Anti-retroviral drugs.

History

In the 1960s, a failed anti-cancer drug called zidovudine was shelved and rejected by the medical fraternity, due to unpleasant side effects. Twenty years later, under the name AZT, it became the vanguard of medicines in the fight against HIV.
AZT was seen as a breakthrough: the first medication that seemed to attack the virus itself. It was thus the first real hope for people infected with HIV, which until then had almost certainly led to death.

In an article, AZT’s Inhuman Cost (NYT, Aug ‘89) “...at $8,000/yr, AZT is said to be the most expensive prescription drug in history.”
Despite the cost and due to the imperative nature of conducting research for an epidemic that was gaining horrid momentum in the 1980s, the drug industry worldwide injected huge resources into HIV and AIDS research. In 1986 a clinical trial on patients in eight American cities was stopped after four months because AZT seemed to have such dramatic effects on the virus. The next year AZT (Retrovir) became available commercially as the first antiretroviral to be registered by the US Food and Drug Administration (FDA).

Unfortunately, follow-up research was not so optimistic. Clinical trials in Europe found no long-term benefit from using AZT, especially if patients started taking the drug before they showed signs of AIDS. And, worryingly, healthy patients taking AZT seemed to die faster than their sicker counterparts.
What was not appreciated then was that taking only one antiretroviral at a time—monotherapy—has only a short-term benefit, because the virus mutates so rapidly that drug-resistant strains swiftly become dominant.

Until 1991 AZT was the only (very expensive and often unaffordable) hope available for people sick with HIV and dying from AIDS. In that same year another antiretroviral, DDL (Didanosine, Videx), was created specifically for patients who had become resistant to AZT. It was registered by the US FDA. By the early 1990s, the World Health Organisation estimated that 10 million people were infected with HIV worldwide, of whom 1 million were in the United States. It was a similar experience to what the world is currently experiencing with Ebola, an epidemic that was gaining momentum and getting out of hand. Fear had been hugely prevalent in the 1980s when no drug therapy was available, and the drug companies were finally rushing to find a treatment that was affordable and effective. There was a period of time in the 1980s where drug companies possibly buried their heads in the sand, as the cost of developing such a drug was prohibitive and the profit margin was as yet unknown. This is a subjective opinion and may have inaccuracies, as some drug companies were working very hard behind the scenes to find a cure or drug for AIDS or develop a drug that could slow down the virus.

In 1992 ddC (zalcitabine, Hivid), was approved for use in the US, followed by d4T (Zerit) in 1994 and 3TC (Epivir, lamivudine) in 1995.

All these drugs are classified as nucleoside reverse transcriptase inhibitors (NRTIs or “nukes”) - which resemble the chemical building blocks (nucleosides) used by reverse transcriptase, a key enzyme required by HIV for intracellular replication. NRTIs have a chemical twist, which ensures that, once taken up by the enzyme, the NRTI molecules terminate the building of the viral DNA chain, stalling virus production.

The problem is that HIV can show cross-resistance to different drugs in the same group. For example, a patient treated with AZT monotherapy is likely to quickly show some resistance to other NRTIs, but as they are all slightly different, dual therapy using two drugs in the same class is still more effective and sustainable than monotherapy. This was demonstrated in 1997 when the FDA registered Combivir, a combination drug containing both AZT and 3TC. In this case, resistance to one drug appeared to counter resistance to the other.

1996 brought registration of nevirapine (Viramune, NVP), the first in a new class of antiretrovirals: non-nucleoside transcriptase inhibitors (NNRTI). NNRTIs are a group of drugs that stop the duplication of viral DNA by directly disabling the reverse transcriptase enzyme itself. This was an extremely important breakthrough for the drug industry, as the virus had become resistant to NRTIs. Researchers quickly found that dual therapy (using two drugs simultaneously) was most effective when the drugs were from two different groups. Other NNRTIs, such as delarvirdine (Rescriptor, DLV) and efavirenz (Sustiva, EFV) were developed in 1997 and 1998.

NNRTIs were overshadowed by the arrival of a third class of drugs—protease inhibitors (PIs). These work at a later stage of the HIV life cycle by interfering with the protease enzyme, the other key enzyme required by HIV for intracellular replication. Initially, the FDA approved saquinavir (Fortovase, SQV, Invirase) in 1995, followed by ritonavir (Norvir, RTV) and indinavir (Crixivan, IDV). In 1996, nelfinavir (Viracept, NFV) was approved and in 1999, amprenavir (Agenerase, APV) was approved.

With three groups of anti-HIV drugs now available, HAART began to evolve, and antiretrovirals became known as Lazarus drugs because they appeared to resurrect patients from near death. The latest class of antiretrovirals that was developed is fusion inhibitors, which prevent HIV from infecting human cells by blocking the viral proteins used to dock into cell membranes. To date, there is only one FDA-registered fusion inhibitor—enfuvirtide (Fuzeon, T-20), which was registered in March 2003. Fuzeon has to be administered by injection, is very expensive and has many side effects. Most importantly, because it is the first of a totally different class of drugs, it offers another chance to patients who have become resistant to other treatment regimes.

Reference: http://hedrick.ucsd.edu/BICD136/Lectures/Lecture11-ARV.pdf

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