When to switch

Generally, an ARV regimen should be switched if an undetectable viral load is not reached within four to six months of beginning treatment. If a regimen originally succeeds in suppressing viral load to an undetectable level and this changes, a repeat viral load test should be done before deciding to make a change.

When the viral load remains between 50 and 400 copies/ml, factors such as adherence, drug metabolism, drug-drug and drug-food interactions, incorrect dosing, and co-morbidities should be explored. Resistance testing is not always successful in persons with fewer than 1000 copies/ml, but should be considered.

Changing therapy promptly upon the first sign of viral load rebound can help prevent the emergence of drug resistance. Even a low level of continued HIV replication in the presence of a drug can allow the virus to develop mutations that enable it to escape the drug’s effects. This not only reduces the effectiveness of the current drug, but may also impair the activity of other similar drugs in the same class. (However, see the discussion below on treatment changes in resource-limited settings.)

Most experts advise a prompt change from an non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen that is failing to suppress viral load to an undetectable level. NNRTIs have a low ‘barrier to resistance’ - meaning a single HIV mutation can render them ineffective. A study mentioned earlier in this section revealed that a delay of more than three months in switching from an ineffective NNRTI-based regimen is associated with increased mortality.

The median time between treatment failure and change in treatment was eight months. The researchers calculated that for patients on an NNRTI-based combination, a three-month delay in changing treatment involved a statistically significant risk of CD4 decline (21%) and of mortality (23%).

A similar delay in changing a failing protease inhibitor (PI)-based regimen does not carry the same consequences. Resistance to PIs usually evolves gradually, as additional HIV mutations progressively reduce the drugs’ activity. However, some earlier studies indicated that the sooner people switched protease inhibitors after resistance started to develop, the better their chances of success with a subsequent drug in this class. An analysis of nearly 1000 participants in the EuroSIDA study found that people who switched protease inhibitors when their viral load was still low were much more likely to achieve undetectable viral load.¹

Studies have shown little or no genotypic or phenotypic evidence of major protease resistance mutations amongst patients who experienced virological failure while taking lopinavir/ritonavir, boosted amprenavir, or boosted atazanavir.^{2 3 4} Further, unlike NNRTIs, resistance to one protease inhibitor generally does not confer cross-resistance to the entire class.

Virologic suppression should be achievable in the majority of patients, even those who are highly treatment-experienced and who have multidrug-resistant HIV. The approval of drugs in the fusion inhibitor, CCR5 inhibitor and integrase inhibitor classes, as well as the development of a new NNRTI with an altered resistance profile and second-generation protease inhibitors greatly expands treatment options. A new regimen should include at least two, and preferably three, active agents, and use of a drug from one new drug class if possible.

Only if treatment options are limited and the CD4 cell count is stable would it be preferable to stay on a ‘failing’ regimen. Research has shown that even partially suppressive treatment has clinical benefits.⁵

However, this must be balanced against the risk of developing further drug resistance and the long-term effects of ongoing viral replication and increased immune activation. The ability to monitor resistance and drug levels means that ARV treatment can be customised to the individual. Past ARV treatment, all resistance test results over time, potential drug interactions, reasons for past treatment failure, and an individual's preferences and circumstances all factor into a decision on when and how to change an ARV regimen.

In resource-limited settings where repeated viral load testing may not be feasible, a substantial number of people showing initial viral rebound may achieve control without switching therapies. A retrospective cohort study conducted in South Africa found that viral resuppression occurred in 41% of people who continued taking the same antiretroviral drug regimen after experiencing a viral load increase on treatment.⁶ Among this largely male cohort of 3727 HIV-positive adults who initiated antiretroviral therapy with AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and either efavirenz (Sustiva, Stocrin) or nevirapine (Viramune), 815 subsequently developed HIV viraemia (defined in the study as “HIV RNA >1000 copies/mL while on first-line therapy after an initial drop >1 log10 copies/mL from the [pre-treatment] level," and had follow-up laboratory results available. Three hundred and thirty one (41%) of this group achieved viral resuppression, defined as HIV RNA supression to <400 copies/mL while continuing to receive the same first-line antiretroviral regimen after one HIV RNA assay that demonstrated viraemia.NRTI cross-resistance also emerged relatively slowly in a subset of participants who underwent multiple rounds of resistance testing.