Is a viral load just below 50 copies/ml low enough to ensure the long-term success of HIV therapy?

Suppressing viral load to below 50 copies/ml may not be enough to ensure the long-term success of antiretroviral therapy, according to a UK study published in the March edition of Clinical Infectious Diseases.

Using ultra-sensitive viral load assays, investigators at the Royal Free Hospital, London, found that patients with a viral load between 40 to 49 copies/ml were significantly more likely to experience a rebound in viral load above 50 copies/ml, when compared to individuals with viral load between 39 and 3-to-10 copies/ml and to people with a truly undetectable viral load.

The investigators recommend “treatment efficacy should be reviewed” for patients whose viral load is above the very lowest levels.

However, the authors of an editorial accompanying the study are less convinced about the significance of its findings.

The goal of HIV therapy is an 'undetectable' viral load, currently defined as one below 50 copies/ml (the level at which tests most commonly used for routine monitoring can detect viral load). Studies have shown that a sustained increase above this level is associated with the virological failure of therapy and the emergence of drug-resistant strains of HIV.

Assays capable of accurately measuring viral load to 40 copies/ml have been developed. In approximately two-thirds of cases, the assays can also detect viral load to a threshold of 10 copies/ml.

Viral load at an ultra-low level – between 3 to 10 copies/ml – is often labelled 'residual viraemia' and cannot be eradicated with treatment intensification.

In 2006, the Royal Free Hospital started to use the Roche Real Time viral load assay with a lower detection limit of 40 copies/ml in routine HIV care.

Investigators wished to see if a low but detectable viral load was associated with an increased risk of subsequent rebound in viral load above 50 copies/ml and 400 copies/ml, when compared to individual whose viral load was completely undetectable.

The retrospective study involved 1247 patients, all of whom were taking suppressive HIV therapy.

A random viral load measurement for each patient was extracted from his or her records. This showed that 19% of patients had a viral load between 40 and 49 copies/ml; 41% had a viral load between 39 copies/ml and residual levels; and 40% had a truly undetectable viral load.

There were significant differences between these categories of patient.

Most notably, individuals with a viral load between 40 and 49 copies/ml had been taking HIV therapy for a median of 0.2 years. This compared to a median of 1.9 years for patients with viral load between 39 copies/ml and residual levels, and a median of 3.2 years for patients with undetectable viral load (p < 0.001).

In addition, patients with a viral load between 40 and 49 copies/ml had significantly poorer adherence than those with lower viral loads.

A total of 211 out of the 1247 patients experienced a rebound in viral load above 50 copies/ml, with viral load increasing above 400 copies/ml for 40 patients.

The risk of rebound differed significantly according to viral load at the time of random measurement.

Just over a third (34%) of patients with a viral load between 40 and 49 copies/ml experienced a rebound in their viral load above 50 copies/ml. This compared to 11% of those with a viral load between 39 copies/ml and residual levels, and 4% of patients with an undetectable viral load (p < 0.001 for all comparisons).

An increase in viral load above 400 copies/ml occurred in 13% of patients with viral load above 40 copies/ml, compared to 4% of individuals with a viral load between 39 copies/ml and residual levels and 1% of those with an undetectable viral load.

Analysis confirmed an association between detectable viral load and an increased risk of rebound.

Compared to patients with only residual viraemia, individuals with a viral load between 40 and 49 copies had a more than four-fold increase in their risk of viral load rebounding above 50 copies/ml (HR = 4.68; 95% CI, 2.40-9.12). For patients with a viral load between 39 copies/ml and residual levels the risk was increased two-fold (HR =  2.33; 95% CI, 1.26-4.31).

Length of viral suppression was also an important determinant of rebound above the 50 copies/ml threshold (p = 0.005).

A detectable viral load was also associated with an increased risk of viral rebound above 400 copies/ml.

Once again, the risk was highest for those with a viral load in the 40 to 49 copies/ml range (HR = 10.71; 95% CI, 3.30-34.81) when compared to individuals with an undetectable viral load. However, the risk was also increased for patients with a viral load between 39 copies/ml and residual levels (HR = 3.78; 95% CI, 1.23-11.59).

Time since starting effective HIV therapy was associated with a lower risk of rebound above 400 copies/ml (p = 0.03).

However, the risk of resistance did not differ according to viral load before rebound above 400 copies/ml.

Adherence was not associated with a risk of rebound in multivariate analysis. There was no significant difference in efavirenz levels according to viral load level in a subset of 186 patients taking efavirenz, who were equally divided between those with viral loads above the residual level and those with completely undetectable viral load.

“The goal of HAART [highly active antiretroviral therapy] may need to be revised to a lower cutoff than 50 copies/ml,” conclude the investigators.

However, the authors of the accompanying believe “there are reasons to pause before adopting this recommendation”.

In particular, they note that viral load had been suppressed for a significantly shorter duration in patients with a viral load between  40 to 49 copies/ml, compared to those with a truly undetectable viral load. This suggested that these individuals had not yet achieved the full viral suppression that can be accomplished with longer-term HIV therapy.

US treatment guidelines now recommend that 200 copies/ml should be considered the threshold for suppressive HIV therapy.

“The findings of the current study suggest that this threshold may be too high for a patient who has quantifiable and persistently detectable viremia, but confirmatory studies are needed,” suggest the authors.

“Until such studies are available, a careful assessment of adherence should be the first response to low levels of viremia. Whether treatment for such individuals should be modified or intensified is currently unknown.”

Doyle T et al. Plasma HIV-1 RNA detection below 50 copies/ml and the risk of virologic rebound in patients receiving highly active antiretroviral therapy. Clin Infect Dis, 54: 729-37, 2012 (click here for the free abstract).

Gandhi RT et al. Plasma HIV-1 RNA levels during antiretroviral therapy: how low is low enough? Clin Infect Dis, 54, 2012 (click here for the free abstract).