Association of Initial CD4 Cell Count and Viral Load With Response to Highly Active Antiretroviral Therapy

To the Editor: Considerable uncertainty and debate exist regarding the appropriate time for initiating antiretroviral therapy for the treatment of HIV (human immunodeficiency virus).¹ British guidelines suggest that treatment should be initiated based on CD4 cell count alone,² while US guidelines recommend treatment based on a CD4 cell count below 500/mm³ or a viral load above 10 000 to 20 000 per mL.^{3 - 4} No prospective study of starting vs delaying the initiation of highly active antiretroviral therapy in patients with higher viral loads has been performed.

We retrospectively compared the outcomes of starting highly active antiretroviral therapy at varying CD4 cell counts and viral loads in a clinical cohort of HIV-infected patients in an ongoing study.⁵ Patients who were starting their first combination antiretroviral regimen with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor after July 1, 1996, were analyzed. Only patients who received at least 6 months of combination antiretroviral therapy were included. We examined 2 outcomes: reduction of HIV RNA to less than 400 copies/mL on at least 1 occasion within 6 months of starting treatment (initial response) and response with no subsequent elevation of HIV RNA to more than 1000 copies/mL (durable response). Baseline characteristics were compared with outcomes using conditional logistic regression.

A total of 553 patients starting highly active antiretroviral therapy received treatment for at least 6 months and were eligible for analysis, with a mean follow up of 824 days. The patients were 74% male, 70% black, 44% injecting drug users, 35% homosexual men, 18% heterosexually infected, and had a mean age of 37 years. The median baseline CD4 cell count was 202/mm³ and median baseline HIV RNA was 35 810 copies/mL. Treatment included nucleoside analogues in all patients and 1 protease inhibitor in 76%, 2 protease inhibitors in 21%, and efavirenz in 3%.

An HIV RNA of less than 400 copies/mL was achieved by 351 patients (63.5%). Only 147 patients had durable responses (42% of initial responders, 27% of total). Table 1 shows the proportion of patients with an initial response and a durable response by baseline CD4 and viral load level. Patients with initial CD4 cell counts greater than 350/mm³were significantly more likely to achieve both an initial and a durable response than patients with lower baseline CD4 cell count levels. Patients with initial CD4 cell counts greater than 500/mm³ had a slightly higher rate of initial and durable response than those with initial CD4 cell counts of 350 to 500 per mm³ (82% vs 73% and 42% vs 35%, respectively). Similarly, patients with baseline HIV RNA levels of 25 000 copies/mL or less were significantly more likely to have virologic responses than those with higher viral loads.

Table 2 shows conditional logistic regression analyses using initial response and durable response as the dependent variables. Patients with initial CD4 cell count levels greater than 350/mm³ were almost twice as likely to achieve an initial and a durable response than patients with lower CD4 cell count, after adjustment for other factors, including viral load. Patients with initial RNA levels of 25 000 copies/mL or less were also significantly more likely to achieve initial and durable responses than those with higher viral loads, after adjustment for CD4 cell count and other factors. The number of nucleoside analogue drugs received prior to combination therapy was inversely associated with achieving an undetectable viral load. Age, sex, and injection drug use history were not associated with outcomes, while black race was associated with a lower odds of achieving a durable response.

These data suggest that the initial timing of antiretroviral therapy should consider both CD4 cell count and viral load. Patients with CD4 cell count levels greater than 350/mm³ or with viral loads of 25 000 copies/mL or less had more favorable initial and durable responses than those with lower CD4 cell counts or higher viral loads. It is possible that patients with lower CD4 cell counts and higher viral loads have more a virulent phenotype of HIV, although there is no evidence of reduced in vitro susceptibility to antiretroviral drugs of viruses from such patients. Because we focused on the specific outcome of virologic response rather than survival, we do not think these data are subject to lead time bias.

Although guidelines have been developed based on the natural history of untreated HIV infection, rather than the likelihood of treatment success, our results support both the British and US guidelines, which recommend starting treatment for patients before the CD4 cell count falls to less than 350/mm³ and for a CD4 cell count less than 500/mm³ or viral load greater than 10 000 to 20 000 copies/mL, respectively. Although these observational data are not derived from a randomized trial, we think they indicate that highly active antiretroviral therapy is more likely to succeed in suppressing viremia when given before immunodeficiency has progress to a moderate or severe level.