CMV replication associated with increased mortality risk in Thai patients starting HIV therapy

Michael Carter
Published: 12 April 2013

Ongoing cytomegalovirus (CMV) replication is associated with an increased mortality risk for people who start antiretroviral therapy with a low CD4 cell count, Thai investigators report in the online edition of Clinical Infectious Diseases.

Over a quarter of patients had CMV viremia when HIV treatment was initiated and 5% still had detectable virus six months later. A high CMV viral load at baseline was associated with a more than sevenfold increase in mortality risk during the first two years of antiretroviral therapy.

“CMV viremia was associated with mortality irrespective of CD4 counts,” write the authors.

Very little is known about the prevalence of CMV viremia and its association with HIV disease progression and death among people starting antiretroviral treatment in poorer countries.

An international team of researchers therefore retrospectively analysed stored blood samples obtained from 293 people in Thailand who started HIV therapy when their CD4 cell count was below 200 cells/mm3. The researchers examined the prevalence of CMV viremia at baseline and after six months of treatment and its association with mortality and progression to new AIDS-defining events. They also explored the factors associated with the persistence of CMV during HIV treatment.

Most of the patients were men (57%) and their median age was 33 years. The patients had severe immune suppression at baseline, median CD4 cell count being just 82 cells/mm3 and median viral load was approximately 80,000 copies/ml.

CMV was detected in 26% of patients on entry to the study. The prevalence of CMV viremia was related to immune suppression and was highest among patients with the lowest CD4 cell counts (below 50 cells/mm3  = 46% vs 101-200 cells/mm3 = 10%, p < 0.001).

Median baseline CMV viral load was 548 copies/ml.

Overall, the patients had a good response to HIV therapy. After six months, 80% had a HIV viral load below 200 copies/ml and median CD4 cell count had increased to 198 cells/mm3, with 48% of patients having a CD4 cell count above 200 cells/mm3.

Repeat CMV testing was performed for 199 patients at the six-month timepoint. Viremia was detected in nine people (5%) and their median CMV viral load was 114 copies/ml.

A total of eight deaths and 28 new AIDS-defining events were observed over two years. The overall mortality rate was 1.42 per 100 person-years, and the median time to death was 7.5 months after the initiation of treatment. The rate of new AIDS-defining illnesses was 5.39 per 100 person-years, with the median time to the diagnosis of an event being 2.1 months after starting antiretrovirals. No deaths were directly attributed to CMV and only two AIDS-defining illnesses corresponded to CMV disease.

However, six of the eight deaths occurred in patients with a baseline CMV viral load above 500 copies/ml.

Indeed, the investigators’ first analysis showed that a high CMV viral load at baseline was the most important risk factor for death (HR = 21.09; 95% CI< 4.26-104.53, p < 0.001). Also significant were low haemoglobin (HR = 6.87; 95% CI, 1.72-27.49, p = 0.011) and CD4 cell count, with each 50 cell/mm3 increase reducing the risk of death by approximately 20% (p = 0.022).

However, after controlling for potential confounders, a baseline CMV load above 500 copies/ml was the only factor associated with an increased mortality risk (HR = 7.28; 95% CI, 1.32-40.29, p = 0.023).

The investigators’ initial analysis showed that both immune suppression and CMV viremia were associated with the development of new AIDS-defining events. However, in their multivariate analysis only a low CD4 cell count retained a significant association with their outcome (p = 0.048).

Baseline factors associated with ongoing CMV replication after six months of HIV therapy were baseline haemoglobin below 10 g/dl and baseline CMV viral load above 500 copies/ml (HR = 6.63; 95% CI, 1.41-31.08, p = 0.016).

“The prevalence of CMV viremia in our study resembles that seen in several studies in severely immune-suppressed HIV-infected patients in high-income countries,” write the authors. “The association between CMV viremia and increased mortality in HIV patients, even in the context of ART, has also been long reported.”

They believe their findings have significant implications for the care of patients in resource-limited settings. Many people in poorer countries initiate HIV treatment with severe immune suppression and mortality rates during the early months of treatment are high.

The investigators recommended “a large-scale prospective study be conducted to better document the extent of the problem of CMV viremia in severely immune-suppressed HIV patients in resource-limited settings…we believe that a well-powered trial is required to convincingly answer if pre-emptive therapy could reduce early mortality in CMV viremic HIV patients starting ART.”

Reference

Durier N et al. Cytomegalovirus viremia in Thai HIV-infected patients on antiretroviral therapy: prevalence and associated mortality. Clin Infect Dis, online edition, 2013.

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