When to change treatment

• The latest British HIV Association (BHIVA) treatment guidelines recommend that if your viral load has previously been undetectable and rises above 400 copies/ml on two consecutive tests, that should be a trigger to think about changing treatment.

• However, the decision about when and whether to change will also depend upon what drug options are left open to you.

• If your CD4 count is unstable and falling close to or below 200 cells/mm³, there is a strong argument to change regimens even if that means recycling or taking mega-HAART.

• You may also want to change from a regimen which is successfully suppressing HIV if you are unable to tolerate it due to side-effects, or you are unable to take the medication as prescribed, or both.

• You may be on a regimen that is no longer recommended by the latest BHIVA guidelines, for example, if you are on your first combination and it contains d4T (stavudine, Zerit) or you are on less than three drugs.

• If you have recently become co-infected with hepatitis B or hepatitis C viruses, you may need to change your therapy

• Your chances of achieving and maintaining undetectable viral load tend to get smaller with each new combination that you take, because of the development of drug resistance.

• Resistance testing before switching therapy should help exclude drugs which are unlikely to work.

• A full review of the causes of treatment failure should happen before any change in regimen, including a review of adherence.

Changing due to side effects or adherence

• Toxicity (or side effects) is the most common reason for stopping the first antiretroviral drug regimen.

• Although you may have a good viral load response after starting antiretroviral therapy, you may find the side effects of some drugs hard to live with. Changing treatment is an option if side effects cannot be controlled.

• The main problem with changing treatment due to side effects is that the new combination may not be able to control HIV as well as the old combination. It is also possible that the new regimen will bring its own unwanted effects.

• Changing when your viral load is between 50 and 500 copies/ml, i.e. just beginning to rebound or not yet fully suppressed might be a problem. A lot of people who switch at this viral load level go on to suffer a further viral load rebound.

• There is also a bigger risk that the new combination will fail if you have lots of previous experience of treatment.

• Switching from a PI to a PI-sparing combination may bring about improvements in levels of fats in the blood (lipids), but results from studies so far are conflicting.

• An experimental strategy for people with drug-resistant virus who are experiencing toxicities is to stop the protease inhibitor or NRTI component of their regimen.

• Another reason to change is because you are finding it hard to take many pills. Studies have been looking at treatment simplification, and if you are only on your first or second antiretroviral therapy regimen, and have an undetectable viral load, this might be suitable.

• A new formulation of a drug you are currently might be available which makes it easier to take.

• You might find that if you are suffering from depression, a switch from efavirenz to ritonavir-boosted lopinavir (Kaletra) might bring improvements.

Viral load blips

• If you have achieved an undetectable viral load (below 50 copies/ml) and then get a viral load result above that level, only to return to undetectable the next time, that is called a blip.

• Sometimes a blip doesn't signify anything, but if you have several blips you may be on the way to failing treatment.

• However, some people have higher CD4 count rises with blips than other people who are always undetectable, so having a blip is not always a bad thing.

• Blips are not usually your fault: that is, they usually have nothing to do with whether you are taking your HAART on time, or missing doses.

Options when treatment is failing

• You may be able to reach an informed conclusion about which of your drugs is failing by taking account of your previous treatment history and the relative risk of developing resistance to different drugs.

• In addition to, or instead of, using your treatment history, when viral load is above 1000 copies/ml, UK treatment guidelines suggest using resistance resting to help select your next HAART combination.

• For people who are considering salvage regimens, using resistance testing to optimise your background therapy - the backbone drugs used in addition to the new drug or drug class being used - has been shown to be useful, especially if information on your full treatment history is also available.

• Testing drug levels (therapeutic drug monitoring) can be very useful, especially when using combinations of PIs and NNRTIs. If levels are too low, the dose can be increased, or boosted. If they are too high, side-effects can be reduced by reducing the dose.

• Stopping therapy altogether for a predetermined period of time (treatment interruption) might be possible, depending on your CD4 level and antiretroviral options.

• If you have detectable viral load and few immediate options for new treatment, continuing with existing treatment may be advantageous, particularly if your viral load is below 10,000 copies/ml.

• People who have low CD4 counts despite control of viral load may consider augmenting their antiretroviral regimen with the immune stimulant, interleukin-2.

Choosing a second-line regimen

• The current wisdom is to switch to as many new drugs as possible, though this will depend on the reason for switching.

• If treatment has resulted in side-effects but has successfully reduced viral load to below 50 copies/ml, then it should be possible to switch only the offending drug and maintain control of HIV replication.

• If you have been on PI-based antiretroviral therapy, you should generally change to NNRTI-based antiretroviral therapy or a new boosted PI-based antiretroviral therapy regimen with or without an added NNRTI.

• If you have been on NNRTI-based antiretroviral therapy, you should generally change to a boosted PI regimen.

• If you were previously on triple NRTI-based antiretroviral therapy, you should change to two new NRTIs, guided by resistance testing, adding either a boosted PI, an NNRTI or both.

Choosing a salvage regimen

• Treatment for people who have taken most of the available anti-HIV drugs is called salvage therapy.

• Before choosing a salvage regimen, you and your doctor should consider and investigate the reasons previous treatments failed. Some factors, such as drug resistance and low blood concentrations of particular drugs, may influence your approach to salvage therapy.

• With the availability of T-20 (enfuvirtide, Fuzeon), it is now possible for a large minority of highly antiretroviral-experienced people to achieve an undetectable viral load.

• However, undetectable viral load is not necessarily needed for successful salvage therapy, since even small declines in viral load can increase survival.

• Given all the right options - including resistance testing, drug level testing and good adherence - people on salvage therapy can survive just as long as those just starting their first antiretroviral therapy regimen,

• In general, the more new drugs you can put together, the better the chance of doing well with salvage therapy.

• Resistance testing and therapeutic drug monitoring should be used where there are difficult choices to make.

• Other strategies include staying on a combination which is failing to keep viral load undetectable until new drugs become available. It is unclear which is the best approach.

Changing due to side-effects

• Although you may have a good viral load response after starting antiretroviral therapy, you may find the side effects of some drugs hard to live with. Changing treatment is an option if side effects cannot be controlled.

• The main problem with changing treatment due to side effects is that the new combination may not be able to control HIV as well as the old combination.

• This may be more of a problem if your viral load is between 50 and 500 copies/ml, i.e. just beginning to rebound or not yet fully suppressed. A lot of people who switch at this viral load level go on to suffer a further viral load rebound.

• There is also a bigger risk that the new combination will fail if you have lots of previous experience of treatment.

• Studies are looking at the effect of switching from a PI-containing combination to a PI-sparing combination in people who have developed body fat changes on antiretroviral therapy. So far there is little evidence that a switch will improve the body fat changes.

• Switching from a PI to a PI-sparing combination may bring about improvements in levels of fats in the blood (lipids), but results from studies so far are confusing.

• An experimental strategy for people with drug-resistant virus who are experiencing toxicities is to stop only the protease inhibitor component of their regimen.

Protease inhibitor boosting

• Using a small additional amount of ritonavir has been found to increase levels of all other PIs, except for nelfinavir.

• This means that HIV which was once resistant to a PI can be suppressed by boosting that PI with the addition of ritonavir.

• Not all boosted PIs are equal, either in effectiveness or in their side-effect profile.

• Some doctors are now double boosting, that is using ritonavir to boost two different PIs. This can be very powerful, but also have many side-effects.

• Two PIs can also be used together without ritonavir, but this is a very experimental strategy.

Mega-highly active antiretroviral therapy

• Some clinics are trying an approach called 'mega-HAART' which involves taking at least five or six drugs in an effort to keep HIV under control.

• Some of the reasons some mega-HAART regimens work better than others include the extent of prior antiretroviral exposure, interrupting treatment prior to mega-HAART, and the availability of support when treatment begins.

• Although some people who have tried mega-HAART seem to do better - at least over the short-term - if they stop treatment for a few months before going onto it, this may be a risky option for anyone who has a low CD4 count (less than 100) or past experience of CMV, PCP, MAC or other AIDS-related illnesses.

• Viral fitness may play a role in mega-HAART. The M184V mutation associated with abacavir, 3TC and FTC treatment appears to be important in this respect.

Recycled, unlicensed and new drugs

• Although there are few studies to back it up, many people are re-using drugs they have been on before as part of salvage therapy.

• Some people use drugs approved for other purposes to boost their salvage regimen. Drugs like hydroxycarbamide and mycophenolate are extremely experimental and should only be used with expert advice.

• New drugs which are active against cross-resistant HIV may become available in the next year.

• If you have taken most of the available drugs and have broad cross-resistance, it is probably important for you to start at least two new drugs.