Q&A: Understanding persistent low-level viremia in people with HIV

Paul E. Sax, MD
Paul E. Sax

Persistent low-level viremia among people living with HIV who are adhering to treatment is a challenging issue for clinicians, and there is not much guidance available.

In a 2017 blog post, Paul E. Sax, MD, clinical director of the HIV program and the division of infectious diseases at Brigham and Women’s Hospital in Boston, responded to a clinician caring for a patient who was experiencing persistent low-level viremia despite adherence to medication. He acknowledged the challenge of treating these patients, but also asked if the clinician had switched to using RT-PCR, which is more sensitive than bDNA testing and could account for a patient going from being “undetectable” to low-level detectable. However, some patients have persistent low-level viremia even when the assay has not changed.

According to Sax, it can be tough to address concerns about “Undetectable = Untransmittable” because it is not clear if patients with low-level viremia are more likely to transmit HIV compared with people who are undetectable. However, he noted that major HIV studies set the viral threshold higher than levels seen in most patients with low-level viremia, which is “at least somewhat reassuring,” Sax wrote.

Infectious Disease News spoke with Sax about the causes of low-level viremia, the risk for treatment failure or transmission and the impact on long-term outcomes. – by Marley Ghizzone

What are the causes of persistent low-level viremia?

It is a very complicated topic. There are a variety of risk factors for people who have [low-level viremia]. One is that it seems people who have very large HIV reservoirs are more likely to have persistent low-level viremia. Those typically are people who have had very high viral loads before treatment, or have long-term HIV infection with years of uncontrolled viremia — mostly the former.

In addition, several studies have found that people who were on protease inhibitor-based regimens are more likely to have low-level viremia than people receiving regimens based on integrase inhibitors or on non-nucleoside reverse-transcriptase inhibitors (NNRTIs).

Separate from this group are those people who inconsistently take their antiretrovirals, which you can determine by scrutinizing their medication adherence. I think of them as people who have the equivalent of “white coat adherence,” meaning that a week or two before they are about to see their doctor, they start taking their HIV medication more faithfully.

Is low-level viremia common?

Low level viremia is common enough that every experienced HIV clinician has seen at least one — and usually more than one — patient with this condition, and sometimes a bunch of them. I lead many educational sessions where I am talking to people who are in ID/HIV practice and I say, “Raise your hand if you have a patient who always has a detectable viral load, somewhere between 20 and 100, 200 copies.” Almost invariably, almost everyone in the room — if it is a group if experienced HIV clinicians — will raise their hand. One large study from Spain found that around 4% had low-level viremia.

Does low-level viremia in HIV patients put them at greater risk for treatment failure , or does it increase the risk for transmission?

If patients are truly faithful in taking their treatment and they have no history of resistance, we now know they do not develop resistance to their treatment, especially among those with between 50 and 100 copies/mL — those with really low-level viremia. However, if you consider in that group people with intermittent/poor adherence, then those individuals are at greater risk for treatment failure. That probably has more to do with the fact that they are not taking their medication consistently. The latest evidence on this is — leaving out adherence issues — in people who take their medication but always have some degree of detectable virus, that virus is not replicating in the same way and not developing resistance to their regimen. We know from prospective studies that intensification — meaning adding drugs — does not help, nor generally does switching the regimen.

This is very important. Studies clearly show that the next threshold above 50 to 200 copies/mL —200 to 500 copies/mL and especially 500 to 1,000 copies/mL — is clinically significant. Patients do develop resistance in that threshold. In summary, it goes very quickly from what is probably a relatively benign observation (50 to 200 copies/mL) to one that is potentially impactful (above 500 copies/mL).

What regimens do clinicians recommend to patients who hover just above the detectable threshold?

I do not think there is any difference in the regimens that I would recommend. If you are worried that your patient’s adherence is partially the issue, then you want to have a regimen that has a high resistance barrier, meaning that it will be difficult to develop resistance to the components of the regimen. Those would be the second-generation integrase inhibitors — bictegravir and dolutegravir — or a boosted protease inhibitor. Those would be preferable over an NNRTI-based regimen or a first-generation integrase inhibitor. However, for most patients who are adherent to treatment, changes for low-level viremia alone are not recommended.

If a patient is adherent to their medication but has low levels of viremia, can it impact their long-term outcome?

Based on what we know now, for those with viral loads between 20 and 200 copies/mL, the answer is generally no — or if it does, then it represents a factor related to their HIV reservoir and ongoing inflammation and immune activation, and is not amenable to any specific therapy. Regarding transmission, if you look across all the studies that have evaluated risk factors and ask, “What is the lower threshold that they use in those studies?”, they typically had much higher thresholds than what we consider low-level viremia. The Rakai cohort of untreated patients used 1,500 copies/mL, HPTN O52 used 400 copies/mL, and the PARTNERS and Opposites Attract studies used 200 copies/mL. Basically, if you are consistently below 200 copies/mL, we do not have any evidence that transmission is going to occur.

My final point: Anybody who is managing these cases should feel free to reach out to HIV experts if they themselves are not doing a lot of HIV care, just to make sure. Their patients might also be eligible for research studies exploring the causes and implications of this interesting and still perplexing phenomenon.

Reference:

Sax PE. What Should We Do About Persistent Low-level Viremia?. NEJM Journal Watch, HIV and ID Observations. Posted October 9, 2017. https://blogs.jwatch.org/hiv-id-observations/index.php/persistent-low-level-viremia/2017/10/09/. Accessed March 12, 2019.

Disclosure: Sax reports no relevant financial disclosures.

Paul E. Sax, MD
Paul E. Sax

Persistent low-level viremia among people living with HIV who are adhering to treatment is a challenging issue for clinicians, and there is not much guidance available.

In a 2017 blog post, Paul E. Sax, MD, clinical director of the HIV program and the division of infectious diseases at Brigham and Women’s Hospital in Boston, responded to a clinician caring for a patient who was experiencing persistent low-level viremia despite adherence to medication. He acknowledged the challenge of treating these patients, but also asked if the clinician had switched to using RT-PCR, which is more sensitive than bDNA testing and could account for a patient going from being “undetectable” to low-level detectable. However, some patients have persistent low-level viremia even when the assay has not changed.

According to Sax, it can be tough to address concerns about “Undetectable = Untransmittable” because it is not clear if patients with low-level viremia are more likely to transmit HIV compared with people who are undetectable. However, he noted that major HIV studies set the viral threshold higher than levels seen in most patients with low-level viremia, which is “at least somewhat reassuring,” Sax wrote.

Infectious Disease News spoke with Sax about the causes of low-level viremia, the risk for treatment failure or transmission and the impact on long-term outcomes. – by Marley Ghizzone

What are the causes of persistent low-level viremia?

It is a very complicated topic. There are a variety of risk factors for people who have [low-level viremia]. One is that it seems people who have very large HIV reservoirs are more likely to have persistent low-level viremia. Those typically are people who have had very high viral loads before treatment, or have long-term HIV infection with years of uncontrolled viremia — mostly the former.

In addition, several studies have found that people who were on protease inhibitor-based regimens are more likely to have low-level viremia than people receiving regimens based on integrase inhibitors or on non-nucleoside reverse-transcriptase inhibitors (NNRTIs).

Separate from this group are those people who inconsistently take their antiretrovirals, which you can determine by scrutinizing their medication adherence. I think of them as people who have the equivalent of “white coat adherence,” meaning that a week or two before they are about to see their doctor, they start taking their HIV medication more faithfully.

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Is low-level viremia common?

Low level viremia is common enough that every experienced HIV clinician has seen at least one — and usually more than one — patient with this condition, and sometimes a bunch of them. I lead many educational sessions where I am talking to people who are in ID/HIV practice and I say, “Raise your hand if you have a patient who always has a detectable viral load, somewhere between 20 and 100, 200 copies.” Almost invariably, almost everyone in the room — if it is a group if experienced HIV clinicians — will raise their hand. One large study from Spain found that around 4% had low-level viremia.

Does low-level viremia in HIV patients put them at greater risk for treatment failure , or does it increase the risk for transmission?

If patients are truly faithful in taking their treatment and they have no history of resistance, we now know they do not develop resistance to their treatment, especially among those with between 50 and 100 copies/mL — those with really low-level viremia. However, if you consider in that group people with intermittent/poor adherence, then those individuals are at greater risk for treatment failure. That probably has more to do with the fact that they are not taking their medication consistently. The latest evidence on this is — leaving out adherence issues — in people who take their medication but always have some degree of detectable virus, that virus is not replicating in the same way and not developing resistance to their regimen. We know from prospective studies that intensification — meaning adding drugs — does not help, nor generally does switching the regimen.

This is very important. Studies clearly show that the next threshold above 50 to 200 copies/mL —200 to 500 copies/mL and especially 500 to 1,000 copies/mL — is clinically significant. Patients do develop resistance in that threshold. In summary, it goes very quickly from what is probably a relatively benign observation (50 to 200 copies/mL) to one that is potentially impactful (above 500 copies/mL).

What regimens do clinicians recommend to patients who hover just above the detectable threshold?

I do not think there is any difference in the regimens that I would recommend. If you are worried that your patient’s adherence is partially the issue, then you want to have a regimen that has a high resistance barrier, meaning that it will be difficult to develop resistance to the components of the regimen. Those would be the second-generation integrase inhibitors — bictegravir and dolutegravir — or a boosted protease inhibitor. Those would be preferable over an NNRTI-based regimen or a first-generation integrase inhibitor. However, for most patients who are adherent to treatment, changes for low-level viremia alone are not recommended.

PAGE BREAK

If a patient is adherent to their medication but has low levels of viremia, can it impact their long-term outcome?

Based on what we know now, for those with viral loads between 20 and 200 copies/mL, the answer is generally no — or if it does, then it represents a factor related to their HIV reservoir and ongoing inflammation and immune activation, and is not amenable to any specific therapy. Regarding transmission, if you look across all the studies that have evaluated risk factors and ask, “What is the lower threshold that they use in those studies?”, they typically had much higher thresholds than what we consider low-level viremia. The Rakai cohort of untreated patients used 1,500 copies/mL, HPTN O52 used 400 copies/mL, and the PARTNERS and Opposites Attract studies used 200 copies/mL. Basically, if you are consistently below 200 copies/mL, we do not have any evidence that transmission is going to occur.

My final point: Anybody who is managing these cases should feel free to reach out to HIV experts if they themselves are not doing a lot of HIV care, just to make sure. Their patients might also be eligible for research studies exploring the causes and implications of this interesting and still perplexing phenomenon.

Reference:

Sax PE. What Should We Do About Persistent Low-level Viremia?. NEJM Journal Watch, HIV and ID Observations. Posted October 9, 2017. https://blogs.jwatch.org/hiv-id-observations/index.php/persistent-low-level-viremia/2017/10/09/. Accessed March 12, 2019.

Disclosure: Sax reports no relevant financial disclosures.