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Low but Detectable Viral Load Can Lead to HIV Rebound


People with HIV RNA levels < 50 copies/mL but detectable may still experience viral rebound while on antiretroviral therapy, and should consider switching to a more effective regimen if low-level viral load persists, according to a study described in the January 11, 2012, advance online edition of Clinical Infectious Diseases.

Modern highly active antiretroviral therapy (HAART) can reduce HIV RNA to a low level, but typically some residual viral replication continues. The goal of therapy is to achieve "undetectable" viral load, but this threshold changes as more sensitive tests become available. Studies indicate that lower viral load is associated with less resistance and rebound, but outcomes at very low HIV RNA levels have not been well studied.

Thomas Doyle from the Royal Free Hospital in London and colleagues looked at virological outcomes among 1247 HIV positive people with viral load < 50 copies/mL while on HAART. About three-quarters were men and the median age was about 40 years.

The researchers assessed viral load using a sensitive test -- the Abbott RealTime assay -- that can measure HIV RNA down to 40 copies/mL, and below that can determine whether HIV is present, but not its precise level. At the start of the study the authors picked a random prior viral load measurement from patients' records, and used this to retrospectively classify participants as having HIV RNA levels of 40-49 copies/mL, < 40 copies/mL but detectable, or not detected even with the sensitive test.


  • Overall, 19.2% of patients had a random viral load of 40-49 copies/mL, 40.7% had < 40 copies/mL but detectable, and 40.1% had undetectable viral load by the sensitive test.
  • Participants with HIV RNA of 40-49 copies/mL had been on treatment for a significantly shorter period (median of about 2 months) than those with < 40 copies/mL (1.9 years) or undetectable (3.2 years).
  • 211 participants experienced viral rebound to > 50 copies/mL and 40 patients showed a rise to > 400 copies/mL.
  • People with higher random HIV RNA levels were more likely to experience viral load rebound to > 50 copies/mL than those with lower levels:
    • 40-49 copies/mL: 34.2% rebound;
    • < 40 copies/mL but detectable: 11.3% rebound;
    • Undetectable: 4.0% rebound.
  • Rebound to > 400 copies/mL occurred in 13.0%, 3.8%, and 1.2% of patients, respectively.
  • After adjusting for other factors, hazard ratios for rebound to > 50 copies/mL were 4.67 (or nearly 5-fold more likely) for people with 40-49 copies/mL and 1.97 (or twice the risk) for those with < 40 copies/mL but detectable, both statistically significant increases.
  • Looking at rebound to > 400 copies/mL, hazard ratios were 6.91 and 2.88, respectively, again both significant.
  • People with 40-49 copies/mL had significantly poorer treatment adherence than those with lower levels, but the association between random viral load and rebound to > 400 copies/mL was independent of adherence levels.

"In treated patients monitored by RealTime, a viral load of 40-49 copies/mL and, to a lesser extent, RNA detection < 40 copies/mL predict rebound [to] > 50 and > 400 copies/mL independently of other recognized determinants," the study authors concluded.

"[A] viral load < 50 but > 40 copies/mL, and, to a lesser extent, qualitative RNA detection < 40 copies/mL, indicate that treatment efficacy should be reviewed," they elaborated. "The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL."

In an accompanying editorial, Rajesh Gandhi from Massachusetts General Hospital and Steven Deeks from San Francisco General Hospital asked whether people with low but measurable viral load < 50 copies/mL should be considered to be on failing therapy. Current U.S. treatment guidelines put the failure threshold at 200 copies/mL.

"The findings of the current study suggest that [the 200 copies/mL] threshold may be too high for a patient who has quantifiable and persistently detectable viremia," they wrote.

However, they noted, people with HIV RNA of 40-49 copies/mL or < 40 copies/mL but detectable typically had been on treatment for a shorter duration, and suggested they might simply need more time on the same regimen to achieve full viral suppression.

Investigator affiliations: Departments of Virology, and HIV Medicine, Royal Free Hampstead NHS Trust; Departments of Virology, Infection and Population Health, and HIV Medicine, University College London Medical School, London, UK; Department of Molecular and Clinical Pharmacology, Institute of Infection and Global Health, University of Liverpool, UK.



T Doyle, C Smith, P Vitiello, et al. Plasma HIV-1 RNA Detection Below 50 Copies/mL and Risk of Virologic Rebound in Patients Receiving Highly Active Antiretroviral Therapy. Clinical Infectious Diseases. January 11, 2012 (Epub ahead of print).

R Gandhi and S Deeks. Plasma HIV-1 RNA Levels During Antiretroviral Therapy: How Low Is Low Enough? Clinical Infectious Diseases. January 11, 2012 (Epub ahead of print).