ABSTRACT
At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as (S)-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John's first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (i), TDF and TAF for the treatment of hepatitis B (HBV) infections (ii), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections (iii).
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Tenofovir/therapeutic use , Alanine/therapeutic use , Anti-HIV Agents/history , Drug Therapy, Combination , Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/history , Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/therapeutic use , HIV/drug effects , HIV Infections/history , HIV Infections/prevention & control , Hepatitis B/drug therapy , History, 20th Century , History, 21st Century , Humans , Pre-Exposure Prophylaxis , Reverse Transcriptase Inhibitors/history , Reverse Transcriptase Inhibitors/therapeutic use , Tenofovir/analogs & derivatives , Tenofovir/historyABSTRACT
HIV/AIDS not only represents the most severe epidemic in modern times, but also the greatest public health challenge in history. The response of the scientific community has been impressive and in just a few years, turned an inevitably fatal disease into a chronic manageable although not yet curable condition. The development of antiretroviral therapy is not only the history of scientific advancements: it is the result of the passionate 'alliance' towards a common goal between researchers, doctors and nurses, pharmaceutical industries, regulators, public health officials and the community of HIV-infected patients, which is rather unique in the history of medicine. In addition, the rapid and progressive development of antiretroviral therapy has not only proven to be life-saving for many millions but has been instrumental in unveiling the inequities in access to health between rich and poor countries of the world. Optimal benefits indeed, are not accessible to all people living with HIV, with challenges to coverage and sustainability in low and middle income countries. This paper will review the progress made, starting from the initial despairing times, till the current battle towards universal access to treatment and care for all people living with HIV.
Subject(s)
Anti-Retroviral Agents/history , HIV Infections/drug therapy , Antiretroviral Therapy, Highly Active/history , Developed Countries , Developing Countries , Dideoxynucleosides/history , HIV Protease Inhibitors/history , History, 20th Century , History, 21st Century , Humans , Reverse Transcriptase Inhibitors/historyABSTRACT
The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogues for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A number of previously synthesized nucleoside analogues were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clinical evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
Subject(s)
Dideoxynucleosides/history , Dideoxynucleosides/pharmacology , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/history , Reverse Transcriptase Inhibitors/pharmacology , Stavudine/history , Stavudine/pharmacology , Dideoxynucleosides/therapeutic use , HIV Reverse Transcriptase/antagonists & inhibitors , History, 20th Century , History, 21st Century , Humans , Reverse Transcriptase Inhibitors/therapeutic use , Stavudine/therapeutic use , United StatesABSTRACT
It is almost 20 years since NNRTIs were identified as a new class of antiretroviral drugs for the treatment of HIV-1 infection. Although they belong to different and diverse chemical families, they share a common and unique mechanism of action: their interaction with HIV-1 reverse transcriptase induces conformational changes that inhibit the catalytic activities of the enzyme. They are characterized by their specificity for HIV-1, which makes them very selective inhibitors of the virus. First generation NNRTIs nevirapine and efavirenz, in combination with other antiretroviral drugs, have become a cornerstone for the treatment of HIV-1 infection, in patients initiating antiretroviral therapy. Further research has led to the discovery and development of next generation NNRTIs with an increased genetic barrier to the development of resistance. Etravirine is the first NNRTI to show sustained virologic efficacy in patients with NNRTI resistant HIV-1. This review covers the NNRTI class of anti-HIV-1 drugs, from the initial discovery of the class in 1990 to the current compounds in clinical development, i.e. around 20 years of research and development efforts. It describes the characteristics of the NNRTIs, their mechanisms of action, HIV-1 resistance to the inhibitors, and the drugs that have been approved for the treatment of HIV-1 infection, or are currently in clinical development. The role of NNRTIs in prevention of HIV transmission is also addressed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
Subject(s)
HIV Infections/drug therapy , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/therapeutic use , Drug Resistance, Viral , History, 20th Century , History, 21st Century , Humans , Reverse Transcriptase Inhibitors/historyABSTRACT
In 1959, 5-iodo-2'-deoxyuridine (IDU) was described, the first antiviral drug ever to be (and still) marketed (for the topical treatment of herpetic keratitis). Now 50 years following the description (of the synthesis) of IDU, we have 50 compounds on the market that have been licensed for clinical use in the treatment of virus infections. Of those 50, exactly 25 have been formally approved as anti-HIV drugs; the other 25 have been formally approved for the treatment of other virus infections: herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and influenza virus infections.
