Canadian investigators have established that individuals who do not experience both an increase in their CD4 cell count of at least 50 cells/mm3, and a fall in their viral load to below 500 copies/ml, within three-to-six months of starting antiretroviral therapy have an increased risk of death. The research, published in the November 1st edition of the Journal of Acquired Immune Deficiency Syndromes, also revealed that less than 95% adherence was a risk factor for not achieving optimum treatment outcomes.
The investigators from the British Columbia Centre for Excellence in HIV/AIDS found that patients who had a discordant response to HIV therapy, defined as either an increase in CD4 cell count but a failure to achieve an undetectable viral load, or an undetectable viral load but no substantial increase in CD4 cell count, were up to two and a half times more likely to die than patients whose treatment had the desired effect on viral load and CD4 cell count.
“Our work has demonstrated that immunologic and virologic responses are important in determining responses”, write the investigators.
Effective antiretroviral therapy can dramatically improve the health and prognosis of HIV-positive individuals by lowering viral load which leads to an improvement in immune function. Research suggests, however, that only 40% - 60% of individuals treated with antiretroviral therapy experience both significant falls in viral load and increases in CD4 cell count, and that between 12% - 23% of patients have neither of these responses. The other patients see an improvement in only one marker – either an increase in CD4 cell count or a fall in viral load – and it is often said that these patients have had a “discordant response” to treatment.
Most of the research on individuals who have had a discordant treatment response has involved patients with previous experience of antiretroviral therapy. To further understand the significance of discordant CD4 and viral load treatment responses, the Canadian investigators designed a study to determine the relationship between discordant responses and non-accidental mortality in patients taking antiretroviral treatment for the first time. Over 1500 patients were involved in the investigators’ analysis which ran between 1996 and 2003.
Demographic details were collected from patients’ records and viral load and CD4 cell count were monitored at baseline, after four weeks of treatment and then at three-monthly intervals.
On the basis of their follow-up CD4 cell counts and viral loads, patients were divided into one of four categories: complete responders (CD4 cell increase of 50 cells/mm3 or more and a fall in viral load to below 500 copies/ml); complete non-responders (CD4 cell increase of less than 50 cells/mm3 and a viral load above 500 cells/mm3); immunologic responders (CD4 cell gain of at least 50 cells/mm3 but a detectable viral load); and, virologic responders (viral load below 500 copies/ml, but CD4 cell gain less than 50 cells/mm3).
The median duration of follow-up was 45 months. A total of 56% of patients were complete responders; 15% had only a virologic response; 12% had only an immunologic response; and 17% had neither a virologic or immunologic response to treatment.
A total of 172 non-accidental deaths occurred during follow-up. The mortality rate was 6% amongst patients who had a complete response to therapy; 11% amongst patients with only a virologic response only; 18% amongst patients who only had an immunologic response; and, 23% amongst patients who had neither response. The difference between these mortality rates was statistically highly significant (p
Compared with individuals who had both an immunologic and virologic response to treatment, patients who only had a virologic response were 1.87 times more likely to die, and the patients who only had an immunologic response were 2.47 times more likely to die. Patients who had neither a virologic nor an immunologic response had a relative hazard of death of 3.48.
Amongst patients who only had a virologic response, older age, a baseline viral load below 100,000 copies/ml and a CD4 cell count below 50 cells/mm3 were associated with a discordant response, as was adherence below 95%.
Individuals who only had an immunologic response were more likely to be younger, injecting drug users, have a viral load above 100,000 copies/ml at baseline and have less than 95% adherence.
“Our analysis has demonstrated that both forms of discordant immunologic and virologic responses to therapy as determined six months after HAART initiation are predictive of non-accidental mortality in treatment-naïve individuals”, write the investigators.
They note that attention is often focused on virologic response to treatment, but they stress that their “analysis has also shown that immunologic responses are important determinants of later mortality on HAART.”
Moore DM et al. Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr 40: 288 – 293, 2005.