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ICAAC 2012: People with Low-level Viral Load Are at Risk for Treatment Failure and Poor CD4 Recovery


Individuals who still have low levels of plasma HIV RNA despite taking antiretroviral therapy (ART) may experience treatment failure, and those with HIV residual DNA in their T-cells may not achieve expected CD4 cell gains, according to 2 studies presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) this week in San Francisco.

Combination antiretroviral regimens can suppress viral replication in most people with HIV, but low-level viremia may occur in patients with "undetectable" viral load according to standard tests (typically < 50 copies/mL). The implications of this persistent residual virus are not fully understood.

Virological Failure

NoémieBoillat Blanco and fellow investigators with the Swiss HIV Cohort Study conducted a case-control study of cohort participants enrolled between January 2000 and December 2010.

This retrospective analysis included 179 case patients with undetectable HIV RNA for at least 24 weeks on stable ART who presented with persistent low-level virus (21-400 copies/mL) in at least 3 consecutive plasma samples. They were compared against 5389 control patients without low-level viremia, that is, with at least 3 consecutive viral load values < 20 copies/mL for at least 32 weeks. Most were white men and the average age was about 45 years.


  • Compared with the control patients, individuals with low-level viremia had poorer adherence on average.
  • Patients with low-level viremia were also significantly less likely to be taking NNRTI-based ART regimens versus protease inhibitor combinations or regimens consisting only of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).
  • Two-thirds of case patients still had low-level viremia at week 48 of the study.
  • 12% of case patients experienced virological failure, defined as viral load rising to > 400 copies/mL by week 48.
  • Suboptimal adherence and diabetes predicted virological failure, but neither associationreached statistical significance.
  • None of the 26 case patients with very low-level viremia (21-49 copies/mL) experienced virological failure.
  • 48 weeks after the last low-level viremia measurement, 28% of case patients intensified their ART combination.
  • Predictors of switching regimens included ART consisting only of NRTIs and onset of low-level viremia after 2008.
  • Among the case patients who intensified their regimen, 63% had undetectable viral load 24 weeks later, compared with 33% of those who did not switch, a statistically significant difference.
  • 9% of patients who intensified treatment went on to experience virological failure, compared with 12% of those who remained on unchanged ART, not a significant difference.

"Progression to virological failure occurs in a minority of patients up to a year post-low-level viremia and in no patient with very low-level viremia," the researchers concluded.

Combination ART change is driven mainly by the specific regimen at the onset of low-level viremia and the availability of new classes of antiretroviral drugs, they added. While the majority of patients who switched achieved undetectable viral load, the change did not affect the likelihood of virological failure.

CD4 Cell Recovery

In related study, Katerina Psomas from University Hospital of Montpellier in France and colleagues looked at residual viral DNA in CD4 T-cells, and whether its presence was associated with poor CD4 cell recovery.

Impaired CD4 cell restoration in people with undetectable viral load on ART could be explained by ongoing infection of new cells, they noted as background. Even "abortive HIV infection" that does not result in sustained viremia can cause inflammation and CD4 cell apoptosis (cell suicide) in lymphoid tissue.

The researchers collected CD4 cells from 35 ART-treated patients with HIV RNA levels < 50 copies/mL. Their mean age was 48 years and they had been HIV-infected for 7 years on average.

After subcellular fractionation, the researchers used a PCR assay to test for HIV DNA in the cell cytoplasm.


  • HIV DNA was detected in the cytoplasm of CD4 T-cells from 11 patients, or 31%.
  • CD4 cell counts were significantly lower in these individuals than in the other patients without detectable cytoplasm HIV DNA (mean -4 vs +12 cells/mm3 per month).
  • In a subgroup of 20 patients, the percentage of activated CD8 T-cells expressing the CD38 surface marker increased in people with detectable cytoplasm HIV DNA (mean +0.5% per month), compared with a decrease in people with undetectable HIV DNA (mean -1.3% per month).

"These data argue for a role of ongoing HIV infection in persistent immune activation and in the lack of immune restoration in some virologic responders," the investigators concluded. "Our assay could be used to monitor ART simplification, to determine in which patients ART intensification could be beneficial, and to discriminate ongoing infection from other causes of poor [CD4] cell restoration.



N Boillat Blanco, K Darling, F Schöni-Affolter, et al. Persistent Low-level Viraemia in HIV-1-infected Patients: Swiss HIV Cohort Study. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-1566.

KC Psomas, C Mettling, J Reynes, et al. Poor CD4+ T Cell Restoration Linked to Residual HIV-1 Reverse Transcription under Antiretroviral Therapy. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-1570a.