Almost, but not quite, HIV undetectable. Is that a problem?

If your viral load isn’t undetectable—but is close—is there any impact on your health?

Most people living with HIV who are taking antiretrovirals (and are adherent) maintain undetectable viral loads. Yet a small number of people experience viral “blips,” where their viral loads spike and then come back down to undetectable levels, or persistent low-level viremia, where viral loads hover at levels just above undetectable.

A new study, by Enrique Bernal, MD, PhD and colleagues published in JAIDS, investigated the impact of low-level viremia on the health of people living with HIV. People who experienced mid-level* persistent viremia were at a significantly higher risk of virologic failure, AIDS-related conditions and death than people who remained undetectable, while people who experienced low-level viremia had clinical outcomes similar to people who remained undetectable.

“This study confirms what we already know about HIV treatment,” said HIV specialist Neal Sheran, MD, clinical chief of special populations at Clinica Esperanza HIV and Homeless Services (who was not affiliated with the study). “It’s not entirely surprising that people who had viral loads between 200 and 500 copies go on to have worse outcomes. The biggest take-away for me—which was actually really reassuring—was the people with low-level viremia don’t seem to have clinically significant differences in outcomes than people with undetectable viral levels.”

What did the study find?

The study included 5,986 people living with HIV who were on antiretroviral therapy (ART) for at least six months and had achieved viral suppression (less than 50 copies/mL) within the first 3 – 9 months after ART start. People participated in the study for different lengths of time, with the median length of follow-up time being more than three years.

Most people remained undetectable

Out of the nearly 6,000 people included in the study, 93% of people remained undetectable throughout the duration of the study.

A total of 237 (4%) experienced low-level viremia (at least two consecutive viral loads in the range of 50 – 199 copies/mL for at least one month, with no viral loads over 199 copies).

A total of 168 (3%) experienced mid-level viremia (at least two consecutive viral loads between 50 and 499 copies/mL for at least one month, with at least one viral load between 200 and 499 copies).

ART regimen and initial viral load influence risk of persistent viremia

Compared to people who remained undetectable, people were more likely to experience low-level viremia if they were taking ART regimens that were not composed of 2 NRTIs and 1 integrase inhibitor, if they started HIV treatment before 2012, and if they started HIV treatment with viral loads over 100,000 copies/mL.

Similarly, people were more likely to experience mid-level viremia if they were taking a protease inhibitor-based regimen, if they had CD4 counts less than 200 cells/mL, if they started HIV treatment before 2012, and if they started HIV treatment with a viral load over 100,000 copies/mL.

Higher risk of death or AIDS events for people with mid-level, but not low-level, viremia

There were significant differences in the proportion of people who experienced an AIDS-related condition or who died after five years of follow-up between the different groups:

• 9% in participants with no low-level viremia
• 0% in participants with low-level viremia
• 19% in participants with mid-level viremia

Nearly one-fifth of people experiencing mid-level viremia developed an AIDS-related condition or died after five years, a finding the researchers describe as “particularly noteworthy.”

“We identified a strong association between viremia 200-499 copies per mm and the development of AIDS events/death, whereas viremia between 50-199 was not significantly associated with clinical progression. This finding substantiates that persistent low-grade HIV replication may accelerate disease,” said Enrique Bernal, MD, PhD, and colleagues.

Higher risk of virological failure for people with mid-level, but not low-level, viremia

A total of 280 people experienced virological failure during the study. (Virological failure means that HIV medications have stopped working completely against HIV.) People who experienced mid-level viremia experienced the highest rate of virological failure.

• 4% of people with no low-level viremia experienced virological failure
• 3% of people with low-level viremia experienced virological failure
• 5% of people with mid-level viremia experienced virological failure

The difference in virological failure rates between people who remained undetectable and those experiencing low-level viremia was not significant after adjusting for patient characteristics at the beginning of the study.

The study’s take-aways

Most people who achieved an undetectable viral load within 3 – 9 months of starting ART remained undetectable through the follow-up period—a testament to the efficacy of modern-day ART regimens when adherence is high.

“The majority of patients who are undetectable, stay undetectable,” said Sheran. “When everything is going properly, when you’re on a regimen and you don’t have resistance, when you’re taking the medications the way you’re supposed to, if you’re taking medications with food if necessary, if you’re not taking any interacting medications, most people stay undetectable.”

People who experience low-level viremia between 50 – 200 copies can be reassured by the study, said Sheran, since the differences in health outcomes did not reach clinical significance between people experiencing low-level viremia and those who remained undetectable.

Mid-level viremia, between 200 – 500 copies, carries the risk of drug resistance developing and virologic failure, along with the longer-term health consequences identified by this study.

“The longer you’re on medications with a viral load over 200, there is the potential to develop resistance,” said Sheran. “This viremia could be explained by difficulties with adherence, a drug-drug interaction, or existing underlying resistance. For these patients, we would make sure to really focus on interacting medications, food requirements, and medication adherence—follow these people closely, to figure out if it’s worth switching their medication regimen.”

Source

Bernal, E. and colleages. Low-level viremia is associated with clinical progression in HIV-infected patients receiving antiretroviral treatment. JAIDS, July 2018.

*The term “mid-level viremia” is used in this article for ease of understanding although the study authors did not use this terminology in the original paper. The study authors designated two different levels of “low-level viremia”: between 50 – 199 copies/mL and between 200 – 499 copies/mL (the latter which is here termed “mid-level”). Also of note is that current DHHS guidelines classify viral loads over 200 copies/mL as virologic failure, in contrast to the study author’s classification of viral loads between 200 – 500 copies/mL as “low-level viremia.”