NAPWA

Two new drugs have recently become available through the Special Access Scheme, providing people with limited treatment options two important new possibilities. KIRSTY MACHON reports.

It wasn’t so long ago that the HIV drug development ‘pipeline’ seemed depressingly empty. While the number of HIV drugs has expanded fairly steadily over the decade since the arrival of combination therapyHighly Active AntiRetroviral Therapy ??? aggressive treatment of HIV infection using several different drugs together., until the arrival of T-20 a couple of years ago all these medications had come from the same three classes of drugs.

The oldest drugs – the nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as AZT, 3TC, d4T and ddI, have been around for close to twenty years now. Until the mid-1990s, they were the only anti-HIV treatments available. NRTI monotherapy usually produced modest improvements in people’s CD4 count, but only for a limited time, and deaths from AIDS were still depressingly common.

Then, in 1995 and 1996, two new classes emerged which could be combined with the NRTIs in what was then dubbed ‘cocktail therapy’. The non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) and protease inhibitors revolutionised HIV medicine and brought many positive people back from the brink. Before long, we started to think of HIV infection as a treatable, manageable condition, not a terminal illness, and we waited eagerly for the next quantum leap in HIV medicine.

And we waited.

For several years, it seemed there were few new ideas in the drug pipeline. Even as it became apparent that combinations of the existing three classes of drugs could not remain effective forever, treatment-limiting side effects and absurd pill burdens took their toll. More frustratingly, the virusA small infective organism which is incapable of reproducing outside a host cell. continued to adapt, becoming resistantHIV which has mutated and is less susceptible to the effects of one or more anti-HIV drugs is said to be resistant. to the drugs and often, such as in the case of the non-nucleosides, resistant to other drugs in the same class, wiping out valuable treatment options.

While new drugs have become available over the years, most of these have offered only marginal gains over older treatments, and (with the exception of T-20) none have come from an entirely new class. Clinicians, researchers and treatment advocates all agree that the development of better drugs and new drug classesA group of anti-HIV drugs with the same target of action. Anti-HIV drug classes include nucleoside analogue reverse transcriptase inhibitors, protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors, as well as several others. Combining drugs from three or more classes is the basis of Highly Active Antiretroviral Therapy (HAART). is essential if we are to continue the successes of the last decade.

HIV treatments research has therefore had two main areas of interest. There’s been a huge focus on developing drugs which target entirely different parts of the HIV life cycle (like T-20, which prevents the virus fusing with host cells). Of equal interest has been the search for so-called second and third generation drugs from existing classes, which aim to overcome the failings of current drugs in terms of tolerability, efficacy and effectiveness(Of a drug or treatment). The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the standard procedure, Phase II clinical trials gauge efficacy, and Phase III trials confirm it. against resistant virus.

The good news is that some of this research is now starting to pay off.

Two new drugs, both currently in Phase-3 clinical trials, have recently become available in Australia through the Special Access Scheme, which allows people with limited treatment options and at high risk of HIV disease progression to access new drugs before they are licensed. The two new arrivals reflect the two major targets of recent research: one, MK-0518, is from an entirely new class, and the other, etravirine or TMC-125, is a next-generation non-nucleoside which promises to work for people who’ve previously developed resistance to NNRTIs.

MK-0518

To infect a human host cell, HIV undertakes a complex enterprise. It must attach to the cell, fuse with it, and finally ‘reprogram’ the human cell with its own genetic material, producing new copies of itself and going on to infect more cells with new viral particles.

Theoretically, we can target this life cycle and attempt to interfere with HIV replication at any of a number of different points, often by inhibiting the enzymes which are crucial to a particular stage of the virus’s development. Nucleoside and non-nucleoside drugs work by targeting an enzyme called reverse transcriptase, for example, while protease inhibitors target a different enzyme called protease.

MK-0518 works by inhibiting another enzyme, integrase, which HIV uses to integrate its genetic material with the host cell. Without this enzyme, HIV can’t reprogram the human host cell’s DNA, and its life cycle is cut short. Integrase inhibitors have long been a kind of ‘holy grail’ for HIV drug development, and their arrival (MK-0518 is only one, albeit the most advanced, of several in development) represents an important development: used in combination with drugs from the other classes, this approach provides a fresh front for attacking HIV, which may help control it more effectively.

MK-0518, being developed by Merck, is now in Phase-3 clinicalPertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science. studies in Australia and around the world. It has not yet been licensed for use in Australia or elsewhere, and is currently only available to those participating in the clinical trials and those who qualify for the restricted Special Access Scheme. Like all other anti-HIV drugs, it is taken in combination with other treatments.

To date, the experience with this drug has largely been in people who are already treatment-experienced and have taken a variety of previous HIV treatments, although some studies as first-line therapy (for people haven’t taken HIV drugs before) are also underway. So far, it’s been shown to have an impressive effect against HIV, whether or not it is used with T-20, with over 70 percent of participants in Phase-2 studies having undetectable HIV viral loads after taking the drug for six months.

Particularly encouraging has been the news of how well this drug appears to be tolerated. There have been no serious adverse side effects attributed to this drug in studies so far, and the common side effects of many HIV drugs, such as nausea, headache and diarrhoea, occurred in very low numbers of people. In fact, its side effect profile was very similar to that of the people on the placeboA dummy medical treatment, designed to have no pharmacological effect, administered to the control group of a clinical trial. armAny of the treatment groups in a randomised trial. Most randomised trials have two "arms," but some have three "arms," or even more. (their current combination plus a dummy pill).

All this has led to speculation that MK-0518, assuming it passes the final clinical trial and regulatory hurdles, is likely to be an important new treatment alternative. Results from Phase-3 studies, as well as treatment-naive studies, will be reported over the next 12 months.

Accessing MK-0518

A Special Access Scheme (SASBefore a drug has been approved, manufacturers often provide the drug free of charge to people who cannot participate in a clinical trial and who meet certain criteria under a Special Access Scheme (SAS). ) has been negotiated between NAPWHA and the manufacturer of MK-0518, Merck Sharp & Dohme. The scheme is designed to make MK-0518 available to people with HIV who urgently need it, and not all positive people will be eligible. To qualify for the SAS, you must have a CD4 (T-cell) count of less than 200, and be unable to construct a viable treatment regimen from currently-licensed and available antiretroviralA medication or other substance which is active against retroviruses such as HIV. drugs, due to virological failure (current drugs aren’t effectively suppressing your HIV), or due to intolerance or toxicities.

Etravirine (TMC-125)

The non-nucleosides nevirapine (Viramune) and efavirenz (Stocrin) are widely used in Australia; they are attractive as first-line therapy because they’re highly effective against HIV and, for many people, easier to take and more tolerable than some of the protease inhibitors. A major downside, however, has been cross-resistance within the class: if you use one of these drugs and develop resistance to it, you will also be resistant to all other existing non-nucleosides.

A long-term goal of research has been to develop a non-nucleoside drug which remains effective against virus that has resistance to other non-nukes, and which does not develop resistance so readily, or in the same way, as the currently licensed drugs. TMC-125, known generically as etravirine, is being developed by Tibotec with that aim in mind. Etravirine has a striking and promising characteristic: it has been engineered to incorporate a degree of ‘molecular flexibility’ – as the virus changes and begins to evade the drug, the drug’s chemical shape can also ‘change’, making it harder for HIV to get around.

Etravirine has been designed to be effective in people with pre-existing resistance to nevirapine and efavirenz. Clinical trials so far have been promising in this regard, with investigators noting that etravirine does indeed have good antiviralA medication or substance which is active against one or more viruses. May include anti-HIV drugs, but these are more accurately termed antiretrovirals. activity against HIV in people with prior use of and resistance to the other two drugs. A Phase-3 trial is currently underway.

To date, the most common side effects reported with etravirine have included diarrhoea, headache and nausea, but these occurred at the same rate in those taking etravirine as those taking their background combination plus a placebo. Dizziness, flatulence and diarrhoea were reported during the first few days of treatment with etravirine, but these effects were usually mild and usually resolved or disappeared after a few days. Skin rash, a common side effect of both efavirenz and nevirapine, was no more common in those taking etravirine compared to people taking placebo.

One concern with the drug, however, is its potential to interact with other treatments, with studies suggesting that etravirine can interfere with and lower the blood levels of some protease inhibitors. The company is conducting a number of interaction studies with key HIV and non-HIV medications as part of the licensing process.

Accessing etravirine

A Special Access Scheme (SAS), negotiated by NAPWHA in partnership with the manufacturer Janssen-Cilag, is now open to allow early access to etravirine. The SAS is designed to make etravirine available to people who urgently need it, and not all positive people will qualify. To be eligible for the program, you must be unable to construct viable combinations of treatment from the currently licensed and available antiretroviral drugs, due to virological failure (current drugs aren’t effectively suppressing your HIV), or due to intolerance or toxicities.

Currently, the two drugs cannot be used at the same time, until further information about how they may interact together becomes available.

If you would like to know more, or think you may be eligible for one of these programs, you can discuss this with your HIV doctor. If you meet the criteria, your doctor can arrange for you to be enrolledThe act of signing up participants into a study. Generally this process involves evaluating a participant with respect to the eligibility criteria of the study and going through the informed consent process..

Since this article was published, one of the drugs mentioned – raltegravir – has become available on the PBS[Pharmaceutical Benefits Scheme] The federal government program which subsidises medication costs in Australia. Anti-HIV drugs are part of a special part of the PBS called Section 100 (S100) which is used for expensive, highly specialised drugs..