As of 2008, that is, 25 years after the discovery of HIV as the causative agent of AIDS Citation[1–3], exactly 25 compounds had been officially approved for the treatment of AIDS Citation[4,5].
Then, in 2009, we commemorated what could be considered the 50th anniversary of the start of antiviral chemotherapy – that is following the synthesis 50 years ago of 5-iodo-2´-deoxyuridine (IDU) Citation[6], which would later become the first antiviral drug to be licensed for clinical use Citation[7]. IDU is still used in eye drops or as an ointment for the topical treatment of herpetic eye infections.
This year, 2010, marks another anniversary: 25 years ago since azidothymidine (AZT; zidovudine, Retrovir®) was first described as an antiretroviral agent Citation[8]. Then, in 1987 it became the first drug to be specifically approved for the treatment of AIDS Citation[9].
Now, 50 years after the first antiviral drug was described, there are approximately 50 antiviral compounds approved by the US FDA. Half of these compounds are for the treatment of HIV infections; the other half are for the treatment of herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus, hepatitis B virus (HBV) and hepatitis C virus (HCV) and influenza A virus infections.
HIV infections
For the treatment of HIV infections, we now have 25 approved anti-HIV drugs Citation[4,5]. The explosion of anti-HIV drugs could hardly be foreseen when AZT was reported in 1985 Citation[8]. AZT was far from ideal, but it launched the search for newer compounds with increased potency and safety, thereby divulging new targets and options for therapy. The result of these endeavors was phenomenal: 25 compounds within 25 years: nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine (a brief history on the discovery of stavudine Citation[10] and NRTIs in general can be found elsewhere Citation[11]); one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir disoproxil fumarate (TDF, Citation[12]); four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, efavirenz and etravirine (recent review on NNRTIs can be found elsewhere Citation[13]); ten protease inhibitors (PIs): saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir; one fusion inhibitor: enfuvirtide; one coreceptor inhibitor: maraviroc; and one integrase inhibitor (INI): raltegravir (the significance of integrase strand-transfer inhibitors in antiretroviral therapy is discussed elsewhere Citation[14]).
The treatment of HIV infections has brought about a barely explored antiviral strategy, that is combination therapy, particularly between an NRTI, an NtRTI and either a PI or a NNRTI. A fixed-dose triple drug combination is Atripla®, a single pill (to be taken daily) combining one NRTI, one NtRTI, one NNRTI and another fixed-dose combination, the quadruple combination in a single pill, such as one containing the NtRTI TDF, the NRTI emtricibatine, the INI elvitegravir and a booster, cobicistat, is forthcoming.
HBV infections
Hepatitis B virus replicates through a similar reverse transcription step (catalysed by a similar RNA-dependent DNA polymerase) as HIV. In addition HBV is transmitted by the same routes as HIV, that is, parenterally, sexually, or perinatally (from mother-to-child). Of essence, TDF (Viread®) Citation[12,15,16] has recently been approved for the treatment of HBV infections, thus bringing the total number of licensed anti-HBV drugs, besides interferon, to five (lamivudine, adefovir dipivoxil, entecavir, telbivudine and TDF). While drug combination is the ‘standard’ care for the treatment of HIV infections, this procedure has not (so far) received wide acceptance for the treatment of HBV infections. TDF (at a dose of 300 mg/day) has proven more efficacious than adefovir dipivoxil (at a dose of 10 mg/day) in the treatment of chronic hepatitis B Citation[17].
HCV infections
In the case of HCV infections, the prospects of eradicating the virus from its reservoirs should, in theory, be better than for HBV or HIV infections, given that HCV, as an RNA virus, does not have a proviral DNA hideaway (as do retroviruses, such as HIV, or hepadnaviruses, such as HBV). Standard care for chronic hepatitis C currently exists of (pegylated) interferon combined with ribavirin Citation[18], efforts are currently underway in the pharmaceutical industry Citation[18], aimed at developing HCV inhibitors that are targeted at HCV-specific enzymes such as the viral protease and viral RNA-dependent RNA polymerase Citation[19].
A new antiviral strategy specifically intended to treat HCV infections is based upon cyclophilin inhibitors Citation[20], including the nonimmunosuppressive cyclosporine A analogue, Debio 025 (alisporivir), which is currently in Phase IIb development, and which could become part of the future standard care for hepatitis C.
Influenza virus infections
Recent progress in the chemotherapy or prophylaxis of influenza virus infections has not been as impressive as for HIV, HBV or HCV infections, despite the continuous reminders of the importance of seasonal influenza A H3N2 and H1N1 epidemics, the avian influenza H5N1 threat and the recent swine influenza A H1N1 outbreak (‘pandemic’). Neuraminidase inhibitors oseltamivir (Tamiflu®) and zanamivir (Relenza®) have remained the ‘standard’ antiviral drugs for the treatment of influenza virus infections Citation[21,22].
A novel swine-origin influenza A virus S-OIV was identified as the cause of outbreaks of febrile respiratory infection ranging from self-limited to severe illness Citation[23]. It is likely that the number of confirmed cases is an underestimation. A triple-reassortant strain was identified in specimens from patients with infection with triple-reassortant swine influenza viruses before the current epidemic of human infection with S-OIV Citation[24].
It is hard to predict how S-OIV, avian influenza and/or other influenza A epidemics will evolve in the near, let alone, distant future. Continuous vigilance is warranted, and, as a standard precaution, neuraminidase inhibitors (e.g., oseltamivir) ought to be considered to block the virus infection and prevent its spread.
Dengue virus
The WHO has estimated that 40–100 million people are infected each year with Dengue viruses (any of the four serotypes), in the worst cases resulting in dengue hemorrhagic fever and dengue shock syndrome. In the absence of any vaccine, the rapid development of chemotherapeutics is urgently needed, but despite this urgency, and the multitude of approaches that are being considered Citation[25], we are still eagerly waiting for a druggable product to treat Dengue virus infections.
Future perspective
There are at present approximately circa 50 antiviral drugs available, half of them for the treatment of HIV infections. Combination of anti-HIV drugs has made AIDS a treatable chronic disease. While for chronic hepatitis B, treatment is generally based on monotherapy, the treatment of hepatitis C will again be driven by multiple drug combinations, initially containing ribavirin and (pegylated) interferon. Treatment of influenza virus remains governed by neuraminidase inhibitors, and for the treatment of hemorrhagic fever virus infections, such as Dengue, antiviral drug strategies are being developed. Where the viral disease cannot be controlled by vaccination, such as AIDS, the prophylactic use of anti-HIV agents could have a profound global impact on the spread of the disease.
Table 1. Antiviral drugs approved by the US FDA.
Acknowledgements
The author would like to thank Mrs Christiane Callebaut for her proficient editorial assistance.
Financial & competing interests disclosure
The author is co-discoverer of tenofovir. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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