Having a persistent low level of detectable HIV – above 50 copies but below 1000 copies – may raise the risk of experiencing serious non-AIDS conditions such as chronic kidney disease, heart disease and some cancers, a large US cohort study reports in the journal Open Forum Infectious Diseases.
The study investigators say that more research is needed to confirm this finding, but they draw attention to differences in recommendations on how to respond to low-level viraemia. Whereas US guidelines recommend against changing treatment in cases of low-level viraemia, both the European AIDS Clinical Society and the British HIV Association recommend a more active policy. If low-level viraemia above 50 copies is confirmed, resistance testing should follow, the European guidelines recommend. Existing treatment should be maintained only when resistance is not found and the regimen contains a drug with a high barrier to resistance, such as dolutegravir or darunavir.
The study distinguishes between one-off viral blips above 50 copies/ml which are followed by resuppression of HIV, with no change in treatment, and viral load measurements above 50 copies which are confirmed by a second detectable result.
Viral load tests have lower cut-off points of 50 copies/ml or 20 copies/ml below which they do not count the precise number of virus copies detectable.
Viral load detectable above this cut-off but below a specific threshold is defined as low-level viraemia. This threshold varies between guidelines. The World Health Organization defines low-level viraemia as any measurement below 1000 copies/ml, on the basis that if viral load rebounds above this level, this is an indisputable sign of treatment failure. US and UK guidelines, on the other hand, define low-level viraemia as a viral load between 50 copies and 200 copies/ml and define treatment failure as viral load above 200 copies/ml.
The future implications of single or multiple low-level viral load measurements are uncertain; in some circumstances drug resistance may begin to develop when viral load rises above 50 copies/ml, but for others, low-level viraemia may represent a one-off random variation in the test rather than a genuine increase in viral replication. However, several studies have shown that persistent low-level viraemia predicts treatment failure.
Low-level viral replication may contribute to immune activation and might also contribute to subtle organ and blood vessel damage. Because of the lack of research on these questions, researchers of the US Military HIV Natural History Study carried out a study of the relationship between episodes of low-level viraemia and the subsequent risk of experiencing serious non-AIDS events such as cancers, heart disease, vascular disease, kidney disease or liver disease.
The study population consisted of 2528 members of the US Military HIV Natural History Study cohort. The cohort enrols military service personnel who test positive for HIV during active service. Participants were eligible for inclusion in the analysis if they began antiretroviral treatment between 1996 and 2020 and had at least three viral load measurements taken more than six months after starting treatment. Viral load was measured every 6-12 months.
Participants were classified into four mutually exclusive categories which represented their highest-ever viral load measurements during follow-up:
- Virologic failure: at least two viral loads above 200, three months apart, or one viral load measurement above 1000 more than six months after starting treatment
- High-level low viraemia: viral load between 200 and 1000 that did not meet the criteria for virologic failure and was not a single viral blip
- Low-level viraemia: any viral load measurements between 51 and 200
- Virally suppressed: all viral loads below 50 (people who experienced single viral blips above 50 but below 1000, and then resuppressed viral load, were classified as virally suppressed).
Ninety-three percent of study participants were male, 42% were African American, 40% White and 17% Hispanic or of other ethnicity. The median age at diagnosis was 28 years and the median CD4 count at diagnosis was 459. Sixty-three percent started treatment after the year 2000.
Participants were followed for a median of 11 years after starting antiretroviral treatment. During follow-up, 8% reached the low-level viraemia category, 4% the high-level viraemia category and 33% experienced virologic failure. However, when the analysis was restricted to people who started treatment after 2006, the incidence of virologic failure fell dramatically, reflecting improvements in the tolerability and effectiveness of antiretroviral treatment, so that only 7% experienced virologic failure. After 2006, when easier-to-take fixed-dose combinations became the standard form of treatment for HIV,10% reached the low-level viraemia category and 3% reached the high-level viraemia category.
A total of 439 serious non-AIDS events occurred in participants. They included stage 3 chronic kidney disease (192 cases, affecting 7% of all participants), coronary artery disease without heart attack (50 cases), prostate cancer (23 cases) heart attack (22 cases), anal cancer (21 cases), deep vein thrombosis (20 cases) and liver cirrhosis (19). Serious non-AIDS events occurred at a median age of 51 years.
Serious non-AIDS events occurred more frequently in females and White people, as well as in people who were older at the time of HIV diagnosis, diagnosed before 1996, with a longer duration of untreated HIV after diagnosis, with a lower nadir CD4 count or a higher viral load at treatment initiation.
Regression analysis showed that one or more episode of low-level viraemia was associated with a 31% increase in the risk of a serious non-AIDS event compared to remaining virally suppressed, while one or more episode of higher low-level viraemia was associated with a 57% increased risk. Virologic failure raised the risk of a serious non-AIDS event by 75%. These associations persisted when the analysis was restricted to people who started treatment after 2006 and were heightened for higher low-level viraemia (twice the risk).
However, the risk of serious non-AIDS events was much higher in people who took older types of antiretroviral drugs, especially boosted protease inhibitors (3.74 times higher compared with people who took an integrase inhibitor). This raised risk may partially reflect the cardiovascular and metabolic side-effects associated with boosted protease inhibitors. The risk was also higher in people who took non-nucleoside reverse transcriptase inhibitors (2.69 times higher compared to people who took an integrase inhibitor).
The risk of serious non-AIDS events increased with age (37% higher for every 10-year increment in age) and was 37% higher in women.
Why low-level viraemia should raise the risk of serious non-AIDS events is unclear. The study investigators say that low-level viraemia may cause persistent immune activation that is harmful. Another possibility is that if low-level viraemia is caused by inconsistent adherence to antiretroviral treatment, this may be a sign of difficulties in adhering to medications for other chronic conditions too. But the researchers found that low-level viraemia remained associated with serious non-AIDS events even after adjusting for adherence in those who started treatment after 2006.
The study investigators say that a multi-cohort collaborative study is needed to look at the relationship between low-level viraemia and serious non-AIDS events in a larger, more diverse population.
Ganesan A et al. Low-level viremia is associated with serious non-AIDS events in people with HIV. Open Forum Infectious Diseases, published online 30 March 2024.