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Two New Looks at the Question of "When to Start?" Reemphasize 200 as the Critical Threshold

Neither achieving virologic suppression nor excellent medication adherence countered the impaired survival associated with starting therapy after the CD4-cell count fell below 200.

Since there has never been -- and might never be -- a randomized clinical trial comparing outcomes of antiretroviral therapy initiated at varied CD4-cell-count thresholds , the best guidance on when to start therapy comes from cohort studies. Despite their inherent biases, these studies have proven invaluable in shaping our current treatment guidelines, particularly around the question of when to initiate therapy. Reports from two large, well-established clinical cohorts provide additional important observations regarding this key clinical question.

Sterling and colleagues identified patients from the Johns Hopkins HIV Cohort who started triple-drug antiretroviral therapy between July 1996 and June 2002 and continued therapy for at least 90 days. They then categorized these patients according to whether they achieved durable virologic suppression, which was defined as having more undetectable (<400 copies/mL) than detectable viral load measurements after starting treatment.

Of the 1173 patients who initiated triple-drug therapy, 628 (54%) met the study criteria for durable virologic suppression. Despite their good virologic responses, it was apparent during follow-up (median, 36 months) that patients who started therapy with CD4 counts <200 cells/mm³ experienced significantly more rapid disease progression than those who started therapy with baseline CD4 counts >350 cells/mm³. A trend toward more rapid disease progression was also noted among those with baseline CD4 counts of 201-350 cells/mm³ (P=0.09); disease progression did not differ significantly between patients who started therapy at CD4 counts of 201-350 cells/mm³ and those who started therapy at CD4 counts >350 cells/mm³.

Wood and colleagues studied patients who initiated treatment between August 1996 and July 2000 in the British Columbia HIV/AIDS drug-treatment program, which is the source of antiretrovirals for 99% of the HIV-infected individuals in the province who are receiving therapy. Thus, prescription refill rates at this center are an extremely accurate proxy for medication adherence. The primary endpoint was the time to death.

Evaluable data were available for 1422 patients (84% men) who started triple-drug therapy during the study and were followed for 2 to 6 years. The primary analysis compared patients who were moderately adherent (filling at least 75% of prescriptions during the first year of therapy) with patients who were less adherent; a subanalysis evaluated patients with excellent adherence (filling at least 95% of prescriptions).

Among patients with moderate adherence and among the subgroup with excellent adherence, starting treatment at a CD4 count <200 cells/mm³ was associated with lower overall survival compared with starting therapy at a higher CD4-cell count. For patients with moderate adherence and for the subgroup with excellent adherence, survival did not vary significantly, based on comparisons between any CD4 strata >200 cells/mm³ at the time of therapy initiation. However, those who were less adherent had higher mortality rates than moderately adherent patients, regardless of their CD4-cell count when starting therapy.

How do these studies add to our understanding of when to start treatment in asymptomatic patients? Both provide further evidence of worse clinical outcomes when treatment is started after the CD4 count has fallen below 200 cells/mm³, even when other factors, such as virologic suppression or medication adherence are optimal. These findings suggest a degree of irreversible immunosuppression with advancing HIV disease, a hypothesis supported by other clinical and laboratory studies (see AIDS 2003; 17:2015 and ACC Research Notes December 2003). The study by Wood shows that starting therapy at higher CD4 thresholds does not counter the effects of poor adherence. On the controversial subject of whether therapy should be started before the CD4 count dips below 350 cells/mm³, neither of these studies demonstrated any advantage to starting at this threshold rather than at the 200 cells/mm³ threshold.

— Paul E. Sax, MD

Dr. Sax is Editor-in-Chief of ACC.

Published in AIDS Clinical Care February 1, 2004

Citation(s):

Sterling TR et al. Improved outcomes with earlier initiation of highly active antiretroviral therapy among human immunodeficiency virus-infected patients who achieve durable virologic suppression: Longer follow-up of an observational cohort study. J Infect Dis 2003 Dec 1; 188:1659-65.

• Medline abstract (Free)

Wood E et al. Effect of medication adherence on survival of HIV-infected adults who start highly active antiretroviral therapy when the CD4+ cell count is 0.200 to 0.350 x 10⁹ cells/L. Ann Intern Med 2003 Nov 18; 139:810-6.

• Original article (Subscription may be required)
• Medline abstract (Free)