The chances of achieving and maintaining a CD4 count of 800 or higher are best among those who start antiretroviral therapy early, according to long-term data published in the June 1 issue of the Journal of Acquired Immune Deficiency Syndromes. Results from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study suggest that restoration of CD4 counts to levels normally seen in uninfected individuals takes a long time and is not feasible within seven years in most patients who initiate treatment with CD4 counts below 350.
Researcher Luuk Gras, MSc, of the HIV Monitoring Foundation in Amsterdam and his colleagues looked at long-term CD4 count gains among 5300 HIV-positive patients starting antiretroviral therapy for the first time.
Three major study objectives were defined by the authors. The first was to determine the time it took all patients in the study to get their CD4 counts above 800 while on treatment. The second was to determine the average CD4 cell count increase after seven years of uninterrupted combination drug therapy among a subset of 544 patients. The third was to evaluate the leveling off, or plateau, in the CD4 counts among 366 patients with undetectable viral loads while on treatment for five years.
Overall, 46% of patients who commenced therapy with a CD4 count between 200 and 350 – the start point currently recommended by the U.S. Department of Health and Human Services (DHHS) and other expert panels in their HIV treatment guidelines – got their counts above 800 after seven years of uninterrupted treatment. Among those starting with CD4s between 350 and 500 or above 500, 73% and 87%, respectively, ended up with CD4 counts above 800.
Women and people with higher pre-treatment viral loads (greater than 100,000) required less time to get their CD4 counts above 800. Older age, being of a Southeast Asian or sub-Saharan African origin, or having acquired HIV through intravenous drug use were associated with longer times in reaching a CD4 count of 800 or better.
While the researchers note that patients beginning therapy with low CD4 counts experienced a much slower increase in the number of their disease fighting cells, the CD4 count gains seen were not insignificant. Among those who started treatment with CD4 counts between 200 and 350, for example, the average CD4 count seven years later was 660. Among those with a pre-treatment CD4 count of less than 50 or between 50 and 200, the average CD4 counts after seven years of treatment was 410 and 548 – all robust responses to antiretroviral therapy.
The study authors also point out that there were patients who experienced sharp CD4 cell gains during the first few years of therapy, only to hit a plateau and slow CD4 decrease after five years. Even where decreases were observed, CD4 counts remained within the normal ranges. According to Mr. Gras and his colleagues, the plateaus were associated with "insufficient suppression of HIV replication and with older age at the start of drug combination therapy." The authors suggested that it may be appropriate to begin patients over the age of 50 on HIV treatment sooner than younger patients.
Although these new data suggest that it may be best to start antiretroviral therapy early in order to maintain maximal CD4 cell counts, not all HIV specialists are convinced. "While this study appears to be promising, we can't know for sure that there is a real clinical benefit in those extra cells," said Lloyd E. Bailey, MD, an HIV-treating physician at St. Vincent's Midtown Hospital in New York City. "We need more information on the risk these medications cause to patients – their side effects, their cost, and their ability to produce drug resistance – against the possible benefits of putting people on drug therapies sooner."
In light of these concerns, experts have generally refrained from recommending therapy to patients with CD4 counts above 350. But as Mr. Gras's team writes in their conclusion, "given the better toxicity profiles of the currently used antiretroviral combinations, particularly in patients older than 50 years of age, it may be beneficial to start [antiretroviral therapy] earlier than current guidelines recommend.
And editorial that accompanies the ATHENA data, prepared by Evan Wood, PhD, and Julio S. Montaner, MD, of the British Columbia Centre for Excellence in HIV/AIDS, seems to concur. "As [treatment] evolves over time," Drs. Wood and Montaner write, "newer regimens tend to be simpler and safer. This progressively opens the door for a broader re-evaluation of the ideal time to start therapy, incorporating outcomes other than survival, such as the level of immune reconstitution demonstrated by [Gras's group]."
Wood E, and Montaner JSG. When to initiate HIV antiretroviral therapy: do benefits other than survival deserve greater attention? J Acquir Immune Defic Syndr 45(2):131-2, 2007.
Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr 45(2):183-92, 2007.