Low HIV viral load doesn't cause inflammation or increase the risk of death

Low level viral load does not increase inflammation or the risk of death, US investigators report in the online journal PloS One.

The investigators had hypothesised that a low viral load would be linked with important markers of inflammation and coagulation, such as C-reactive protein (CRP), fibrinogen and interleukin-6 (IL-6).

Ultra-sensitive assays capable of measuring viral load below 20 copies/ml were used by the researchers.

“Contrary to our hypothesis,” write the investigators, “we found little association of low level viremia with levels of CRP, IL-6 and fibrinogen. Rather there was little association of any HIV RNA level with CRP, and only HIV RNA level > 10,000 copies/ml had a relatively strong association with IL-6 and fibrinogen levels.”

Lead investigator Dr PC Tien said that the study results were likely to prove reassuring for many patients, answering “an important question…namely whether low level viremia is associated with persistent immune activation in patients being treated with HIV".

Long-term HIV infection is associated with chronic inflammation. It has been suggested that this is due to viral replication and the associated immune activation.

Some research has suggested that inflammation can persist even when a patient is taking HIV therapy and has a low viral load. However, these studies used viral load assays with lower limits of detection of 75 or 400 copies/ml.

The availability of an ultra-sensitive assay capable of measuring viral load below 20 copies/ml provided investigators from the Study of FAT Redistribution and Metabolic Change in HIV Infection (FRAM) group to assess the effect of continued HIV replication at extremely low levels on key markers of inflammation and coagulation: CRP, fibrinogen and IL-6. The investigators adjusted their results to take into account immune status, cardiovascular risk factors and demographics. The impact of viral load and inflammation on mortality was also assessed.

“We hypothesized that even low levels of viremia would be associated with ongoing inflammation,” write the investigators.

Their racially diverse study sample included 1116 patients. On the basis of their viral load, they were divided into five categories: undetectable; 1 to 19 copies/ml; 20 to 399 copies/ml; 400 to 10,000 copies/ml and above 10,000 copies/ml.

Overall, little association was detected between viral load and CRP. There was a trend (p = 0.054) for CRP levels to be higher among patients with a viral load above 100,000 copies/ml. “However, the variation in CRP was wide at these very high levels of viremia,” comment the investigators, “and only 86 study participants had levels of HIV RNA above 100,000 copies/ml.”

Even after the investigators adjusted their results for CD4 cell count, demographics, lifestyle factors and levels of adipose tissue, they still failed to find an association between viral load and CRP.

However, higher viral loads were associated with increased levels of IL-6 (p = 0.0031). But the relationship was not linear, and was most apparent for patients with a viral load above 10,000 copies/ml.

Statistical analysis that controlled for demographics, lifestyle factors and adipose tissue showed that there IL-6 levels for similar for patients with a viral load below 10,000 copies compared to those with a viral load zero.

In contrast, individuals with a viral load above 10,000 copies/ml had IL-6 levels that were 89% higher than those observed in patients with a viral load of zero copies. This difference was weakened when CD4 cell count was included in the model but still remained significant (p = 0.022).

Increasing viral load was strongly associated with fibrinogen levels. But once again the relationship was not linear, with steeper increases seen in those with a viral load above 10,000 copies/ml (p = 0.0048).

After adjustment for CD4 cell count, demographics, lifestyle factors and adipose tissue levels fibrinogen was still significantly higher among patients with a viral load above 10,000 copies/ml compared to those with a viral load of zero copies/ml (p < 0.001).

“Our finding that low level viremia had little association with CRP, fibrinogen and IL-6 was somewhat unexpected,” comment the researchers.

Nevertheless, their data showed an association between higher viral load and an increased risk of death (p < 0.001). The five-year mortality rate ranged from 7% for individuals with a viral load of zero copies to 23% for those with a viral load above 10,000 copies/ml. Moreover, after adjusting for mortality the investigators found that every ten-fold increase in viral load increased the risk of death by 39% (p < 0.001).

However, this relationship between viral load and mortality ceased to be significant when the investigators adjusted for CD4 cell count.

‘We conclude that there is little association of low level viremia with levels of CRP, fibrinogen, and IL-6,” write the authors. “Our findings suggest that the mechanisms by which HIV causes inflammation, influences coagulation, and causes mortality are complex. Additional study of mechanistic pathways including markers of microbial translocation are needed.”

Eastburn A et al. Association of low level viremia with inflammation and mortality in HIV-infected adults. Plos One, 6 (11): e26320. doi: 10.1371/journal.pone.0026320, 2011 (click here for the open-access article).