scriptgen Pharmaceuticals, Inc.
  
• SciClone Pharmaceuticals, Inc. completed acquisition of worldwide rights to thymosin alpha 1 (Zadaxin) from Alpha 1 Biomedicals.
  
• ZymeTx, Inc. licensed ZX0851, an anti-HIV drug, from the Oklahoma Medical Research Foundation.
  
• Nabi licensed rights to Ring Expanded Nucleosides and Nucleotides from the University of Maryland.
  
• Cantab Pharmaceuticals PLC optioned Novasome technology from Novavax, Inc. for use as an adjuvant with human papillomavirus immunotherapeutic vaccines.
  
• Southern Health SCD.BHD optioned rights for leukocyte interferon in several Pacific Rim territories from Viragen, Inc.
  
• Apollon Inc. nonexclusively licensed hepatitis B virus antigen DNA sequences from Biogen Inc.
  

• Chiron Corp. filed suits alleging that Eli Lilly & Co., Vertex Pharmaceuticals Inc., Gilead Sciences, Inc. and Agouron Pharmaceuticals, Inc. are infringing U.S. patents covering recombinant hepatitis C virus protease.
  
• Shearwater Polymers concluded an agreement with Hoffmann-La Roche Inc. for manufacture of PEGylated-40K interferon alfa-2a (Pegasys). Enzon, Inc., developing another PEG-interferon with Schering-Plough Corp., filed an infringement suit against Shearwater Polymers.
  
• A federal court stayed a patent infringement suit filed by Emory University against BioChem Pharma and Glaxo Wellcome Inc. concerning lamivudine (Epivir-HIV and Epivir-HBV), effectively putting this infringement case in the hands of the patent office.
  
• Chiron Corp. filed an infringement suit against Hoffmann-La Roche, Ltd. concerning hepatitis C virus oligonucleotides and polymerase chain reaction assays.
  

• Biogen, Inc., Schering-Plough Corp., Hoffmann-La Roche Inc. and Genentech Inc. settled a long-running patent dispute concerning alpha interferon.
  
• The U.S. District Court reinstated an intracellular antisense patent assigned to Enzo Biochem Inc.
  
• SmithKline Beecham Corp. and Chiron Corp. settled litigation over use of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoters (claimed by Chiron) used for expression of recombinant antigens, including SKBÕs recombinant hepatitis B vaccine (Engerix-B).