Disease progression is rare in HIV-positive individuals who start highly active antiretroviral therapy (HAART) with a CD4 cell count below 50 cells/mm3 and then achieve a sustained increase in CD4 cell count of over 100 cells/mm3, according to a long-term follow-up study published in the November 15th edition of Clinical Infectious Diseases. The US investigators also found that the only factor significantly associated with disease progression was a detectable viral load on HAART.
An improvement in immune function is expected in patients whose antiretroviral therapy suppresses viral load. However, there are concerns that individuals who start HAART when they have very severe immune suppression may not experience complete or durable immune recovery. In addition, the long-term immunological and health benefits of HAART for severely immunosuppressed patients have not been extensively investigated.
US investigators involved in the AIDS Clinical Trials Group (ACTG) 362 study (an investigation into the safety of stopping prophylaxis for the opportunistic infection Mycobacterium avium intracellulare [MAI] after experiencing immune recovery with HAART), examined the long-term clinical and immunological outcomes of patients who started HAART with a CD4 cell count below 50 cells/mm3
To be included in the study individuals were required to have had a CD4 cell count below 50 cells/mm3 prior to starting antiretroviral therapy and to have had a sustained gain of at least 100 cells/mm3 after starting HAART. Individuals were recruited from the autumn of 1997 to the spring of 1999 and follow-up was provided until May 2002.
Investigators focused their analysis on occurrences and rates of opportunistic infections, changes in CD4 cell count, and alteration in viral load.
A total of 612 individuals were included in the investigators’ analysis. Median age was 40 years, 87% were male, the median CD4 cell count was 227 cells/mm3 and 63% of patients had a viral load below 500 copies/ml. Prior to entry to the study 62% of patients had been diagnosed with at least one AIDS-defining illness.
During the follow-up period, which provided 1882 person-years of follow-up, a total of 33 patients developed at least one new AIDS-defining condition. The overall rate of new AIDS events was 1.75 per 100 person years. Twelve of the individuals diagnosed with an AIDS-defining illness had never previously been diagnosed with AIDS.
Interestingly, over 40% of individuals developed an AIDS-defining condition when their CD4 cell count was above 200 cells/mm3, the usual threshold suggesting an increased vulnerability to opportunistic infections.
In both univariate and multivariate Cox proportional hazards models only a detectable viral load on entry to the study was found to be significantly associated with an increased risk of developing an AIDS-defining condition (p
There were a total of 31 deaths during 1934 person-years of follow-up, the overall death rate being 1.60 per 100 person-years. However, only five deaths were directly attributable to HIV-related causes. Of note five patients died of cardiovascular events, and five patients died from liver failure related to coinfection with hepatitis B or C virus.
Using a Cox proportional hazard model, the investigators established that only a detectable viral load (p = 0.02) and a Karnofsky score below 80, an indicator of increased care needs (hazard ratio 2.47) were associated with a decreased risk of AIDS-free survival.
Overall, median CD4 cell count increased by 5.9 cells/mm3 every eight weeks. The degree of increase in CD4 cell count was related to whether or not an individual had a undetectable viral load at baseline. Patients with a viral load below 500 copies/ml gained a median of just over 7 cells/mm3 compared to a median gain of only 3 cells/mm3 every eight weeks for patients with a viral load above 500 copies/ml.
The investigators conclude that in their population of severely immune suppressed patients who started HAART and experienced an immunological benefit “opportunistic infections and / or complications (including death) are relatively infrequent but can occur at any time, even for patients who maintain increases in their CD4 cell count. Physicians…must be aware of atypical presentations or altered natural histories of classic opportunistic infections. There are likely to be a number of immune factors that affect immune recovery.”
Koltar SL et al. Long-term follow-up of HIV-infected individuals who have significant increases in CD4 cell counts during antiretroviral therapy. Clin Infect Dis 39: 1500-1506, 2004.