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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

  1. Timothy R. Sterling1,2,a,
  2. Richard E. Chaisson1,2,3,
  3. Jeanne Keruly1 and
  4. Richard D. Moore1,2
  1. 1Division of Infectious Diseases, Johns Hopkins University School of Medicine, and
  2. 2Departments of Epidemiology and
  3. 3International Health, Johns Hopkins University School of Public Health, Baltimore, Maryland
  1. Reprints or correspondence: Dr. Timothy R. Sterling, Vanderbilt University Medical Center, 1161 21st Ave. South, A4103 Medical Center North, Nashville, TN 37232 (timothy.sterling{at}vanderbilt.edu)
 
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Abstract

On the basis of studies with relatively short follow-up, treatment guidelines currently recommend that highly active antiretroviral therapy (HAART) be initiated in asymptomatic human immunodeficiency virus–infected patients when the CD4+ lymphocyte count is ⩽200 cells/mm3. We assessed the development of a new opportunistic infection or death among 1173 patients initiating HAART. Durable virologic suppression was defined as having more undetectable (<400 copies/mL) than detectable virus loads after the initiation of therapy. The median durations of therapy and follow-up were 29 and 36 months, respectively. Among patients who achieved durable virologic suppression, those with baseline CD4+ lymphocyte counts of <200 cells/mm3 tended to progress faster than those with baseline CD4+ lymphocyte counts of 201–350 cells/mm3 (P=.09) and progressed faster than those with baseline CD4+ lymphocyte counts of >350 cells/mm3 (P=.01). Among those with durable virologic suppression, there was no difference in disease progression between those with baseline CD4+ lymphocyte counts of 201–350 cells/mm3 and those with durable virologic suppression with baseline CD4+ lymphocyte counts of >350 cells/mm3 (P=.40). Initiating HAART with a CD4+ lymphoctye count of <200 cells/mm3 was associated with a higher risk of disease progression, even with durable virologic suppression. HAART should be initiated at CD4+ lymphocyte counts of >200 cells/mm3

Although the benefit of highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV) disease progression and death has been well documented [1, 2], the optimal time to initiate therapy remains uncertain. In general, HAART, once it is initiated, must be continued (and adhered to) indefinitely, and it is associated with substantial toxicity [3]. In addition, currently available therapy is unlikely to eradicate HIV infection [4]. Previously published observational cohort studies have attempted to determine the optimal time to initiate HAART in asymptomatic HIV-infected patients, to maximize benefit and minimize toxicity. The risk of clinical disease progression is particularly high among patients who initiate therapy when the CD4+ lymphocyte count is <200 cells/mm3 [5–7] or when HIV-1 RNA load is >100,000 copies/mL [6, 8]. HAART appears to confer minimal [9, 10] or no benefit [11] in asymptomatic patients who initiate therapy at CD4+ lymphocyte counts of >350 cells/mm3. Among patients with CD4+ lymphocyte counts of 200–350 cells/mm3, HAART may decrease the risk of clinical disease progression [6, 7], but the optimal CD4+ lymphocyte count within this range at which to initiate therapy is unknown

The virologic response to therapy predicts long-term clinical outcome [12, 13], and the optimal immunologic response (as measured by increases of CD4+ lymphocyte counts) occurs in patients who achieve durable virologic suppression [14]. In addition, virologic suppression limits the development of viral resistance; thus, durable virologic suppression is the goal of therapy. It is unknown whether clinical disease progression varies according to baseline CD4+ lymphocyte count among patients who achieve durable virologic suppression. Given the substantial toxicity of therapy, delaying its initiation would be beneficial, as long as the delay does not increase the risk of clinical disease progression. It is therefore important to assess for possible differences in disease progression among patients with durable virologic suppression and to characterize the level of CD4+ lymphocytes below which disease progression is increased even if durable virologic suppression is achieved

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Patients and Methods

Study populationThe Johns Hopkins HIV Clinic provides care for a large proportion of HIV-infected patients in the Baltimore metropolitan area. Longitudinal primary and subspecialty care are integrated in 1 hospital-based clinic. An observational clinical database of patients receiving care through the clinic has been maintained since 1990. Information from clinical records is reviewed and abstracted, by trained medical-records technicians, onto structured data collection forms and then is entered into an automated database. The clinical medical record, the main-hospital medical record, and various institutional automated databases are abstracted. Comprehensive demographic, clinical, laboratory, pharmaceutical, and psychosocial data are collected at enrollment into the Clinic and at 6-month intervals thereafter. Information on death is obtained from a death registry maintained by the clinic, which receives reports from families, funeral homes, other medical institutions, and local coroners. In addition, death records of the Maryland Bureau of Vital Records and the national Social Security death index are regularly searched. Details of database design and method of follow-up have been published elsewhere [15]

For this analysis, all patients who initiated HAART after 1 July 1996 and received therapy for at least 90 days were included. HAART was defined as 2 nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with ⩾1 protease inhibitor (PI) or with 1 nonnucleoside reverse-transcriptase inhibitor (NNRTI). Regimens containing 3 NRTIs were also considered as HAART. Patients who received saquinavir hard-capsule therapy but no other PI or NNRTI were excluded, because of the relatively poor bioavailability of hard-capsule saquinavir when used alone. Follow-up was performed through 30 June 2002

Disease progression was defined as either death or a new AIDS-defining illness, on the basis of the 1993 Centers for Disease Control clinical case definition [16], excluding CD4+ lymphocyte counts of <200 cells/mm3. Durable virologic suppression was defined as having more undetectable (<400 copies/mL) than detectable virus loads after the initiation of therapy. The cutoff level of 400 copies/mL was used because the second-generation virus load assay (<50 copies/mL) was not available for the entire study period

Laboratory analysisCD4+ lymphocytes were quantified by flow cytometry [17]. HIV-1 RNA loads were quantified by reverse-transcriptase polymerase chain reaction (Roche Molecular Systems)

Statistical analysisCategorical variables were compared by Yates’s corrected χ2 test. Continuous variables were compared by Mann-Whitney U test or Kruskal-Wallis test. Kaplan-Meier analyses of time to a new AIDS-defining illness or death (combined end point) were performed and compared by use of the log-rank test. Cox multivariate proportional hazards analyses were also performed, to assess predictors of disease progression. Multivariate models adjusted for age as a continuous variable, male sex, black race, injection drug use, and HIV-1 RNA loads of >100,000 copies/mL. P<.05 was considered to be statistically significant

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Results

A total of 1173 patients initiated HAART; their clinical and demographic characteristics are shown in table 1 (according to status of virologic suppression) and table 2 (according to baseline CD4+ lymphocyte count). Among all study patients, the median time of HAART was 29 months (interquartile range [IQR], 13–48 months; maximum, 75 months), and the median duration of follow-up was 36 months (IQR, 20–54 months; maximum, 75 months). The median number of virus load measurements was 12 (IQR, 6–19): 14 among patients with durable virologic suppression and 9 among patients without durable virologic suppression (P<.0001)

Figure 1
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Figure 1

Kaplan-Meier estimates of new opportunistic infection or death, among all study participants. HAART, highly active antiretroviral therapy

Figure 2
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Figure 2

Kaplan-Meier estimates of new opportunistic infection or death, among patients with durable virologic suppression. HAART, highly active antiretroviral therapy

Table 1
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Table 1

Demographic and clinical characteristics of the 1173 study patients, according to virologic suppression

Table 2
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Table 2

Demographic and clinical characteristics of the 1173 study patients, according to baseline CD4+ lymphocyte count, before initiating highly active antiretroviral therapy (HAART)

Patients with lower CD4+ lymphocyte counts at the initiation of HAART were significantly less likely to achieve durable virologic suppression, as reported elsewhere [18]. The number and rate of clinical events, according to baseline CD4+ lymphocyte counts and status of virologic suppression, are shown in table 3. Among patients with CD4+ lymphocyte counts of <200 cells/mm3, the rate of clinical events was clearly higher among those without durable virologic suppression. However, among patients with baseline CD4+ counts of >200 cells/mm3, clinical-event rates did not differ substantially between patients with and patients without durable virologic suppression

Table 3
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Table 3

Number of patients and clinical events, according to CD4+ lymphocyte count and status of virologic suppression

Among all patients who initiated HAART, the risk of clinical disease progression was significantly greater as the baseline CD4+ lymphocyte count decreased (figure 1). Among patients with durable virologic suppression, clinical disease progression among those with baseline CD4+ lymphocyte counts of <200 cells/mm3 was more rapid than among those with baseline CD4+ lymphocyte counts of 350–499 cells/mm3 (P=.01) and tended to be more rapid than among those with CD4+ lymphocyte counts of 201–350 cells/mm3 (P=.09; figure 2). However, there was no difference in disease progression among those with baseline CD4+ lymphocyte counts of 201–350 cells/mm3 and those with baseline CD4+ lymphocyte counts of 351–499 cells/mm3 (P=.40). These relationships are also demonstrated in Cox proportional hazards models (table 4)

Table 4
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Table 4

Proportional hazards models of clinical disease progression, according to baseline CD4+ lymphocyte count, among patients with durable virologic suppression

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Discussion

Current treatment guidelines recommend that therapy should be initiated when the CD4+ lymphocyte count is ⩽200 cells/mm3; therapy should be considered at CD4+ lymphocyte counts of >200 cells/mm3, but more-specific recommendations are not provided, due to limitations of available data [19, 20]. Of note, these recommendations are based on data from observational cohort studies with relatively short follow-up periods (median duration, 23–29 months) [5, 7, 21]. In the present study, follow-up was as long as 75 months, median follow-up was 36 months, and 25% of the cohort received at least 54 months of follow-up. Interestingly, when we previously assessed for differences in clinical disease progression among patients with durable virologic suppression (i.e., the best possible response to therapy), we found no statistically significant difference among patients with baseline CD4+ lymphocyte counts of <50, 51–200, or 201–350 cells/mm3 [22]. However, using longer follow-up periods, we now have noted that, among patients who achieved durable virologic suppression, those with baseline CD4+ lymphocyte counts of <200 cells/mm3 had higher rates of disease progression than did patients with baseline CD4+ lymphocyte counts of 201–350 cells/mm3. This finding strongly supports initiating therapy at CD4+ lymphocyte counts of >200 cells/mm3 and suggests that guidelines for treatment of HIV should clearly state the importance of initiating therapy before CD4+ lymphocyte counts decrease to <200 cells/mm3

Interestingly, patients with baseline CD4+ lymphocyte counts of 201–350 cells/mm3 who achieved durable virologic suppression did not progress at a faster rate than did patients with baseline CD4+ lymphocyte counts of 350–499 cells/mm3 who achieved durable virologic suppression. The 2 Kaplan-Meier curves in figure 2 closely approximate one another at the end of follow-up (75 months), suggesting that they are unlikely to become significantly different with longer follow-up. Given the similar rate of disease progression and the high rates of antiretroviral toxicity [23], these findings argue for initiating therapy at CD4+ lymphocyte counts of 201–350 rather than 351–499 cells/mm3

When interpreting our results, to determine when to initiate HAART, one may assess 2 distinct groups of patients. One approach is to look at disease progression among all patients included in the study (i.e., all patients who received at least 90 days of HAART and met all of the other study-entry criteria). This would be analogous to an intention-to-treat analysis of a randomized, controlled clinical trial. Such an approach incorporates data from all patients and takes into account the fact that, at the time of initiation of therapy, the clinician does not know who will achieve durable virologic suppression. Among all patients in this study who received HAART, patients with baseline CD4+ lymphocyte counts of 351–499 cells/mm3 progressed at statistically significantly lower rates than did patients with CD4+ lymphocyte counts of <200 or 201–350 cells/mm3. This is consistent with other studies that have assessed disease progression among all patients who initiated HAART [24, 25]. Although such results argue for initiating therapy at CD4+ lymphocyte counts of 351–499 cells/mm3, these analyses are of limited usefulness because they do not account for the duration of therapy (beyond 90 days), adherence to therapy, or patients who achieve the goal of therapy: durable virologic suppression. Therefore, the rates of disease progression in figure 1 do not provide the most accurate information with regard to disease progression while receiving HAART and may more closely reflect the natural history of untreated HIV infection than that of disease progression while receiving therapy

A second, perhaps better, way to assess the true effect of HAART on clinical disease progression is to evaluate patients who achieve durable virologic suppression. This approach takes into account the optimal effect of HAART on disease progression, as well as adherence to therapy, given the close link between adherence and virologic suppression [26]. If, according to baseline CD4+ lymphocyte counts, there are differences in disease progression among such a population of patients, it is likely that such differences are real and not due to confounding factors, such as nonadherence. In support of such an approach, recent studies have demonstrated rates of clinical disease progression among patients adherent to therapy who are similar to those patients with durable virologic suppression noted in the present study [5, 8]. In addition, a recent, large multicenter study found that, among patients treated with HAART, the CD4+ lymphocyte count and HIV-1 RNA load after 6 months of therapy predicted disease progression but that baseline values did not predict progression, after controlling for 6-month levels [27]. This finding suggests that immunologic status before initiation of therapy is not as important as immunologic status after 6 months of therapy. If an optimal CD4+ lymphocyte range at which to initiate therapy is identified, clinicians can make interventions to improve patient adherence, before patients reach such a level, thereby optimizing the likelihood of treatment success (i.e., durable virologic suppression)

The present study was an observational cohort study and not a randomized clinical trial. Although observational studies can have biases due to both observed and unobserved differences in the comparison groups, among the different baseline CD4+ lymphocyte counts, there were no differences in the duration of therapy or loss to follow-up; the difference in median follow-up among patients in the 3 groups was of borderline significance. Lead-time bias can occur, such that the slower disease progression among patients initiating therapy at higher CD4+ lymphocyte counts may be, in part, due to therapy being initiated at an earlier stage of disease rather than due to treatment. However, studies that have accounted for lead-time bias have come to similar conclusions as has our study [10, 28]. These issues would be addressed by a randomized, controlled clinical trial; however, one such trial currently underway will take several years to complete [29]

Another limitation of this study was that data on adherence were not available for all patients. On the basis of a previous analysis, overall rates of adherence were likely low [30]. However, durable virologic suppression is an excellent marker of adherence, and data on it were available for all patients. Additionally, the cutoff for virologic suppression was 400 copies/mL instead of 50 copies/mL, because the former was available for more patients. It is unlikely that use of the more stringent cutoff for undetectable virus load would have resulted in any differences in the study results, since virus loads of 400 copies/mL are unlikely to result in significant clinical decline, compared with virus loads of <50 copies/mL. Sample size was relatively small, such that we were unable to detect very small differences in clinical disease progression. Additional studies among larger populations are needed to confirm our findings. Finally, although HAART has always been potent, there have been improvements in potency and drug-dosing intervals during the study period of 1996–2002. Although it would be interesting to assess for differences in disease progression, according to the type of regimen used or the year in which therapy was initiated, this would markedly decrease sample size and follow-up time and therefore would limit the ability to detect differences in disease progression, which has been a criticism of previous observational studies

With the above limitations noted, the longer follow-up time of our study helps to clarify when HAART should be initiated in asymptomatic patients. It is clear that clinical disease progression is slower when therapy is initiated at CD4+ lymphocyte counts of >200 cells/mm3. Among patients who achieved durable virologic suppression, the lack of difference in disease progression among patients with baseline CD4+ lymphocyte counts of 201–350 or 351–499 cells/mm3, after up to 75 months of follow-up, argues that therapy could be initiated at CD4+ lymphocyte counts of 201–350 cells/mm3. However, waiting until the CD4+ lymphocyte count reaches 201–350 cells/mm3 requires that efforts to both maximize adherence to therapy and achieve durable virologic suppression are implemented

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Footnotes

  • Presented in part: 10th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 10–14 February 2003 (abstract 570)

    Financial support: National Institute on Drug Abuse (grants RO1-DA-11602 and K24-DA-00432); National Institute of Allergy and Infectious Diseases (grants K23-AI-01654 and K24-AI-01637)

  • ↵Present affiliation: Vanderbilt University Medical Center, Nashville, Tennessee

  • Received May 22, 2003.
  • Accepted June 23, 2003.
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  1. J Infect Dis. (2003) 188 (11): 1659-1665. doi: 10.1086/379741
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