Low level viremia

Francesco R. Simonetti, M.D.
Low level viremia is a topic covered in the Johns Hopkins HIV Guide.

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DEFINITION

Antiretroviral therapy (ART) halts HIV-1 replication resulting in the rapid reduction of plasma viral load to undetectable levels. Some people living with HIV-1 (PLWH) experience viral load above limit of detection of clinical assays (20-50 copies/mL) even after years of full suppression. The following definitions can help to frame viremia based on its magnitude, temporal pattern, and clinical implications[12].

  • Low-level viremia (LLV): HIV-1 plasma viral load above the limit of quantification of clinical assays (20-50 copies/mL), usually between 20-500 copies/mL.
  • Viral blip: an episode of LLV that is preceded and followed by suppression below the quantification limit.
  • Persistent LLV: At least two consecutive episodes of LLV. In some individuals LLV can be persistent-intermittent, with episodic viral load below the limit of quantification and/or detection.
  • Very low-level viremia (VLLV): HIV-1 plasma viral load detected by clinical assays but below their limit of quantification cutoffs. In this module, we made no distinction between VLLV and LLV, unless otherwise stated.
  • Residual viremia: cryptic viral load present in most individuals on ART, between 1-10 copies/mL, is detected only by ultrasensitive assays.
  • Virologic failure: repeated HIV-1 plasma viral load of >200 copies/mL after >6m of ART.

Causes: Whether residual viremia is the result of new cycles of HIV-1 replication or viral production from persistently infected cells has been extensively debated[5]. On ART, HIV-1 RNA sequences in plasma usually do not evolve over time, lack resistance to the concurrent drug regimen, and are predominantly identical (clonal), likely being the result of viral production from long-lived infected cells[11]. Recent work has confirmed that HIV-1 viremia nonsuppressible by ART is the result of virus production from clonally expanded CD4+ T cells[7][2]. Reports of viral replication on ART due to low drug penetration and exclusion of immune cells in anatomical sanctuary sites suggest that some residual low-level viral replication on ART cannot be definitively ruled out[14][13]. Nevertheless, the weight of the current evidence argues against viral replication as the major source of persistent viremia.

Risk Factors: Whether ART initiation in more advance stages of HIV-1 infection is associated with a higher frequency of LLV is unclear. However, patients diagnosed and treated during primary HIV-1 infection had 2-fold-lower rates of LLV compared to those who initiated treatment in the context of chronic HIV-1 infection[21]. In several studies, having LLV compared to suppression below the assay detection limit (which varied between studies) was associated with higher pre-ART plasma viral load, larger reservoir size[15], amount of proviral HIV DNA and cell-associated HIV RNA[6], lower CD4 cell count, higher CD8/CD4 ratios[8], and more advanced CDC stage[17].

LLV and risk of virologic failure: There is consistent evidence of increased risk of virologic failure in patients with persistent viremia of 50 to 1,000 copies/mL[12]. However, risk of virologic failure is low in patients with reported high adherence, lack of documented drug resistance, and stable levels of LLV over time.

Immune alterations: There is no clinically meaningful impact of persistent viremia of < 400 copies/mL on the CD4+ T-cell trajectory[12]. In a study of 832 patients on ART, CD8 activation was 1.9% higher among those with LLV of 50 to 200 copies/mL than those with consistent viral suppression[16]. Another study reported an association between viral load >20 copies/mL at least once (median, 81 copies/mL) during 24 months of follow-up and increase in activated CD8+ CD38+ and CD8+ HLA-DR+ cells[20]. More studies are needed to fully understand the impact of persistent LLV on immune activation, inflammation, and microbial translocation.

Morbidity and Mortality: There is no association between LLV and AIDS progression and/or overall mortality[19][18]. However, evidence of other adverse clinical outcomes in patients with LLV is lacking. Any impact on morbidity and mortality is likely to be modest and require a long period of follow-up and a large number of participants to be detected.

HIV-1 Transmission: The risk of HIV-1 transmission is likely to be lower during persistent LLV than during untreated HIV-1. The transmission risk during LLV is unknown but expected to be exceedingly low. Indeed, studies providing evidence that undetectalbe equals untransmissible (U=U) used 200 copies/mL as definition of undetectability[3].

Unanswered questions: To which extent LLV is caused by infectious virions is yet to be determoned. Since only intact gag gene products are required for the production of viral particles, defective proviruses are likely to also contribute to LLV. It is also unclear whether virus responsible for rebound upon ART interruption originates from the same source of LLV. Finally, which immune stimuli cause infected cells to produce virions and maintain LLV for prolonged periods of times remains unknown.

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DEFINITION

Antiretroviral therapy (ART) halts HIV-1 replication resulting in the rapid reduction of plasma viral load to undetectable levels. Some people living with HIV-1 (PLWH) experience viral load above limit of detection of clinical assays (20-50 copies/mL) even after years of full suppression. The following definitions can help to frame viremia based on its magnitude, temporal pattern, and clinical implications[12].

  • Low-level viremia (LLV): HIV-1 plasma viral load above the limit of quantification of clinical assays (20-50 copies/mL), usually between 20-500 copies/mL.
  • Viral blip: an episode of LLV that is preceded and followed by suppression below the quantification limit.
  • Persistent LLV: At least two consecutive episodes of LLV. In some individuals LLV can be persistent-intermittent, with episodic viral load below the limit of quantification and/or detection.
  • Very low-level viremia (VLLV): HIV-1 plasma viral load detected by clinical assays but below their limit of quantification cutoffs. In this module, we made no distinction between VLLV and LLV, unless otherwise stated.
  • Residual viremia: cryptic viral load present in most individuals on ART, between 1-10 copies/mL, is detected only by ultrasensitive assays.
  • Virologic failure: repeated HIV-1 plasma viral load of >200 copies/mL after >6m of ART.

Causes: Whether residual viremia is the result of new cycles of HIV-1 replication or viral production from persistently infected cells has been extensively debated[5]. On ART, HIV-1 RNA sequences in plasma usually do not evolve over time, lack resistance to the concurrent drug regimen, and are predominantly identical (clonal), likely being the result of viral production from long-lived infected cells[11]. Recent work has confirmed that HIV-1 viremia nonsuppressible by ART is the result of virus production from clonally expanded CD4+ T cells[7][2]. Reports of viral replication on ART due to low drug penetration and exclusion of immune cells in anatomical sanctuary sites suggest that some residual low-level viral replication on ART cannot be definitively ruled out[14][13]. Nevertheless, the weight of the current evidence argues against viral replication as the major source of persistent viremia.

Risk Factors: Whether ART initiation in more advance stages of HIV-1 infection is associated with a higher frequency of LLV is unclear. However, patients diagnosed and treated during primary HIV-1 infection had 2-fold-lower rates of LLV compared to those who initiated treatment in the context of chronic HIV-1 infection[21]. In several studies, having LLV compared to suppression below the assay detection limit (which varied between studies) was associated with higher pre-ART plasma viral load, larger reservoir size[15], amount of proviral HIV DNA and cell-associated HIV RNA[6], lower CD4 cell count, higher CD8/CD4 ratios[8], and more advanced CDC stage[17].

LLV and risk of virologic failure: There is consistent evidence of increased risk of virologic failure in patients with persistent viremia of 50 to 1,000 copies/mL[12]. However, risk of virologic failure is low in patients with reported high adherence, lack of documented drug resistance, and stable levels of LLV over time.

Immune alterations: There is no clinically meaningful impact of persistent viremia of < 400 copies/mL on the CD4+ T-cell trajectory[12]. In a study of 832 patients on ART, CD8 activation was 1.9% higher among those with LLV of 50 to 200 copies/mL than those with consistent viral suppression[16]. Another study reported an association between viral load >20 copies/mL at least once (median, 81 copies/mL) during 24 months of follow-up and increase in activated CD8+ CD38+ and CD8+ HLA-DR+ cells[20]. More studies are needed to fully understand the impact of persistent LLV on immune activation, inflammation, and microbial translocation.

Morbidity and Mortality: There is no association between LLV and AIDS progression and/or overall mortality[19][18]. However, evidence of other adverse clinical outcomes in patients with LLV is lacking. Any impact on morbidity and mortality is likely to be modest and require a long period of follow-up and a large number of participants to be detected.

HIV-1 Transmission: The risk of HIV-1 transmission is likely to be lower during persistent LLV than during untreated HIV-1. The transmission risk during LLV is unknown but expected to be exceedingly low. Indeed, studies providing evidence that undetectalbe equals untransmissible (U=U) used 200 copies/mL as definition of undetectability[3].

Unanswered questions: To which extent LLV is caused by infectious virions is yet to be determoned. Since only intact gag gene products are required for the production of viral particles, defective proviruses are likely to also contribute to LLV. It is also unclear whether virus responsible for rebound upon ART interruption originates from the same source of LLV. Finally, which immune stimuli cause infected cells to produce virions and maintain LLV for prolonged periods of times remains unknown.

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Last updated: September 7, 2022