This article summarizes and reviews some of the more significant and interesting antiviral therapeutics-related news and developments reported in 1996 issues (Volume 9) of the Antiviral Agents Bulletin. Various indexes (Organization, Agent, Virus/Disease and Keyword) of 1996 news articles are also included in this issue. Indexes of 1996 U.S. patents will be presented in an upcoming issue of the Bulletin.

In 1996, the Bulletin presented over 350 news articles and over 380 pages of news, patent and literature abstracts, and other information concerning antiviral therapeutics and vaccine development. HIV-infection remains the predominant target for antiviral therapeutics development activities, with about half of 1996 Bulletin articles related to HIV-infection. However, important advances, including the approval of new drugs and many clinical trial reports of significant efficacy, occurred with drugs for treatment of herpes simplex virus, cytomegalovirus and hepatitis B and C virus infections.

In terms of healthcare, the major antiviral news from 1996 was the rapid adoption of HIV combination drug therapy, with combinations of multiple nucleoside analog HIV reverse transcriptase inhibitors plus an HIV protease inhibitor becoming standard therapy; and 3TC replacing AZT as the largest selling HIV drug. The reporting of various combinations of HIV reverse transcriptase inhibitors and protease inhibitors resulting in drastic reductions in HIV plasma viral load, often below detectable levels, increases in CD4+ T-cell count and alleviation of symptoms has almost become commonplace. However, little is known about the long-term clinical efficacy and safety of various drugs and combinations, while in the short-term many HIV-infected patients cannot afford or tolerate combination treatments. Despite the availability of new drugs and more combinations, HIV-infection remains a terminal disease with available therapeutics not yet proven to affect its long-term course. HIV-infection treatment is now largely following the cancer chemotherapy modelÑinvolving treatment with a number of drug combinations. However, while cancer therapy has reached the stage of about a 50% cure rate, with "cure" being five years with no disease advancement, HIV therapy has not yet reached this stage.

One trend that has become very evident is the contraction in the area of HIV prophylactic vaccine development, even though prophylactic vaccines are recognized as the only way to effectively control the HIV epidemic worldwide. There were hardly any substantive news stories in 1996 concerning HIV vaccines, and much of the news was not positive, e.g., vaccines dropped from development, committees citing inadequate resources, etc. No vaccines moved into large efficacy trials, incentives remain too few and uncertainty too high for private sector development, and the U.S. and other major governments have yet to redirect substantially more resources towards HIV vaccine development and testing.

The opportunities and need for antiviral therapeutics and vaccines remain high. Improved and more cost-effective therapeutics for essentially all viral diseases are needed and will find substantial markets. This remains true even in areas, such as cytomegalovirus retinitis and hepatitis B, where more therapeutics have or will soon become available. Regulatory approvals, particularly in the U.S., are no longer a problem for drug sponsors with many HIV and other antiviral therapeutics approved solely on the basis of early trial results showing effects on surrogate markers or one pivotal clinical trial. A number of novel therapeutic approaches, such as gene therapies and immunotherapeutic vaccines, entered clinical trials or showed safety and indications of efficacy last year.

Encouraging Developments - Product approvals

Product approvals (primarily U.S.) included:

• Nevirapine (Viramune) from Boehringer Ingelheim Pharmaceuticals, Inc. received approval for use in combination with nucleoside analogs for treatment of HIV-infection, becoming the first non-nucleoside reverse transcriptase inhibitor to receive approval.
  
• Indinavir sulfate (Crixivan), an inhibitor of HIV protease, from Merck & Co. was approved for treatment of HIV-infection and the company priced it lower than other HIV protease inhibitors.
  
• Ritonavir (Norvir), an inhibitor of HIV protease, from Abbott Labs. was approved by FDA for treatment of HIV-infection in record time (72 days).
  
• Penciclovir as 1% cream (Vectavir) from SmithKline Beecham Corp. was shown effective and approved for treatment of oral herpes, becoming the first topical treatment available in the U.S.
  
• D4T (stavudine; Zerit) from Bristol-Myers Squibb Co. received full approval for treatment of HIV-infection, becoming the first drug to receive full approval through the FDA's accelerated approval process.
  
• Cidofovir (Vistide) injection from Gilead Sciences Inc. was approved for treatment of cytomegalovirus (CMV) retinitis in AIDS patients.
  
• Respiratory Syncytial Virus Immune Globulin Intravenous (Human) from MedImmune, Inc. was approved for prevention of respiratory syncytial virus (RSV) in high-risk infants, becoming the first agent available for RSV prophylaxis.
  
• Recombinant interferon alpha-2a (Roferon-A; interferon alfa-2a) from Hoffmann-La Roche Inc. (Nutley, NJ) was approved for treatment of chronic hepatitis C, becoming the second treatment available for this indication.
  
• Famciclovir (Famvir) from SmithKline Beecham Corp. was approved for suppression (prophylaxis) of recurring episodes of genital herpes due to herpes simplex virus type 2.
  
• Intravitreal ganciclovir (Vitrasert Implant) from Chiron Vision Corp. was approved for treatment of cytomegalovirus (CMV) retinitis in AIDS patients, becoming the first delivery system approved for local, sustained drug delivery within the eye.
  
• Oral ganciclovir (Cytovene capsules) from Hoffmann-La Roche Inc. was approved for a new indication, prevention of cytomegalovirus (CMV) disease in solid organ (e.g., liver) transplant recipients.
  
• Comvax from Merck & Co. was approved, becoming the first pediatric vaccine combining a hepatitis B virus and Haemophilus influenzae B bacterial vaccine.
  
• AccuSite Injectable Gel, controlled release 5-fluorouracil, from Matrix Pharmaceutical, Inc. was approved in the U.K. for genital warts associated with human papillomavirus infection, but has encountered problems with the FDA in the U.S.
  
• A more concentrated pediatric dosage and simpler vaccination schedule were approved for Hepatitis A Vaccine, Inactivated (Havrix) from SmithKline Beecham Biologicals.
  
• A new 300 mg dosage tablet of AZT (Retrovir) from Glaxo Wellcome Co. was approved.
  
• DDI (Videx; 2',3'-dideoxyinosine) from Bristol-Myers Squibb Co. was approved for first-line treatment of HIV-infection and a "reduced mass" chewable tablet formulation was approved.
  
• DDC (Hivid) from Hoffmann-La Roche Inc. in combination with AZT was approved for first-line treatment of HIV-infection.
  
• Hepatitis A Vaccine, Inactivated (Vaqta) from Merck & Co. was approved for hepatitis A prophylaxis.
  
• The Amplicor HIV-1 Monitor polymerase chain reaction (PCR) assay from Hoffmann-La Roche Inc. was approved for quantification of HIV-1 plasma viral load for diagnosis/prognosis of the status of HIV-1 infection.
  
• A pump spray called "Public Places" and "D-125" concentrate from Microgen, Inc. became the first products to receive approval in the U.S. for hepatitis B virus surface disinfection.
  
• New HIV diagnostics approved included: the OraSure HIV-1 Western Blot Kit, the first oral HIV diagnostic kit, from Epitope, Inc. and SmithKline Beecham Corp.; Confide, the first home/patient use HIV diagnostic assay, from Direct Access Diagnostics and Chiron Corp.; and Calypte HIV-1 Urine EIA, the first urine-based HIV antibody detection assay.
  
• Twinrix, a combination hepatitis A/B vaccine, from SmithKline Beecham Biologicals was approved in the European Union.

Encouraging clinical trial reports included:

• The HIV protease inhibitors in later stages of development demonstrated significant indications of efficacy, particularly decreases in viral load and increases in CD4+ T-cell count, when used in combination with conventional nucleoside analogs.
  
• Most HIV protease inhibitors in combination with nucleoside analog reverse transcriptase inhibitors have shown the ability to reduce HIV plasma viral load below detectable levels. Also, a non-nucleoside reverse transcripase inhibitor, delavirdine mesylate (Rescriptor), from Pharmacia & Upjohn Inc. in combination with nucleosides also reduced viral load below detectable levels.
  
• Several studies demonstrated that combination treatment with reverse transcriptase inhibitors and HIV protease inhibitors can decrease HIV in the lymphatic system to below detectable levels, suggesting that it may be possible to eradicate HIV-infection.
  
• HIV plasma viral load has quickly been adopted as a surrogate marker for predicting survival and following progression of HIV-infection along with CD4+ T-cell counts.
  
• Thymosin alpha 1 (Zadaxin) from SciClone Pharmaceuticals showed efficacy for treatment of chronic hepatitis B in a number of international trials and has received approval in China and other major Asian markets.
  
• 3TC (Epivir) from Glaxo Wellcome PLC and BioChem Pharma Inc. demonstrated clinical efficacy, and became the largest selling anti-HIV drug.
  
• Famciclovir (Famvir) from SmithKline Beecham Corp. showed safety and efficacy for treatment of chronic hepatitis B in a large international trial.
  
• Lamivudine (3TC) from Glaxo Wellcome Co. and BioChem Pharma Inc. showed indications of efficacy for treatment of chronic hepatitis B and for prophylaxis of recurrent hepatitis B in liver transplant recipients.
  
• Thymosin alpha 1 (Zadaxin) from SciClone Pharmaceuticals, Inc. in combination with alpha-2b-interferon (Intron A) showed better efficacy than interferon monotherapy for treatment of chronic hepatitis C.
  
• TA-GW, a human papillomavirus vaccine for treatment of genital warts, from Cantab Pharmaceuticals PLC became the first genital warts vaccine to enter clinical trials and showed safety and indications of efficacy.
  
• AndroVir, an oral plant-derived HIV protein-tyrosine kinase inhibitor drug, showed safety and indications of efficacy in an early trial.
  
• HNK20, a monoclonal antibody specific for respiratory syncytial virus (RSV) F glycoprotein, in a nose drop formulation from OraVax, Inc. showed indications of efficacy for prevention of RSV infection in infants.
  
• A live recombinant intranasal influenza vaccine from Aviron, Inc. and NIAID showed efficacy in a Phase II trial in adults and entered pivotal Phase III pediatric clinical trials.
  
• New data analyses from a clinical trial that tested AZT for prevention of maternal transmission of HIV-infection demonstrated the efficacy and importance of AZT prophylaxis, irrespective of the HIV-infected mother's immune status or HIV plasma viral load.
  
• AR177 (Zintevir), the first HIV integrase enzyme inhibitor to enter clinical trials, from Aronex Pharmaceuticals, Inc. was found safe with a good pharmacokinetic profile in primate studies and a Phase I clinical trial.
  
• Interleukin-2 (Proleukin) from Chiron Corp. showed efficacy for treatment of HIV-infection, including boosting CD4+ T-cell counts for several years and doubling CD4+ T-cell counts for over one year.
  
• A Phase III trial showed that a recombinant herpes simplex virus type 2 subunit vaccine from Chiron Corp. had efficacy in some respects comparable to that of available drugs for treatment of recurrent genital herpes (but no effects were observed on the trial's main endpoints).
  
• A Phase III clinical trial showed that thymosin alpha 1 (Zadaxin) from SciClone Pharmaceuticals in combination with AZT and alpha-interferon can improve the immune status of HIV-infected patients.
  
• GS 840 (adefovir dipivoxil) from Gilead Sciences, Inc. demonstrated indications of efficacy for treatment of chronic hepatitis B.
  
• Intravenous WF10 (tetrachlorodecaoxygen; Oxoferin) from Dimethaid Research Inc. showed indications of efficacy for treatment of HIV-infection.
  
• Intravitreal ISIS 2922 (fomivirsen), a cytomegalovirus (CMV) antisense oligonucleotide, showed safety and indications of efficacy for treatment of CMV retinitis.
  
• TA-HPV, an immunotherapeutic human papillomavirus vaccine, from Cantab Pharmaceuticals PLC demonstrated safety and specific immune responses in an early clinical trial.
  
• Topical cidofovir gel from Gilead Sciences, Inc. demonstrated indications of efficacy for treatment of genital warts due to human papillomavirus.
  
• DMP 266, a non-nucleoside reverse transcriptase inhibitor, from DuPont Merck Pharmaceutical Co. in combination with indinavir sulfate, an HIV protease inhibitor, showed indications of efficacy for treatment of HIV-infection.
  
• The first clinical trial using a combination of two HIV protease inhibitors, saquinavir (Invirase) from Hoffmann-La Roche Inc. and ritonavir (Norvir) from Abbott Labs., showed indications of efficacy.
  
• Amantadine (Symmetrel) from DuPont Merck Pharmaceuticals, a drug marketed for treatment of influenza A, showed indications of efficacy for treatment of chronic hepatitis C.
  
• Theradigm-HBV, a synthetic hepatitis B virus immunotherapeutic vaccine, from Cytel Corp. showed safety, induced immune responses and may be particularly useful in combination with other drugs for treatment of chronic HBV.
  
• Oral GS 840, a prodrug of PMEA, from Gilead Sciences, Inc. showed indications of efficacy for treatment of HIV-infection.
  
• A live attenuated rotavirus vaccine from the Virus Research Institute demonstrated safety and immunogenicity in an early trial.
  
• 141W94 (VX-478), a nonpeptidic HIV protease inhibitor, from Glaxo Wellcome Co. and Vertex Pharmaceuticals showed promise for treatment of HIV-infection in combination with nucleoside analogs.
  
• 1592U89, a nucleoside analog reverse transcriptase inhibitor, from Glaxo Wellcome Co. showed promise in early trials for treatment of HIV-infection and may be positioned to replace AZT.
  
• The efficacy of AZT for prevention of HIV-infection in exposed healthcare workers was further established.
  
• Verex Laboratories, Inc. reported good results with Aztec, a controlled release formulation of AZT, compared with regular AZT; and both Verex and Glaxo Wellcome face difficult AZT patent infringement, enforcement and marketing decisions.
  
• The first combination cytokine trial in HIV-infected patients, testing gamma-1b-interferon from Genentech, Inc. and interleukin-2 from Chiron Corp., demonstrated indications of efficacy for treatment of HIV-infection.
  
• Development of resistance and cross-resistance to HIV protease inhibitors turned out not to be as serious a near-term concern as many feared, but long-term efficacy remains to be documented.
  
• Famciclovir from SmithKline Beecham Corp. showed efficacy for treatment of genital herpes in HIV-infected patients.
  
• Hydroxyurea from Bristol-Myers Squibb Co. (BMS) in combination with DDI (Videx; also from BMS) showed indications of efficacy for treatment of HIV-infection.
  
• An HIV immunotherapeutic antibody (MDX-240) from Medarex, Inc. showed promise in a Phase I trial.
  
• VP 63843 from ViroPharma, Inc. showed indications of efficacy for treatment of enteroviral diseases.
  
• Bio-Hep B hepatitis B vaccine from BioTechnology General showed improved immunogenicity in newborns compared with other recombinant hepatitis B vaccines.
  
• IOT4a (Anti-CD4-Clone), an immunotherapeutic HIV idiopathic antibody directed against CD4, showed indications of efficacy.
  
• Kynostatin, an HIV protease inhibitor, from Japan Energy Co., Ltd. showed indications of efficacy in early trials.
  
• Reticulose, a peptide nucleic acid, from Advanced Viral Research Corp. showed indications of efficacy and entered new trials for treatment of HIV-infection, but regulatory problems persist.
  
• A7-183, an acyclovir prodrug, from Drug Innovation and Design Inc. showed indications of efficacy for treatment of oral herpes.
  
• Combinations of saquinavir (Invirase) and DDC (Hivid), both from Hoffmann-La Roche Inc., demonstrated a significant survival advantage in HIV-infection.
  
• Up to six years of follow-up of the original recipients of the inactivated HIV core immunotherapeutic vaccine (Remune) from Immune Response Corp. and early results from Thai clinical trials show that the vaccine induces specific immune responses.
  

New and ongoing clinical trials included:

• Nelfinavir mesylate, an HIV protease inhibitor, from Agouron Pharmaceuticals, Inc. entered pivotal Phase II/III monotherapy trials.
  
• Cidofovir Eyedrops from Storz Instruments Co. and Gilead Sciences, Inc. entered trials for non-cytomegalovirus (e.g., adenovirus, herpes keratitis) eye infections.
  
• A hammerhead ribozyme gene therapy from Gene Shears Pty. Ltd. entered clinical trials for treatment of HIV-infection.
  
• HIV-1 Rev M10 gene therapy transformation of hematopoietic stem cells from SyStemix, Inc. and Novartis AG entered the first clinical trial using hematopoietic stem cells for gene therapy against HIV-infection.
  
• GEM 132, a cytomegalovirus antisense oligonucleotide, from Hybridon, Inc. entered clinical trials.
  
• An HIV-1 "facilitated DNA injection" prophylactic vaccine from Apollon, Inc. entered clinical trials.
  
• A herpes simplex virus "facilitated DNA injection" vaccine from Apollon, Inc. entered clinical trials for prevention and treatment of genital herpes.
  
• The "prime-plus-boost" HIV vaccine approach using a live canarypox virus vector HIV-1 vaccine from Connaught Labs. followed by an HIV-1SF gp120 vaccine from Chiron Corp. was one of the few HIV prophylactic vaccine protocols to advance into efficacy trials.
  
• Clinical trials with Protovir, a humanized cytomegalovirus (CMV) antibody, from Protein Design Labs. continued, despite one CMV retinitis trial being suspended for lack of efficacy.
  
• HNK20, a nosedrop formulation of a monoclonal antibody specific for respiratory syncytial virus, from OraVax, Inc. entered Phase III trials for prevention of RSV disease in high-risk infants.
  
• MEDI-493, a humanized respiratory syncytial virus monoclonal antibody, from MedImmune, Inc. entered Phase III trials for prevention of RSV disease in high-risk infants.
  
• Human Anti-Hepatitis B Antibody (OST 577), a humanized hepatitis B antibody, from Protein Design Labs. and Boehringer Mannheim GmbH entered multinational trials for treatment of chronic hepatitis B.
  
• Cytolin, a murine monoclonal antibody directed against CD8+ lymphocytes, from CytoDyn, Inc. entered FDA-approved clinical trials for treatment of HIV-infection.
  
• Topical cidofovir gel from Gilead Sciences, Inc. entered trials for treatment of anogenital warts due to human papillomavirus.
  
• PMPA from Gilead Sciences, Inc. entered clinical trials for treatment of HIV-infection.
  
• NIAID, after years of delay, began a large trial using various formulations of low-dose oral (LDO) alpha-interferon for treatment of HIV-infection.
  
• Reticulose, a peptide nucleic acid, from Advanced Viral Research Corp. entered trials for treatment of genital warts.
  
• A recombinant prophylactic HIV vaccine from the Centre for Genetic Engineering and Biotechnology, Cuba, entered clinical trials.
  
• Famciclovir (Famvir) from SmithKline Beecham demonstrated improved efficacy for prevention of recurring genital warts compared with acyclovir and the company initiated clinical trials comparing famciclovir with valacyclovir.
  
• A new injectable, more concentrated formulation of GEM 91, an HIV-1 antisense oligonucleotide drug, from Hybridon, Inc. entered trials.
  
• Oral 2',3'-dideoxy-2'-beta-fluoroadenosine (beta-F-ddA) from U.S. Bioscience, Inc. and NIH entered clinical trials for treatment of HIV-infection.
  
• IDT, Inc. and HemoCleanse, Inc. resumed clinical trials with whole-body extracorporeal hyperthermia for treatment of HIV-infection.
  
• BB-10010, a human MIP-1a variant, from British Biotech Pharmaceuticals, Ltd. entered trials for treatment of HIV-infection.
  
• Virus Research Institute, Inc. and Pasteur Merieux Connaught started clinical trials using an influenza vaccine formulated with Adjumer, a novel adjuvant/controlled release system.
  
• Lidak Pharmaceuticals Inc. started two Phase III trials with topical 10% Lidakol for treatment of oral herpes after other Phase III trials failed to show efficacy (because the placebo showed efficacy).
  
• Trinity Medical Group and Immune Response Corp. started clinical trials with Remune, an inactivated HIV core immunotherapeutic vaccine, in Thailand for HIV-infection.
  
• Cell Genesys, Inc. expanded trials with gene therapy transformed T-cells for treatment of HIV-infection.
  
• The first clinical trials started using Remune, an immunotherapeutic inactivated HIV vaccine, from Immune Response Corp. in combination with anti-HIV drugs.
  
• Oral 1263W94, a benzimidazole riboside compound, from Glaxo Wellcome Co. entered efficacy trials for treatment of cytomegalovirus infection.
  
• Perthon/Abavca, a botanical immune stimulant, from Advanced Plant Pharmaceuticals, Inc. entered efficacy trials for treatment of HIV-infection.
  
• Interferon Sciences, Inc. started a Phase III trial with injectable interferon alfa-n3 for treatment of chronic hepatitis C virus infection.
  
• The United Nations initiated an international Phase III study of Advantage 24 (slow-release nonoxynol-9) from Columbia Laboratories, Inc. for prevention of heterosexual transmission of HIV.
  
• Interleukin-10 (IL-10) from Schering-Plough Corp. entered trials for treatment of HIV-infection.
  
• Cytomegalovirus plasma viral load is showing promise to guide prophylactic drug treatments against cytomegalovirus retinitis.
  
• NABI started clinical trials with a new intramuscular formulation of H-BIG Hepatitis B Immune Globulin [Human] IM 5% (H-BIG).

Encouraging research and preclinical results included:

• Fusin was identified as a cofactor for the entry of HIV-1 into T-cell tropic strains of HIV-1 (CD4+ T-cells).
  
• CC-CKR-5 was shown by multiple research teams to be a cofactor for fusion and entry of HIV virions into macrophage-tropic strains of HIV into macrophages (which have surface CD4 receptors). Mutations in CC-CKR-5, found more frequently in some races, were shown to provide protection against HIV-infection.
  
• The undetectable HIV plasma and lymph viral loads observed with various HIV reverse transcriptase and protease inhibitor combinations raised hope that it may be possible to eradicate HIV from infected patients.
  
• Gilead Sciences, Inc. demonstrated that antisense oligonucleotides as short as seven base units have in vitro efficacy.
  
• Researchers from Vertex Pharmaceuticals Inc. and Agouron Pharmaceuticals Inc. published the three-dimensional structure of the hepatitis C virus NS3 protease enzyme.
  
• The herpesvirus entry mediator (HVEM) cellular receptor was isolated and cloned.
  
• Researchers isolated and cultured Kaposi's sarcoma herpesvirus (KSHV; human herpesvirus-8); and reports further linked KSHV as the cause of Kaposi's sarcoma.
  
• HIV Rev M10 gene therapy was shown to increase resistance to HIV-infection in transformed CD4+ T-cells removed from HIV-infected patients.
  
• An easily modified form of a milk protein, bovine beta-lactoglobulin, showed significant anti-HIV activity.
  
• The poxvirus that causes molluscum contagiosum was cloned and sequenced.
  
• HGP-30, an HIV p17 peptide vaccine, from CEL-SCI Corp. demonstrated "the most significant protective immune response against HIV challenge observed with a potential HIV vaccine to date" in SCID mice.
  
• PMPA from Gilead Sciences, Inc. demonstrated 100% protection against vaginal transmission of simian immunodeficiency virus (SIV) in primates.
  
• Cholic acid, a bile acid, administered intravaginally in mice provided 80% protection against genital herpes.
  
• A fungal peptidoglycan, MMS1, from International Gene Group, Inc. demonstrated activity against murine acquired immunodeficiency syndrome (MAIDS).
  
• Soothing music was reported to increase secretory immunity.
  

Encouraging Developments - Other encouraging news and trends

Other encouraging news and trends included:

• Within several months of its approval, 3TC from Glaxo Wellcome PLC (and BioChem Pharma Inc.) became the largest-selling anti-HIV drug, demonstrating the ability of the medical establishment to quickly adopt new HIV therapies.
  
• Various Internet Web sites are providing access to useful antiviral, HIV and virus-related information, much of it not previously or readily available.
  
• Cytotoxic T lymphocytes were shown to have some unexpected properties that may be adaptable for treatment of viral infections.
  
• AIDS-related, but not antiviralÑDaunoXome, a liposomal formulation of daunorubicin from NeXstar Pharmaceuticals Inc. was approved for Kaposi's sarcoma; and Serostim (recombinant human growth hormone) from Serono Laboratories, Inc. was approved for treatment of AIDS-related cachexia (wasting).
  
• The first comprehensive small animal model for HIV dementia was reported by researchers from the Univ. of Nebraska Medical Center.
  
• Hepatitis A Vaccine, Inactivated (Havrix) from SmithKline Beecham Corp. halted an epidemic in Alaska.
  
• The CDC's recommendations for the influenza virus vaccine antigen composition for the 1996-1997 influenza season were on target.
  
• NIAID and others are developing live attenuated prophylactic HIV vaccines, including HIV vectors that confer susceptibility to thymidine kinase inhibitor drugs.
  
• HLA or major histocompatibility complex (MHC) class I markers on the surface of cells were shown to affect progression of HIV-infection.
  
• Safe sex promotional programs in Thailand are reducing new HIV infections, but this may make prophylactic vaccine testing more complicated.
  
• Hybridon, Inc. completed a plant capable of producing over 1,000 kilograms (one million grams) of synthetic DNA and RNA products annually.

Discouraging Developments - Approvals denied, trials or development suspended, etc.

Discouraging Developments

Approvals denied, trials or development suspended, etc.:

• VaxSyn HIV-1, an immunotherapeutic HIV-1 gp160 vaccine, from MicroGeneSys, Inc. failed to show efficacy and development was halted.
  
• Chiron Corp. halted development of its recombinant herpes simplex virus type 2 subunit vaccine after Phase III clinical trials for genital herpes prophylaxis failed to show efficacy. Development of a cytomegalovirus subunit vaccine was placed on hold.
  
• British Biotech Pharmaceuticals halted development of HIV p17/p24:Ty-VLP, a recombinant virus-like particle (VLP) HIV immunotherapeutic vaccine, after clinical trials failed to show efficacy.
  
• The FDA failed to approve oral sorivudine (Usevir; BV-araU) from Bristol-Myers Squibb Co. for treatment of herpes zoster (shingles), citing concerns about risk for death due to its interaction with 5-fluorouracil, a drug used for cancer treatment.
  
• The Antiviral Drugs Advisory Committee, FDA, failed to recommend approval of delavirdine mesylate (Rescriptor), a non-nucleoside HIV reverse transcriptase inhibitor (NNRTI), from Pharmacia & Upjohn, Inc., leaving the final decision to FDA.
  
• Authorities are investigating allegations of misconduct in trials in India involving use of a live attenuated bovine immunodeficiency virus (BIV) vaccine from Sylka Managing Co. Inc. as an HIV immunotherapeutic.

Discouraging Developments - Discouraging clinical trial reports

Discouraging clinical trial reports included:

• A Phase III trial with topical 10% Lidakol (n-docosanol) cream from Lidak Pharmaceuticals failed to show efficacy for treatment of oral herpes simplex virus type 1, after the placebo vehicle unexpectedly showed efficacy.
  
• SPV-30, an extract from the European boxwood tree, from Arkopharma Labs. failed to show efficacy for treatment of HIV-infection.
  
• Curcumin, the substance in the spice tumeric (used in curries) that provides its yellow color, failed to show efficacy for treatment of HIV-infection.
  
• Cimetidine (Tagamet, commonly used for ulcers) from SmithKline Beecham Corp. (Philadelphia, PA) failed to show efficacy for treatment of HIV-infection.
  
• Routine vaccinations and immune activation in general were associated with increases in HIV plasma viral load in HIV-infected patients.
  
• A nurse was found guilty of scientific misconduct for allowing ineligible patients to enroll in NIAID-supported clinical trials.
  
• Contrary to its effects in vitro, interleukin-12 was shown to decrease natural killer cell cytotoxicity in HIV-infected patients.

Discouraging Developments - Other discouraging news and trends

Other discouraging news and trends included:

• Studies with SIV strongly indicate that HIV may be transmitted orally, particularly by receptive oral-genital contact; and the throat was shown to be a major site for HIV replication.
  
• An upcoming issue in treatment of HIV-infection will be how low and for how long should HIV plasma (and lymph node) viral load be lowered.
  
• Supply shortages and distribution problems and related activist protests were encountered with indinavir, a new HIV protease inhibitor from Merck & Co.
  
• Widespread HIV-1 infection of CD8+ T-cells was reported in AIDS patients, contradicting the belief that these cells are not susceptible to HIV-infection.
  
• The first case of acute hepatitis E virus infection acquired in the U.S. was reported.
  
• A physician's experience with treating HIV-infected patients was shown to strongly influence patient survival, indicating that nonspecialist physicians may not be the best choice for treating HIV-infected patients.
  
• Rhesus monkeys administered progesterone became more susceptible to intravaginal infection with simian immunodeficiency virus (SIV), suggesting that commonly used contraceptives containing progestins may add risk for women sexually exposed to HIV.
  
• AIDS treatment activists and other groups continue to sporadically protest the relatively high prices and price increases for many of the drugs currently available for treatment of HIV-infection.
  
• Warner-Lambert Co. voluntarily recalled much of its influenza vaccine because of insufficient potency.
  
• Controversies over polio vaccines continue, including protests of the change to a vaccination schedule using both inactivated and oral live poliovirus vaccines, and calls to halt the use of monkey kidney tissues for culture of poliovirus vaccine strains due to concerns about contaminating primate retroviruses.
  
• ACT-UP San Francisco, an ACT-UP splinter group, staged a disruptive and violent protest at the International Conference on AIDS.
  
• Some have accused Glaxo Wellcome of slow development of 1592U89, a highly potent nucleoside analog for treatment of HIV-infection, particularly compared with the development of AZT and 3TC.
  
• Combinations of delavirdine (Rescriptor) from Pharmacia & Upjohn with HIV protease inhibitors can lead to serious adverse reactions and toxicity.
  

Corporate and Federal Activities - Corporate linkages and collaborations

Corporate and Federal Activities

Corporate linkages and collaborations included:

• Medivir AB linked with Abbott Labs. for development of drugs for HIV-infection, varicella-zoster virus and herpes simplex virus infections.
  
• LeukoSite, Inc. and Warner-Lambert Co. linked for development of drugs that block the CCR-5 receptor for treatment of HIV-infection.
  
• Genentech, Inc. spun-off a new company, Genenvax, Inc., to develop prophylactic HIV vaccines.
  
• BioChem Pharma Inc. and Oncogene Science Inc. linked for the development of drugs for treatment of hepatitis C virus and HIV infections.
  
• ViroPharma, Inc. and Chiroscience Ltd. linked for discovery and screening of drugs for treatment of hepatitis C virus infection and "newly emerging viral pathogens," such as ebola, dengue and hantavirus.
  
• Pasteur Merieux Serums et Vaccines expanded its naked DNA vaccine collaboration with Vical Inc.
  
• NeXstar Pharmaceuticals Inc. linked with Boehringer Mannheim Therapeutics for development and marketing of an oral lipid conjugate of the drug foscarnet for treatment of cytomegalovirus retinitis.
  
• Gilead Sciences, Inc. linked with Hoffmann-La Roche Ltd. for development and marketing of drugs for treatment and prevention of influenza virus infection, including GS 4104, an orally administered neuraminidase inhibitor from Gilead.
  
• Cantab Pharmaceuticals PLC linked with SmithKline Beecham Biologicals for the development and marketing of Cantab's TA-GW recombinant human papillomavirus genital warts vaccine.
  
• Chiron Corp. linked with General Injectables & Vaccines, Inc. for marketing of its vaccines.
  
• Enzo Biochem Inc. linked with the Albert Einstein College of Medicine for hepatitis B gene therapies.
  
• The Aaron Diamond AIDS Research Center, "the largest private HIV/AIDS research center in the world," affiliated with Rockefeller University.
  
• About forty public and private organizations formed the Forum for Collaborative HIV Research to "facilitate and coordinate" studies with combination therapies.
  
• A number of organizations and individuals formed the International AIDS Vaccine Initiative, affiliated with Rockefeller Foundation, to promote development of HIV prophylactic vaccines.
  
• Innovir Laboratories, Inc. linked with the Scripps Research Institute for evaluation of hepatitis B virus antisense drugs in specialized animal models.
  
• Hoffmann-La Roche Inc. and Gilead Sciences, Inc. linked for co-promotion of Roche's alpha-2a-interferon (Roferon A) for treatment of hepatitis C in the U.S.
  
• CEL-SCI Corp. linked with the Northeastern Ohio Universities College of Medicine for development of a herpes simplex virus vaccine.
  
• Quidel Corp. and Glaxo Wellcome Co. (Research Triangle Park, NC) linked for development of rapid, point-of-care diagnostics for influenza A and B viruses.
  
• SmithKline Beecham Corp. linked with Arris Pharmaceutical Corp. for screening and development of antiviral protease inhibitors.
  
• SRA Technologies, Inc. and Albany Medical Center linked for development of methods for antiviral and other drug screening and preclinical testing.
  
• Solvay Pharmaceuticals, Inc. linked with SmithKline Beecham Corp. for co-promotion of SKB's famciclovir (Famvir) for treatment of genital herpes.
  
• T Cell Sciences, Inc. and ArQule, Inc. linked for discovery and development of small molecule drugs for T-cell activation and suppression.
  
• HemispheRx Biopharma Inc. and Helix BioPharma Corp. linked for development of Ampligen for treatment of viral diseases and immune system disorders.
  
• BioChem Pharma Inc. extended its links with XTL Biopharmaceuticals for screening and development of drugs for hepatitis C.

Corporate and Federal Activities - Corporate acquisitions and mergers

Corporate acquisitions and mergers included:

• Ciba-Geigy Ltd. and Sandoz AG merged to form Novartis AG, with the new company retaining control of Genetic Therapy, Inc. and SyStemix, Inc.
  
• Chiron Corp. purchased a 49% share of the human vaccine business (mostly in Europe) of Behringwerke AG.
  
• Cambridge Biotech Corp. sold its retroviral (including HIV-1) diagnostics business to bioMerieux S.A.
  
• VIMRx Pharmaceuticals Inc. acquired Ribonetics GmbH, a company developing antiviral ribozymes, and subsequently acquired controlling interest in Innovir Laboratories, Inc., another company developing antiviral ribozymes.
  
• Warner-Lambert Co. purchased Glaxo Wellcome's interest in their over-the-counter drug joint venture. One of the drugs covered by the joint venture was oral acyclovir for treatment of herpes simplex virus infections.
  
• Cambridge Biotech Corp. went bankrupt and a new company, Aquila Biopharmaceuticals, Inc., took over the company's adjuvant and vaccine lines of business.
  
• Baxter International Inc. initiated acquisition of Immuno International AG.
  
• Watson Pharmaceuticals Inc. acquired Oclassen Pharmaceuticals Inc.

Federal Activities (other than product approvals):

• Following several critical reports, the NIH plans to put more emphasis on prophylactic HIV vaccines and collaboration with industry.
  
• The Centers for Disease Control and Prevention (CDC) recommended a controversial change in U.S. practices for vaccination against polio, from sole use of live Oral Polio Vaccine (OPV) to a sequential schedule of injectable inactivated poliovirus vaccine followed by OPV.
  
• A federal court cleared ICN Pharmaceuticals, Inc. of allegations of securities fraud regarding misleading public statements made in 1986 and 1987 about ribavirin (Virazole) having efficacy for treatment of HIV-infection.
  
• Dr. D. Baltimore, noted virologist and Nobel Prize winner, was appointed to lead the National Institutes of Health prophylactic HIV vaccine research and development efforts.
  

Patents and Technology Transfer - Patent/product licensing activity

• Triangle Pharmaceuticals, Inc., a new company founded by former antiviral researchers with Burroughs Wellcome Co., entered into an option agreement with Mitsubishi Chemical Corp. for development of MKC-422, a non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-infection. Triangle also exclusively licensed rights to three drugs for HIV and hepatitis B indications: (Ð)-FTC licensed from Emory, and CS-92 and DAPD licensed jointly from Emory Univ. and the Univ. of Georgia.
  
• Avid Corp. exclusively licensed DMP 450, a non-peptide cyclic urea HIV protease inhibitor, from DuPont Merck Pharmaceutical Co.
  
• Interferon Sciences, Inc. completed reacquisition of all marketing rights and licensing for its natural leukocyte alpha-interferon (interferon-alfa-n3; Alferon) products.
  
• Pharmacia & Upjohn, Inc. licensed from Gilead Sciences, Inc. marketing rights for Vistide (cidofovir injection) in all countries outside of the U.S.
  
• Glaxo Wellcome and Vertex Pharmaceuticals nonexclusively licensed HIV protease inhibitor patent applications for a total of $25 million from G.D. Searle & Co. to clear the way for development of 141W94.
  
• Amgen Corp. licensed international rights for its consensus interferon (Infergen) to Yamanouchi Pharmaceutical Co., Ltd.
  
• NeXstar Pharmaceuticals Inc. exclusively licensed rights for anti-HIV nucleoside analog lipid conjugate drugs to Boehringer Mannheim Therapeutics.
  
• Bristol-Myers Squibb Co. exclusively licensed from Lidak Pharmaceuticals, Inc., but later returned, rights to Lidakol cream for treatment of oral herpes.
  
• SmithKline Beecham Corp. licensed an Epstein-Barr virus subunit vaccine from Aviron, Inc.
  
• RiboGene, Inc. and Warner-Lambert Co. exchanged options and licenses for anti-HIV ribosomal frameshifting drugs discovered through a collaborative screening program.
  
• CEL-SCI Corp. licensed T-cell Modulation Process technology from Cell Med Inc. for use with its immunotherapeutic HGP-30 HIV p17 core antigen vaccine.
  
• Cantab Pharmaceuticals Research Ltd. took an option to license monophosphoryl lipid A (MPL) from Ribi ImmunoChem Research, Inc. for use in human papillomavirus vaccines.
  
• Enzon, Inc. licensed PEG-alpha-interferon to Schering Corp.
  
• Pasteur Merieux Connaught licensed DC-Cholesterol cationic lipids from RGene Therapeutics, Inc. for use as vaccine adjuvants/delivery vehicles.
  
• Sequus Pharmaceuticals Inc. took an option to exclusively license Liposome-CD4 for treatment of HIV-infection from Sheffield Medical Technologies Inc.
  
• MedImmune Inc. cross-licensed parvovirus vaccine patents with the Univ. of Leiden.
  
• MedImmune, Inc. exclusively licensed human papillomavirus vaccine technology from the German Cancer Research Center.
  
• SciClone Pharmaceuticals, Inc. expanded its long-term licensing agreement with Schering-Plough K.K. for thymosin alpha 1 (Zadaxin) marketing in Japan.
  
• Isis Pharmaceuticals, Inc. reacquired rights to its cytomegalovirus antisense drug, ISIS 2922 (fomivirsen), from Eisai Co. Ltd.
  
• The Univ. of Minnesota clarified its role in the discovery of 1592U89, an HIV reverse transcriptase inhibitor (carbovir compound), being developed by Glaxo Wellcome Ltd.
  

Patents and Technology Transfer - Patent disputes, new and continuing

Patent disputes, new and continuing, included:

• Emory Univ. filed suit against Glaxo Wellcome Co. alleging infringement of a patent covering a pure enantiomer of 3TC, the largest-selling anti-HIV drug.
  
• The U.S. patent office declared an interference between a patent broadly covering ex vivo gene therapy issued to NIH and licensed to Genetic Therapy, Inc. and two pending patent applications.
  
• Schering-Plough Corp. filed suit charging Amgen Corp. with infringement of a patent concerning recombinant alpha interferons assigned to Biogen Inc. and exclusively licensed to Schering.
  
• A U.S. federal court ruled against Hoffmann-La Roche Inc. in a suit brought by Promega Corp. challenging a key patent concerning Taq DNA polymerase used extensively in polymerase chain reaction (PCR) procedures. The court concluded that Cetus Corp., original developer of PCR, obtained the patent through a series of omissions and misstatements to the patent office.
  
• The European Patent Office granted Hoffmann-La Roche Ltd. a key patent covering Taq DNA polymerase, an enzyme used in PCR.

Patent disputes resolved included:

• The U.S. Supreme Court denied considering appeals by two generic drug companies (and NIH) challenging U.S. patents assigned to Glaxo Wellcome Co. covering use of AZT for treatment of HIV-infection. Glaxo Wellcome remains the sole assignee for the main U.S. patents covering use of AZT (Retrovir) for treatment of HIV-infection and AIDS.
  
• Two British patents for hepatitis B virus surface antigens held by Biogen Corp. were ruled invalid as a result of a challenge by Medeva PLC.
  
• Calgene, Inc. was ruled as not infringing antisense gene therapy patents held by Enzo Biochem and key patents held by Enzo and the State Univ. of New York were invalidated.
  
• Chiron Corp. and Ortho Diagnostic Systems, Inc. reached an agreement with International Murex Technologies Corp., settling their long-running international patent disputes over hepatitis C virus immunodiagnostics.
  
• The U.S. patent office ruled in favor of Hoffmann-La Roche Inc. and Genentech, Inc. in an interference proceeding involving recombinant leukocyte interferon.
  
• Chiron Corp. and Ortho Diagnostic Systems Inc. settled a patent infringement dispute out-of-court with Abbott Labs. concerning a patent covering HIV polypeptides.
  
• The European Patent Office ruled in favor of Chiron Corp. in a challenge of a hepatitis C virus antigen patent.
  
• The U.S. federal court upheld a previous arbitration ruling in favor of Biogen Inc. in its dispute with SmithKline Beecham Corp. over royalty rates for Biogen's hepatitis B virus patents.
  
• The U.S. patent office upheld a patent concerning human leukocyte alpha-interferons assigned to Hoffmann-La Roche Inc., ending challenges to this patent which began in 1985 when the Federal Trade Commission began an investigation into the licensing by Roche of its interferon patents to Schering-Plough Corp.
  
• The merger between Ciba-Geigy Ltd. and Sandoz AG to form Novartis AG required the new company to license out key gene therapy technologies.