Achieving an undetectable viral load is most difficult for people who have already taken several anti-HIV regimens, especially if they used insufficiently potent regimens - such as nucleoside reverse transcriptase inhibitor (NRTI) monotherapy in the past.

Emergence of resistance

Treatment failure happens when HIV develops resistance to one or more drugs in a regimen. This means that the virus has mutated in a way that allows it to continue replicating despite the presence of a drug.

Resistance can happen for a number of reasons. Some drugs and regimens simply are not strong enough to fully suppress HIV over the long term. People who used NRTI monotherapy or dual-NRTI regimens (even briefly) before the advent of multi-class HAART are more likely to have resistant virus, which can lead to greater difficulty achieving viral suppression. In other cases, people may have low (‘sub-therapeutic’) drug levels in their blood due to drug-drug interactions or individual variations in how drugs are processed in the body. Resistance may also develop if a person cannot tolerate a drug or has poor adherence.

For further information on the emergence of resistant virus, see Drug resistance.

Viral fitness

Viral ‘fitness’ refers to HIV’s ability to replicate and infect new cells. Mutations that emerge by chance when HIV replicates may be either beneficial or harmful to the virus. Some mutations allow HIV to replicate in spite of a drug, but these same mutations may also interfere with normal viral functions. HIV strains that develop many mutations - making them resistant to multiple drugs - tend to be weaker and less able to infect cells.

Some drug-resistance mutations are especially likely to affect viral fitness. For example, the M184V mutation associated with resistance to 3TC (lamivudine, Epivir) and emtricitabine (Emtriva) strongly impairs HIV’s ability to replicate, leading some researchers to suggest that it might be beneficial to stay on these drugs even after resistance develops ^[1].

When viral fitness and ability to replicate are impaired, CD4 cell counts may rise even though viral load is not fully suppressed. For this reason, antiretroviral therapy may still have a beneficial effect even when it does not reduce viral load below 50 copies/ml. For further information, see Discordant CD4 and viral load responses.

Some experts suggest that highly treatment experienced patients with few treatment options should stay on ‘failing’ regimen if they are maintaining a CD4 cell count above the pre-treatment level or experiencing slower than expected CD4 cell decline, since this likely indicates that the drugs are impairing viral fitness^[2].

In the Swiss HIV Cohort, individuals on HAART who experienced viral load rebound had a rate of disease progression similar to that of patients with sustained viral suppression, suggesting that even ‘failing’ therapy can have a beneficial effect by encouraging the emergence of less fit virus^[3].