When to Start ART?

Abstract & Commentary

Synopsis: Data from a prospective cohort study demonstrate benefit from initiation of antiretroviral therapy at CD4 counts of 201-350/mm3. The possibility of benefit from initiation at even higher CD4 counts was also raised.

Source: Palella FJ, et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med. 2003;138:620-626.

Members of the CDC and the HIV Outpatient Study (HOPS) investigators prospectively assessed the survival benefit of initiating antiretroviral therapy (ART) at varying CD4+ lymphocyte counts. HOPS is an ongoing prospective, observational cohort study with continuous recruitment since 1993 at 10 clinics in 8 US cities. ART was initiated at the discretion of the treating physician.

Participants in the cohort were grouped by CD4 strata. Most patients who did not begin therapy while in their initial stratum did subsequently start ART at the next lower or lowest strata. These patients who deferred therapy until their CD4 count had dropped them into a lower stratum were considered to have delayed therapy. Analysis at baseline found that "initiators" and "delayers" differed in 2 regards: Patients in the middle CD4 stratum who had private insurance tended to initiate rather than delay ART, and men in the highest CD4 stratum tended to delay therapy.

The mortality rates of those who initiated and those who delayed ART when their CD4 count was 201-350/mm3 were 15.4 and 56.4 deaths per 1000 person-years, respectively (rate ratio, 0.27; [95% CI, 0.14-0.55]; P < .001) (see Table 1, below). There was no significant difference between groups when therapy was either initiated or delayed at CD4 counts of 501-750/mm3. In the middle stratum (CD4 351-500/mm3), the death rates per 1000 person-years were 10.6 and 16.6 for initiators and delayers, respectively (rate ratio, 0.61; [95% CI, 0.22 to 1.67]; P = .17]. Patients in both the low and middle strata who initiated therapy were more likely than those who delayed it to achieve an undetectable plasma HIV viral load.

Table 1

Results of Initiation or Delay of Therapy at Different CD4 Counts

No. Subjects No. Subjects By Deaths/103 Person-Yrs
CD4 Stratum*  Initiated Delayed  Initiated Delayed  P Value
501-750/mm3 55 67 7.5 3.1 > .2
351-500/mm3 240 887  10.6 16.6 .17
201-350/mm3 340 59 15.4 56.4 < .001
*Some clinicians and guidelines use a CD4 threshold of 350 to initiate therapy.

Patients who never initiated therapy (54 initially in the high CD4 stratum, 122 in the middle stratum, and 64 initially in the low CD4 stratum) were analyzed separately. Patients at each of these strata had higher mortality rates than either "initiators" or "delayers" of ART. However, injection drug users were over-represented among this group.

Comment by Stan Deresinski, MD, FACP

Although not a randomized trial, the prospective nature of this study makes it more powerful than the retrospective cohort studies previously used in attempts to evaluate the optimal timing of initiation of antiretroviral therapy. Recommendations based on those studies are presented in Tables 2 and 3. There is no disagreement with regard to symptomatic patients or those with CD4 T-cell counts < 200/mm3—both recommend initiation of therapy. From that point on, the recommendations are less than firm. The DHHS recommendations indicate that for patients with CD4 counts of 200 to 500/mm3, "treatment should be offered, although controversial." The IAS recommendations suggest that therapy need not be routinely initiated ("individualized treatment decision") until the CD4 drops below 200/mm3.

Table 2
Department of Health & Human Services (DHHS): Indications for Initiating ART in Asymptomatic Chronic HIV-1 Infection with CD4 > 200 cells/mm3
CD4 Cell Count/mm3 Plasma HIV RNA Recommendation
> 200 & < 350 Any value Treatment should be offered, although controversial
< 350 > 55,000 Certain experienced clinicians recommend initiating therapy
> 350 < 55,000 Certain experienced clinicians recommend deferring therapy
Reference: Dybul M, et al. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002;
137:381-433.

Table 3

International AIDS Society (IAS): Indications for
Initiating ART in Asymptomatic Chronic HIV-1 Infection with CD4 > 200 cells/mm3
CD4 Cell Count/mm3 Recommendation
> 200 Individualize treatment decision, based on CD4 count & rate of decline,* plasma HIV RNA,** etc
*Some clinicians and guidelines use a CD4 threshold of 350 to initiate therapy.

**A high RNA level is above 50,000-100,000 copies/mL

Reference: Antiretroviral treatment for adult HIV infection in 2002: Updated recommendations of the International AIDS Society—USA Panel. JAMA. 2002; 288:222-235.

The data summarized here provide strong evidence for initiating treatment in asymptomatic patients with CD4 counts of 201-350/mm3. Furthermore, the limited power of the study means that the possibility of benefit of initiating treatment at higher CD4 counts cannot be discounted. A larger cohort and/or longer period of observation may have demonstrated benefit. Furthermore, as therapies improve and become less toxic, further benefit from early initiation may become apparent. In fact, the true value of current therapies was also likely underestimated since only two-thirds of the patients initiated therapy with HAART. Finally, this analysis does not take into account the public health consequences of early initiation—both good and bad. Thus, while more widespread therapy will increase the prevalence of drug-resistant HIV, reduction of viral loads is associated with reduced transmission.

My approach is to usually lean toward treatment. I strongly recommend ART to my patients with CD4 counts < 350 mm3. For patients with counts of 350-500/mm3, I try to give them a picture of the complexity of the data and, taking into account their viral load, often recommend therapy, but with a lesser sense of urgency than for those with lower CD4 counts. In general, I do not recommend initiation of therapy for patients with CD4 counts greater than 500/mm3, but accede if the patient insists on receiving ART. Treatment can always be discontinued if it is poorly tolerated. Finally, I am ready to change my approach as better data become available.

Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center