Changing or stopping therapy

The goal of ARV therapy is an initial and sustained viral load drop to less than 50 copies/ml, leading to immunological improvement and increased quality of life with a lack of clinical progression. Studies have shown that the lowest-ever viral load (or ‘nadir’) reached by someone in the first few months after the start of ARV therapy is predictive of the subsequent risk of virological failure.

If a viral load of <50 copies/ml is not reached within four to six months on initial therapy, possible causes to explore include poor adherence, intolerability, drug interactions, or incorrect dosing. If drug exposure is optimal and the possibility of resistance is low or undetected, the ARV regimen may need to be supplemented. If resistance is detected, or the chance of it is high, all drugs in the regimen may need changing.

A transient rise in viral load to just above a detectable level is known as a ‘viral blip’. Over the course of therapy, many patients will experience at least one viral blip, if not more. When someone on stable therapy for more than three months experiences an increase in viral load, careful monitoring and clinical assessment is needed to distinguish between a viral blip and viral rebound.

Viral replication can be increased by concurrent infections, a recent vaccination, or variation in assay performance. Reduced plasma drug levels may be a result of drug interactions, incorrect dosing, or poor adherence. If the viral load falls to the previous low level in four to six weeks, no further action is needed. The significance of viral blips has yet to be fully understood. If someone experiences viral blips frequently that may be related to inadequate drug dosing, the current regimen might be intensified or changed.

If viral load falls to <50 copies/ml on the initial ARV regimen and later rises to a level between >50 and <400 copies/ml with a CD4 count >200cells/mm³, it would be reasonable to continue the regimen while monitoring carefully. If two viral load levels done at least one month apart show detectable virus, a change to other drugs capable of fully suppressing the virus would be reasonable if resistance is detected.

If resistance mutations are not found using genotypic resistance testing, adherence and drug exposure issues should be considered. At times, mutations in minor virus populations may be present, but undetectable. Increased adherence support should also be considered.

If two tests at least one month apart show a viral load >400 copies/ml, changing all drugs on the regimen is recommended. Data suggest that the likelihood of achieving an undetectable viral load is greatest when CD4 cell count is higher and viral load is lower; changing the regimen earlier rather than later might have the greatest effect. Maintaining someone on a virologically failing regime runs the risk of increasing viral fitness and resistance to other ARV drugs.

A failure to reach undetectable viral levels, or viral rebound, after 24 to 36 weeks on therapy calls for consideration of a change in treatment guided by resistance testing, treatment history, and the availability of a treatment regimen that the patient could adhere to and tolerate. Adding one new agent to a regimen is not a recommended strategy. Though it may be effective in reducing viral load to undetectable levels, the more likely outcome is added toxicity and development of resistance to the new drug.

If the original regimen consisted of three nucleoside/nucleotide reverse transcriptase inhibitor agents (NRTIs), options would include:

• 2 new NRTIs + a non-nucleoside reverse transcriptase inhibitor (NNRTI).

• 2 new NRTIs + a boosted protease inhibitor (PI).

• 1 to 2 new NRTIs + an NNRTI + a boosted PI.

If the original regimen included 2 NRTIs with a NNRTI, the option would be to use:

• 2 new NRTIs + a boosted PI.

If the original regimen were 2 NRTIs with a PI, treatment options would include:

• 2 new NRTIs + an NNRTI.

• 2 new NRTIs + a new boosted PI.

• 1 to 2 new NRTIs + a new boosted PI + an NNRTI.

When treatment options exist, a new regimen should be guided by resistance testing and the patient’s past ARV use. An agent from a new class is also recommended, as well as at least two, or preferably three, new active agents. The guidelines advise against using enfuvirtide (T-20) if it is the only active agent, as resistance can occur in weeks. Darunavir (Prezista) is also most effective when used with other active drugs.

If treatment options are limited and CD4 cell count is being maintained, it may be best to keep a patient on a failing regimen until a switch can be made to a new combination with at least two active agents. Even partial virological suppression of HIV >0.5 log₁₀ copies/ml from baseline can have clinical benefit; however, this must be balanced against the risk of acquiring additional resistance mutations.

Recycling past drugs may have a role in reducing toxicity and drug reactions in treatment-experienced patients, omitting those with little antiviral effect and/or that produce side-effects. In one study, the effect of withdrawing 3TC (lamivudine) from a failing regimen was an average viral load increase of 0.5 log₁₀, indicating that even in the presence of genotypic resistance, 3TC retains antiviral activity.¹ If resistance testing shows that other potent NRTIs are available, they could be used in place of or with 3TC.  

Several clinical trials have looked at structured treatment interruptions in highly treatment-experienced individuals as a way of causing virus to revert to wild-type. Unfortunately, that strategy does not seem to result in any durable benefit. Treatment interruptions or stopping therapy altogether may be associated with a rapid increase in viral load, CD4 cell loss, and clinical progression.

In highly ARV-experienced patients, the guidelines stress customising treatment to the individual, guided by resistance testing and tolerability. The general recommendations for maintenance therapy are to:

• Select nucleosides to which the patient has shown extensive resistance.
• Attempt to induce or maintain resistance patterns associated with reduced viral fitness.
• Examine closely the immunological efficacy of the regimen being followed.