When to begin HAART for the first time continues to be more of an art than an exact science, as randomised clinical trials to assess this conundrum are unfeasible, and experts have to rely on observational data from large clinical cohorts, taking into account factors such as disease progression; short, medium and long-term drug toxicity; and the readiness of patients to take HAART, in order to avoid adherence issues that can lead to resistance.
Whilst current UK guidelines recommend that “treatment should be initiated when the CD4 count is between 200 and 350 cells/mm3,” those who author the US Guidelines say that treatment should begin when the CD4 count hits 350 cells/mm3.
Adding to the debate is a paper published in the latest online issue of Clinical Infectious Diseases which uses data from the Centers for Disease Control and Prevention’s Adult and Adolescent Spectrum of HIV Disease (ASD) Project, a medical record surveillance project from 11 US cities, which began in 1990.
In order to assess progression to AIDS-related opportunistic illness or death as it relates to CD4 count and plasma HIV viral load, data from 2,729 patients who began HAART for the first time after January 1996 were analysed. The cut-off point for all data was December 2002. Although 60% of the patients included in the analysis began HAART prior to 1999, the median follow-up time was only 21 months, which may be too short to detect subtle differences in survival and disease progression.
As expected, the probability of progression to AIDS or death was highest amongst those who began HAART with the very lowest CD4 counts. Compared to those who began HAART with a CD4 count of 500 or above, those who began with a CD4 count below 200 cells/mm3 were much more likely to progress or die, the difference being highly statistically significant (p3 were also at some risk of progression to AIDS or death (p = 0.004) compared with those who began with a CD4 count of 500 or above.
However, when CD4 count and viral load were both taken into consideration, those with a CD4 count below 200, regardless of viral load (pand a high viral load (defined here as above 100,000 copies/ml; p = 0.006) and those with a CD4 count between 350 and 499 and a high viral load (p = 0.002), were all found to be at a significantly higher risk of disease progression or death compared to those who began HAART with a CD4 count of 500 or above, regardless of viral load.
Results from multiple regression models found that the risk of progression or death as measured by hazard ratio (HR) was again highest for those with CD4 counts between 0-50 (HR = 6.3), and 50-199 (HR = 3.5). The difference in hazard ratio for those who began HAART with CD4 counts between 200-349 (HR = 1.7) and 350-499 (HR = 1.5) were similar, with overlapping confidence limits.
However, when taking viral load into consideration a slightly different picture emerges. A CD4 count between 50-199 combined with a viral load below 100,000 copies/ml has essentially the same risk as a CD4 count between 200-349 or 350-499 with a viral load above 100,000 copies/ml (HR = 2.5, 2.2 and 3.1, respectively, with overlapping confidence limits). The risk of progression to AIDS or death is only small with CD4 counts between 200-349 and 350-499 when viral load is below 100,000 copies/ml (HR = 1.3 and 1.4, respectively, with similar confidence limits).
The authors appreciate that due to the observational nature of these data, the results “inform but do not directly address the question of when to initiate HAART”, and suggest that HAART should definitely begin before the CD4 count reaches 200 cells/mm3, as per the UK guidelines. “A decision to initiate therapy when the patient’s CD4 cell count is 200-349 cells/mm3 should clearly be discussed with the patient, and the decision-maker should take into account current uncertainties related to disease progression, development of drug toxicities, emergence of antiretroviral drug resistance, and impact on quality of life,” they conclude.
In addition, they suggest that additional research, “including studies with longer periods of follow-up,” is needed.
Further information on this website
Starting HAART at low CD4 count can mean that functional immune response blunted - news story September 2003
No CD4 plateau found after 4 years on HAART in those with prior severe immune suppression - news story August 2003
When to start anti-HIV therapy - menu of information
HIV therapy - booklet in the information for HIV-positive people series (pdf)
Kaplan JE et al. When to begin Highly Active Antiretroviral Therapy? Evidence supporting initiation of therapy at CD4+ lymphocyte counts Clinic Infect Dis 37: 951-958, 2003.