If a current antiretroviral regimen is no longer suppressing HIV or is causing intolerable side-effects, it may be time to consider adding more drugs or switching one or more drugs in the combination.

One recent analysis of more than 22,000 individuals seen at HIV clinics in the UK found that patients stayed on their first combination regimen for an average of about seven years. The average time on the second and third regimens was about four years each. About 40% changed their first regimen and about 50% changed their second or third regimens due to viral rebound, immune decline or clinical disease progression. This suggests that at least half of treatment changes are due to other factors such as side-effects or lack of convenience ^[1].

Some newly developed drugs and treatment strategies (such as ritonavir boosting) have made anti-HIV therapy easier for many patients. It may be possible to switch to drugs that are taken less often or have a lower pill burden, including fixed-dose coformualtions that combine two or more drugs in a single pill. Treatment simplification usually works best when people are on one of their first regimens and have minimal drug resistance.

There is also reason to consider a change if a person is taking an older regimen that is no longer recommended, such as a combination containing only two drugs, a nucleoside/nucleotide (NRTI/NtRTI) backbone containing d4T (stavudine, Zerit) or an unboosted ‘first-generation’ protease inhibitor. This is also true if a person has a change in health status, for example development of tuberculosis or hepatitis B or C, which may change which antiretroviral drugs are recommended.

Other patients switch because they are experiencing side-effects they find difficult to tolerate, including metabolic complications such as lipodystrophy (body fat changes) or elevated blood fat levels. Drug toxicity is the most common reason for changing a first antiretroviral regimen. With more than 20 antiretroviral drugs now available, it is often possible to switch to a new combination that causes fewer side-effects and enables better adherence.

Switching off d4T, for example, is likely to improve peripheral fat loss (although improvement is usually slow). Changing from a protease inhibitor to a NNRTI, or to atazanavir, can reduce elevated blood fat levels. But many side-effects can be managed effectively without changing antiretroviral therapy.

If viral load remains suppressed, HIV has probably not developed extensive drug resistance. Switching is generally safe under these circumstances, and the focus can be on finding equally effective drugs with fewer toxicities. If a switch is done for simplification or to reduce side-effects, it may be possible to change just one problematic drug and the others will continue to work.

With modern antiretroviral drugs, experts now recommend that suppressing viral load below 50 copies/ml should be the goal for both treatment-experienced patients and those starting therapy for the first time. If viral load has not fallen below 50 copies/ml within six months after starting a new regimen, the drugs may not be working as expected.

People who have successfully suppressed HIV may later experience viral rebound or breakthrough (rising viral load whilst still on therapy). Many patients experience transient viral load ‘blips’ that return to undetectable levels with no change in treatment. For this reason, experts recommend receiving at least two viral load tests to determine a trend before changing drugs.

If viral load remains elevated, it is usually an indication that a new regimen is needed. British HIV Association (BHIVA) guidelines recommend that patients think about changing therapy if viral load rises from undetectable to above 400 copies/ml on two consecutive tests. However, not everyone in this situation should switch immediately, and individual factors such as availability of other active drugs should influence the decision.

CD4 cell counts usually rise when treatment suppresses viral load, thereby allowing the immune system to recover. However, this does not always happen. If CD4 count is falling close to or below 200 cells/mm³, there is a strong argument for changing regimens.

Before choosing a subsequent combination, it is important to try to determine the reason for treatment failure - such as poor adherence, side-effects, low drug levels or drug resistance - and take steps to resolve them so the next regimen does not fail for the same reasons. Resistance testing can determine whether HIV has developed resistance mutations, whilst drug level monitoring can show whether drugs are reaching adequate levels in the body.