The Treatment Era: ART in Africa

Friday 19 May 2006
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The Treatment Era: ART in Africa

AFRICA: A short history of antiretrovirals
From failed cancer drug to multi-billion dollar industry

Once upon a time there was a failed anti-cancer drug called zidovudine, which had been rejected because it was so toxic and had such unpleasant side effects. Twenty years later, under the name AZT, it became the vanguard of medicines in the fight against the human immunodeficiency virus (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 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 - and very expensive - hope available for people sick with AIDS. In that year another antiretroviral, ddI (didanosine, Videx), created specifically for patients who had become resistant to AZT, was registered. By this time the World Health Organisation estimated that 10 million people were infected with the HI virus worldwide, of whom a million were in the United States.

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), which resemble the chemical building blocks - nucleosides - used by reverse transcriptase, a key enzyme required by the HI virus 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. So, for example, a patient treated with AZT monotherapy is likely to quickly show some resistance to other NRTIs but because 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), a group of drugs that stops the duplication of viral DNA by directly disabling the reverse transcriptase enzyme itself.

The development of NNRTIs was a breakthrough because they worked against viruses that had become resistant to NRTIs, and 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) followed 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 the HI virus for intracellular replication.

First off the blocks with FDA registration were saquinavir (Fortovase, SQV, Invirase) in 1995, followed by ritonavir (Norvir, RTV) and indinavir (Crixivan, IDV) in 1996, nelfinavir (Viracept, NFV) in 1997 and amprenavir (Agenerase, APV) in 1999.

With three groups of anti-HIV drugs available, HAART - highly active antiretroviral therapy, using multiple drugs - began to evolve, and antiretrovirals became known as Lazarus drugs because they appeared to resurrect patients from near death.

The latest class of antiretrovirals to be developed are fusion inhibitors, which prevent the HI virus 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), registered in March 2003. Fuzeon has to be administered by injection, is expensive and has many side effects but, 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.


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