With more than 20 antiretroviral drugs now on the market or available through expanded access programs, there are more option than ever for constructing an effective first-line anti-HIV regimen. But with this larger array of choices comes added complexity.

While treatment guidelines suggest combinations that have been shown to be safe and effective for people starting treatment for the first time, which specific drugs to choose remains an individual decision. Starting combination therapy is rarely urgent, so it is worth taking the time to make the best choice based on one’s personal situation.

Many factors are involved when considering what drugs to start with, including readiness to start treatment and ability to achieve good adherence, current state of disease progression (HIV viral load, CD4 cell count and disease symptoms), any existing drug resistance, drug dosing requirements and convenience, side-effects and long-term toxicities, and co-existing conditions such as cardiovascular disease or hepatitis.

Current antiretroviral therapy for people starting treatment for the first time is based on three classes of drugs, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors. There are multiple choices available in each class, with varying dosing requirements and potential side-effects.

Most people starting treatment today use a three-drug regimen that includes two NRTIs/NtRTIs plus either a NNRTI or a protease inhibitor. One common NNRTI-based regimen, consisting of tenofovir, emtricitabine and efavirenz, is now available as a single once-daily pill (Atripla). Using multiple drugs that attack HIV by different mechanisms minimises the risk of drug resistance.

Both NNRTI-based and boosted protease inhibitor-based regimens have a high likelihood of suppressing HIV below 50 copies/ml in people new to treatment. However, studies suggest that regimens containing only NRTIs may not be potent enough to maintain long-term viral suppression.

There are several options when choosing a NRTI/NtRTI ‘backbone’. Both AZT/3TC (the drugs in the Combivir combination pill) and tenofovir/emtricitabine (the drugs in Truvada) have been extensively tested and have demonstrated good potency with manageable side-effects in treatment-naive people. The use of (stavudine, Zerit) in first-line regimens - especially in combination with ddI (didanosine, Videx) - is no longer recommended due to toxicities. But abacavir (Ziagen) is now safer, thanks to a new genetic test that can tell which people are at risk for hypersensitivity reactions.

In addition to traditional three-drug/two-class HAART regimens, other treatment approaches have also been explored for people starting treatment, including NRTI-sparing regimens, three-class regimens, induction and maintenance therapy and protease inhibitor monotherapy. There are also various options for simplifying treatment, which is most likely to be successful when people are new to treatment and have less advanced HIV disease.

Some people newly diagnosed with HIV already have some degree of drug resistance, due to the transmission of resistant virus. Treatment for such individuals, therefore, may be more like that for treatment-experienced patients.

Once treatment has started, it is important to monitor progress, including changes in HIV viral load and CD4 count over time. If the drugs are not working as expected, drug-level monitoring can determine whether there are high enough concentrations in the blood. Regular monitoring can also turn up early signs of side-effects and drug toxicities, many of which can be managed. If viral load does not fall or CD4 count dose not rise, or if side-effects prove intolerable, it may be time to consider adding another drug or switching to a different regimen.

Decisions about what treatment to start with should also include planning for the future, considering what drugs might be used in case the first regimen fails to suppress HIV and increase CD4 cell count over the long term. Appropriate sequencing of drugs can help avoid or overcome the effects of drug resistance, leaving more options open for later.

Two new classes of drugs are now available for treatment-experienced patients, CCR5 antagonists and integrase inhibitors. While these drugs are not yet approved for people starting therapy for the first time, they have already been studied in treatment-naive individuals and offer additional options for the future.