Options for the highly treatment-experienced

If you have used a lot of HIV drugs in the past, it can be can be more difficult to find a combination of anti-HIV drugs that will work for you. The term ‘salvage therapy’ used to be used for people with very limited treatment options.

But it has now become a lot easier for people who have taken a lot of HIV drugs in the past to find a combination of drugs that is effective. This is because new classes of drugs have been approved (fushion inhibitors) or will be approved soon (entry inhibitors and integrase inhibitors), and more potent and tolerable drugs have been developed in the existing classes.

Salvage sorted?

Until recently, the chance of achieving an undetectable viral load (below 40 or 50 copies/ml) if you had taken a lot of HIV drugs in the past was relatively low but new clinical practice and improved drugs are now being developed specifically for people who are having difficulty finding an effective combination of anti-HIV drugs. These advances have increased the possibility of highly antiretroviral-experienced people achieving an undetectable viral load.

First and second line choices of treatment are relatively straightforward in most cases as the range of classes available makes finding a new combinations simple (two nucleoside analogues and a non-nucleoside [NNRTI] can be followed by two nucleoside analogues plus a boosted protease inhibitor). For those whose first or second-line treatment has failed, different factors begin to determine which treatments can be used. Some factors, such as drug resistance, low blood concentrations of particular drugs and adherence issues, may influence the approach this time around. When changing your treatments, you and your doctor should consider the reasons previous treatments have failed, before choosing the next regimen.

Resistance testing

Resistance testing is an important tools used in this decision as it can help to identify which drugs are most likely to be effective for you.

Two types of resistance test are available:

• Genotypic tests - these look for specific changes, or mutations, in the virus which may predict resistance to a drug.

• Phenotypic tests – these measure the amount of drug which is needed to control viral replication. As the virus grows more resistant, the amount of drug needed to control replication will increase. This is called loss of sensitivity or susceptibility.

By using resistance testing and treatment history to select a combination that includes as many drugs that will work as possible, an undetectable viral load in people who have used a lot of anti-HIV drugs in the past is now often possible.

New classes

The development of Fuzeon (T-20, enfuvirtide) introduced a brand new class of drugs, the fusion inhibitors. It shows no cross-resistant to any of the existing drug classes and so is a crucial step towards successfully treating those with treatment experience. While T-20 must be injected twice daily, which some people find difficult, combined with newer therapies, this class has helped many people achieve undetectable viral loads.

Brand new classes of antiretroviral drugs are also in development which will hopefully provide more options when treatment choices become scarce. Integrase inhibitors offer a new mechanism for interrupting HIV’s reproduction. One such drug, raltegravir, is currently being studied and the results of trials are encouraging. CCR5 antagonists are another class in development. Maraviroc and vicriviroc are two examples in development which could provide most benefit to those that have resistance to multiple classes. Maraviroc was approved in the US in the summer of 2007 and European approval is expected later in 2007.

Improving current classes

New drugs in the classes already available have or are been designed to work against HIV even if there is a lot of resistance present. If you currently have experience of multiple protease inhibitors, ritonavir-boosted tipranavir could be an option for you. Tipranavir (Aptivus) is a new protease inhibitor that appears to be more effective than previously licensed protease inhibitors in suppressing drug-resistant virus. Darunavir (Prezista) is another new protease inhibitor that is highly effective against resistant HIV. For many, these protease inhibitors prove to be even more effective when combined with T-20 increasing the chances of success.

NNRTIs are also entering a new generation of development with some potential new drugs looking like they might work against virus with NNRTI resistance. Etravirine (TMC125) is one such drug.

While the currently available drugs may be enough to manage the virus for some, others will be eagerly awaiting the approval of some of these newer therapies. Where drugs are not currently licensed, they may be accessible through clinical trials, although often certain criteria need to be met. Often, drug companies run expanded access schemes so that patients with few treatment options can obtain early access to the drugs. You will need to be eligible to obtain them, but those with extensive treatment experience are a top priority. Speak to somebody at your HIV clinic for further advice.