Persisently detectable viral load at any level increases risk of HIV treatment failure

For people taking HIV therapy, a persistent detectable viral load at any level is associated with an increased risk of virologic failure, Canadian research published in the online edition of Clinical Infectious Diseases shows. Comparison with people who maintained an undetectable viral load showed that ongoing, low-level HIV replication between 50 and 199 copies/ml doubled the risk of a subsequent increase in viral load to above 1000 copies/ml – a recognised benchmark for virologic failure.

“The clearly increased risk of VF [virologic failure] shown here suggests that, for all persistent LLV [low level viraemia] > 50 copies/ml, even when <200 copies/ml, it might be beneficial to act aggressively (adherence, plasmatic ART dosage if available, interactions, genotyping, closer monitoring, etc.),” say the authors.

The goal for almost all people taking modern HIV therapy is an undetectable viral load, typically defined as suppression of virus to below 50 copies/ml. An undetectable viral load allows the immune system to recover and is associated with a very low risk of virologic failure and the development of drug resistance.

Not all people on treatment achieve and maintain an undetectable viral load and the consequences of a persistent low viral load are uncertain. This lack of clarity is reflected in US antiretroviral guidelines, which state “there is no definitive evidence that patients with VL [viral load] quantified as <200 copies/ml…are at increased risk of VF”.

Canadian investigators therefore analysed the impact of three categories of persistent low-level viral load (50 to 199 copies/ml, 200 to 499 copies/ml, 499 to 999 copies/ml) on the subsequent risk of virologic failure.

The study involved 1357 people with HIV receiving routine HIV care in Montreal. They were required to have taken combination antiretroviral therapy for at least twelve months. Follow-up started in 1999 (the year that use of viral load assays with a lower limit of detection of 50 copies/ml became standard) and lasted for up to twelve years.

The majority of participants were white, gay men, their median age was 41 years and the median duration of follow-up was seven years.

The cumulative twelve-month incidence of virologic failure among participants who maintained an undetectable viral load was 7%.

Virologic failure rates were significantly higher for people whose viral load was detectable at low levels for up to six months. Almost a quarter (23%) of participants with a persistent viral load between 50 and 199 copies/ml had an increase in viral load above 1000 copies/ml, as did 24% of participants with a viral load between 200 and 499 copies/ml and 59% of those with a viral load between 500 and 999 copies/ml (p = 0.000).

Results were similar when the investigators looked at the persistence of low-level viraemia for nine and twelve months.

After accounting for potential confounders, the investigators calculated that a persistent viral load of between 50 and 199 copies/ml or 200 and 499 copies/ml for at least six months doubled the risk of virologic failure (HR = 2.22; 95% CI, 1.60-3.09 and HR = 2.15; 95% CI, 1.46-3.17, respectively). A persistent viral load between 500 and 999 copies/ml increased the risk almost five times (HR=4.85; 95% CI, 3.16-7.45).

The authors believe strengths of their study include the large number of participants and the extended period of follow-up. However, they were unable to show if the risk of virologic failure for people with low-level viral replication differed according to type of antiretroviral therapy. Despite this limitation, they believe their results are of clinical significance.

“VF >1000 copies/ml is known to have clinical consequences, and our analyses showed than any persistent LLV >50 copies/ml increased the risk of such failures,” write the investigators. “For patients with LLV (especially 50-199 copies/ml), the decision to either change ART rapidly or observe further is a difficult one to take; the clinician has limited data to support either decision…we hope that our data may contribute to the knowledge required to guide clinical conduct in such situations.”