HIV often makes errors as it copies itself; unlike human cells, it cannot detect or fix these errors. These genetic changes, known as mutations, cause the wrong amino acid building blocks to be inserted into proteins. Some of these mutations will lead to the production of defective virions that cannot infect new cells. But by chance, other changes will allow HIV to continue replicating despite the presence of antiretroviral drugs. This is known as drug resistance.

In general, antiretroviral drugs are most effective against ‘wild-type,’ or non-mutated HIV. When a mutation in an HIV enzyme occurs, a specific drug may no longer be able to block its action, but a different drug might still do so. The more drugs there are, the harder it is for the virus to make new copies that can still infect cells. This is why combination therapy is more effective than a single drug.

In the mid-1990s, results from the Delta and ACTG 175 trials showed that combinations of two NRTIs were more effective than a single drug alone at delaying disease progression^[1][2]. Later studies demonstrated that triple-drug combinations consisting of two NRTIs plus either a NNRTI or a protease inhibitors work even better than two-drug regimens. Further research showed that adding an entry inhibitor improved treatment effectiveness in patients who had developed resistance to the older drug classes ^[3][4]. More recently, studies demonstrated the benefits of combination therapy using the two newest types of drugs, CCR5 antagonists and integrase inhibitors ^[5][6][7][8].

Combination therapy is discussed in more detail in Starting HIV treatment and Changing HIV treatment.