Medscape Awards in Infectious Diseases: Most Important Antiviral Agent

John G. Bartlett, MD

Disclosures

June 12, 2013

Editor's Note: This is the fourth installment of the Medscape Awards in Infectious Diseases, a series that honors the greatest achievements in the field of infectious diseases. In this article, John G. Bartlett, MD, Professor of Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, offers his choice for the most important antiviral agent developed since 1980.

Candidates for the Most Important Antiviral Agent

Many important antiviral drugs have been developed since 1980. The following are the candidates for our award.

Acyclovir. This drug is historically seen as the "father of antiviral therapy." Early studies were conducted by Gertrude Elian,[1] who received a Nobel Prize for the work in 1988. This drug and its relatives have become standards for the treatment of infections caused by herpes simplex and herpes zoster, following the now-classic studies of Rich Whitley in 1982.[2] Concerns about this drug are its inability to eradicate herpes simplex or varicella zoster viral infections.

Lamivudine (3TC). This drug is arguably the most commonly used drug in the world for hepatitis B virus (HBV) (with which 240 million people are chronically infected globally) and HIV (with which 34 million are infected globally). Global use of lamivudine is huge because it is inexpensive and nontoxic, and it has been given for common infections for decades.[3] Concerns about this drug are its inability to achieve cure of either HBV or HIV and resistance.

Oseltamivir. Influenza is the most feared agent of a global pandemic. Oseltamivir is the major antiviral drug for treatment and prevention, with in vitro activity against influenza B and A strains, including most H1N1, H3N2, N5N1, and the more recent H7N9 strains. It is now recommended by the Centers for Disease Control and Prevention for virtually all patients with influenza who are hospitalized or at high risk for complications.[4] Concerns about oseltamivir are its modest clinical benefit and the potential for rapid resistance (eg, the 274Y mutation), as seen in the 2007-2008 season with influenza A (H1N1), when use of the drug was not generally advocated because the resistant strain was the epidemic strain.

Azidothymidine (AZT). Also known as zidovudine, AZT was the first US Food and Drug Administration (FDA)-approved drug for HIV infection, and it was subsequently proven to effectively prevent perinatal transmission of HIV in the famous ACTG 076 trial.[5] Concerns about AZT are toxicity, resistance, and the fact that it is no longer recommended in most national guidelines for HIV care, but its place in history as the first anti-HIV agent should be recognized.

Indinavir. The HIV protease inhibitor indinavir was the critical "third drug" used in the now-famous Merck 035 trial[6] that launched the highly active antiretroviral therapy era, as announced at the 1996 International HIV Conference in Vancouver. This represented the turning point of the HIV epidemic, with clinical and virologic results that were close to those achieved 25 years later: 80% of patients reached a viral load < 50 copies/mL at 48 weeks, compared with no recipients of AZT/3TC or indinavir (alone). Concerns are the now-standard use of alternative drugs as a result of associated toxicity and the frequent dosing requirement of indinavir.

Interferons. These drugs are cytokines that mediate the antiviral activity of host cells. A wide range of viruses are susceptible to interferons, so their potential uses, on the basis of clinical trials, are broad: HBV, hepatitis C virus (HCV), human papillomavirus, HIV, herpes viruses, influenza, respiratory syncytial virus, and coronavirus. Particularly important is the observation that interferon was the first antiviral drug that was effective in the treatment of HCV infection in 1991; this disease is now the most common cause of end-stage liver disease, need for liver transplantation, and death due to liver disease in the United States.

Two decades after the introduction of interferons, it is becoming clear that HCV will be a curable disease for most infected patients. Although interferons are still a standard treatment for HCV, they will soon be antiquated. The major concerns about interferon are the toxic-to-therapeutic ratio and the fact that interferon's unique mechanism of action did not actually launch the current HCV drug avalanche.

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