During the course of HIV infection, the CD4+ T lymphocyte (CD4) count is the main surrogate marker for immune function and the strongest predictor of disease progression.1,2 Initiation of antiretroviral therapy (ART) has improved the prognosis of HIV infection by increasing the CD4 count with a concomitant decline in the risk of opportunistic diseases.3,4 The extent of long-term immunologic recovery is affected by the baseline CD4 count at the beginning of ART.5–7 US guidelines have recommended that CD4 monitoring should be performed every 3–6 months to determine when to start ART in untreated patients to assess the immunologic response to ART and the need for initiation or discontinuation of prophylaxis for opportunistic infections.8
However, CD4 count provides limited information in clinically stable, virally suppressed patients on ART because the CD4 response to ART varies widely,9,10 and a poor CD4 response is rarely an indication for modifying a virologically effective ART regimen.8 Many studies show that a decline in CD4 during ART provides unreliable evidence of virologic failure or drug resistance.4,11,12 Therefore, current national treatment programs that recommend CD4 testing every 6–12 months in clinically stable, virally suppressed patients may be an unnecessary use of resources.
Recently, there have been several reports confirming that a clinically meaningful CD4 decline rarely occurs during viral suppression.9,10,13–18 According to Gale et al,14 patients with a baseline CD4 count >300 cells per microliter had a 97% probability of maintaining CD4 >200 cells per microliter for 4 years during viral suppression. Considering these results, less frequent or clinically driven CD4 testing may be warranted during viral suppression. To further address this issue, we aimed to determine rates and predictors of a CD4 cell count <200 cells per microliter and to determine the effects of the frequency of CD4 monitoring on clinical end points in an Asian cohort of virally suppressed patients.
Data from the TREAT Asia HIV observational database (TAHOD), a prospective observational cohort study of adults with HIV from 21 sites in the Asia-Pacific region, were analyzed. The detailed structure of TAHOD and its mechanisms of data collection have been previously described.19 Briefly, each site enrolls 100–450 HIV-infected patients, both treated and untreated with ART, and biannually transfers deidentified clinical and outcomes data to a central data management and biostatistical analysis center. Ethics approvals were obtained from all participating sites, the analysis center (Kirby Institute, UNSW Australia), and the coordinating center (TREAT Asia/amfAR, Bangkok). Written informed consent was not sought unless required by a site's local institutional review board. Informed consent was waived at some sites as information is collected through an anonymous case report form. All study procedures were developed in accordance with the revised 1975 Helsinki Declaration. Patients who met the following criteria were eligible for inclusion in the analysis: (1) receiving ART >6 months with ≥3 antiretroviral agents, (2) confirmed viral suppression defined as 2 consecutive viral load measurements <400 copies per milliliter and a CD4 count ≥200 cells per microliter after viral suppression, all within a 390-day period, and (3) a minimum of 1 subsequent viral load measurement <400 copies per milliliter at least 12 months after confirmed viral suppression. Follow-up time was only counted when virally suppressed patients had CD4 count monitoring every 6 months. A break in regular CD4 count testing resulted in censoring. A 3-month window on either side of the 6-monthly CD4 cell count date was used. Patients may have had more than 1 CD4 count measurement within this period, but only the measurement closest to the 6-month date was considered.
Collected Data and Definitions
Study end points were (1) the occurrence of a single CD4 count <200 cells per microliter (single CD4 <200), (2) confirmed CD4 count <200 cells per microliter (confirmed CD4 <200), or (3) clinical failure during the patient's first recorded period of viral suppression. Confirmed CD4 <200 was defined as 2 separate CD4 counts <200 cells per microliter within a 6-month period considering all CD4 counts within the 6 months, and clinical failure was defined as a new or recurrent WHO stage 3 or 4 illness or death.
Data included age, sex, mode of HIV exposure, hepatitis B and C serology, history of previous AIDS diagnosis, and ART regimen. AIDS-defining illnesses were defined according to the modified 1993 CDC definitions.20 Baseline was defined as the date of confirmed viral suppression.
Rates and predictors of single CD4 <200, confirmed CD4 <200, and clinical failure were analyzed by Kaplan–Meier curves and Cox regression stratified by study site. Time to event was measured from the date of confirmed viral suppression (ie, date of second viral load <400 copies/mL) until the first single CD4 <200, confirmatory CD4 <200, or clinical failure event. If the last biannual CD4 count was <6 months before an ART class change or a final viral load measurement of <400 copies per milliliter, then time to censoring was measured from date of confirmed viral suppression until date of ART class change or final viral load <400 copies per milliliter (whichever occurred first). If the last biannual CD4 count occurred >6 months before an ART class change or a final viral load of <400 copies per milliliter, then time to censoring was measured from date of confirmed viral suppression until 6 months after the final biannual CD4 count. ART class change was defined as a substitution or cessation of ≥1 antiretroviral drug class in the regimen being used at the beginning of viral suppression. Predictors used in the multivariate model were selected based on a significance level of ≤0.10 in the univariate analyses. Predictors were retained in the multivariate model if 1 or more categories exhibited a P value ≤0.05.
Because the study population consisted of patients with biannual CD4 cell counts, a hypothetical comparison group comprising exactly the same patients with annual CD4 count measurement was generated by removing every second CD4 cell count from the first biannual measurement onward. This allowed comparisons of the time to detection of single CD4 <200 and confirmed CD4 <200 within the study population when different rates of CD4 monitoring were applied. The effect of CD4 monitoring frequency on time to single CD4 <200 and confirmed CD4 <200 was evaluated using Kaplan–Meier estimates. Stata statistical software (version 12.1; StataCorp, College Station, TX) was used for all statistical analysis.
From September 2003 to March 2013, a total of 8493 patients were enrolled in TAHOD, of whom 7041 had a record of more than 6 months of ART. Among them, 3601 had documentation of confirmed viral suppression with CD4 cell count ≥200 cells per microliter, and 1538 of these fulfilled the inclusion criteria with at least 6-monthly CD4 monitoring. The demographics and characteristics of the patients are shown in Table 1. The median age at the time of viral suppression was 39.9 years (interquartile range, 34.6–46.3), and the patients were predominantly male (73.1%). Heterosexual contact was the most common risk exposure (62.3%), and 42.8% of the patients had a previous AIDS diagnosis. Median baseline CD4 count was 393 cells per microliter (interquartile range, 291–536). Patients were classified into 5 groups according to baseline CD4 count: ≥500 cells per microliter, 30.4%; 350–499 cells per microliter, 29.8%; 300–349 cells per microliter, 12.5%; 250–299 cells per microliter, 13.5%; and 200–249 cells per microliter, 13.8%.
We examined the change in mean CD4 count over time, stratified by baseline CD4 count (Fig. 1). During viral suppression, mean CD4 gradually increased and reached a plateau after 48 months, regardless of baseline CD4 count. At each analysis interval during follow-up, mean CD4 count was higher in the group with a higher baseline CD4 count. When the baseline CD4 count was ≥250 cells per microliter, the mean CD4 count after 48 months was >400 cells per microliter.
The overall rate of single CD4 <200 was 3.45 per 100 patient-years [95% confidence interval (CI): 2.91 to 4.09]. The rate of confirmed CD4 <200 was 0.77 per 100 patient-years (95% CIs: 0.57 to 1.09). The rate of clinical failure was 0.57 per 100 patient-years (95% CIs: 0.38 to 0.85).
Univariate and multivariate analyses investigated factors associated with confirmed CD4 <200. Baseline CD4 count of 200–249 cells per microliter was significantly associated with confirmed CD4 <200 (hazard ratio, 55.47; CIs: 7.36 to 418.20, P < 0.001, compared with baseline CD4 >500). There was no significantly increased risk when baseline CD4 count was >250 cells per microliter. HIV exposure through injecting drugs was significantly associated with risk of confirmed CD4 <200 (hazard ratio, 7.54; CI: 1.15 to 49.52; P = 0.035) compared with HIV exposure through heterosexual contact. Previous AIDS diagnosis was associated with confirmed CD4 <200 in the univariate analysis, but not in the multivariate analysis (Table 2). Sex and ART regimen were not associated with either CD4 outcome evaluated.
Cumulative probabilities of single and confirmed CD4 <200 during viral suppression stratified by baseline CD4 count are shown in Figure 2. The differences in cumulative probabilities of single CD4 <200 and confirmed CD4 <200 between patients with biannual CD4 measurement (Figs. 2A, B), and patients with the hypothetical annual CD4 measurement (Figs. 2C, D) are also shown in Figure 2. For patients with a baseline CD4 count of 200–249 cells per microliter, the probability of single and confirmed CD4 <200 at year 5 was 45.42% and 13.78% with biannual CD4 measurement and 28.64% and 10.25% with annual CD4 measurement, respectively. However, patients with baseline CD4 ≥250 cells per microliter had much lower probability of single CD4 <200 and rarely had confirmed CD4 <200 in both biannual and annual measurement. When measuring CD4 count annually, there was a significantly slower time to detection of single CD4 <200 (log-rank <0.001). For confirmed CD4 <200, there was no significant difference between biannual and annual CD4 measurements (log-rank 0.336). The risks of clinical failure were very low for all subjects with baseline CD4 cell count ≥200 cells per microliter, regardless of stratified baseline CD4 counts (Fig. 3).
In general, CD4 cell counts tend to increase and remain stable in patients with viral suppression on ART.21–23 In this context, there have been studies questioning the clinical usefulness of frequent CD4 testing, demonstrating that clinically meaningful CD4 decline rarely occurs in virally suppressed and clinically stable patients. In 2002, Phillips et al13 reported that only 5 of 166 patients showed a decline in CD4 <350 cells per microliter over 47 weeks among virally suppressed patients with baseline CD4 >500 cells per microliter. Similar results have subsequently been reported.14–16 The definition of a clinically meaningful CD4 decline in 2 studies was CD4 <200 cells per microliter, because individuals with CD4 <200 cells per microliter are at higher risk of opportunistic infection and need prophylaxis for Pneumocystis jirovecii pneumonia.14,16 In these studies, to define the threshold of an immunologically stable status, the rate of CD4 decline was stratified by baseline CD4 cell count. Each study showed that individuals with baseline CD4 ≥350 cells per microliter 16 and CD4 ≥300 cells per microliter 14 had a very low risk of subsequent CD4 decline.
Similarly, several previous studies have showed that patients with baseline CD4 <300 cells per microliter had a significantly increased risk of clinically meaningful CD4 declines under 200 cells per microliter than patients with higher baseline CD4.14,17,18 In this study, patients with baseline CD4 <250 cells per microliter had a 13.8% probability of confirmed CD4 <200 after 5 years, whereas the same probability was 1.6% at a baseline CD4 of 250–299 cells per microliter, 1.6% for 300–349 cells per microliter, and 0.3% for ≥350 cells per microliter. In the multivariate analysis, baseline CD4 <250 cells per microliter was associated with a significantly greater risk of confirmed CD4 <200 during virologic suppression. However, there was no association when baseline CD4 was higher. To our knowledge, baseline CD4 of 250 cells per microliter is the lowest value defining immunologically stable status that has been reported.
In contrast to confirmed CD4 <200, the cumulative probability of single CD4 <200 was higher even in patients with baseline CD4 ≥250 cells per microliter. In several studies, end points were single CD4 decline or single CD4 value of the lowest CD4 count.13,14,16,17 However, the clinical significance of single CD4 decline is doubtful. Because there are various non–HIV-related causes of CD4 decline such as acute illness or CD4-lowering treatments, such as trimethoprim-sulfamethoxazole, chemotherapy, or interferon.8,24 Physiologic variation can also lead to a transient CD4 decline. One study reported physiologic CD4 variation around a median of 119 cells per microliter ranged from 35 to 395 cells per microliter over 2 weeks.25 According to Gale et al,14 24 of 61 patients with a CD4 decline of <200 cells per microliter during viral suppression had an alternative reason causing non-HIV CD4 lymphopenia, and subsequent examination showed some of those patients had steady CD4 increases after the decline. The study of Ford et al17 also showed that 97% of cases with a single CD4 <200 during HIV suppression had CD4 recovery above this value in follow-up testing. Considering these points, it is difficult to regard the category of single CD4 <200 as a meaningful CD4 decline. We were unable to identify other studies of the clinical significance of 2 consecutive CD4 values <200 cells per microliter in comparison with a single CD4 value of <200 cells per microliter during HIV infection. However, we believe that 2 consecutive CD4 measurements <200 cells per microliter indicate sustained CD4 decline and better represents HIV-related CD4 lymphopenia. When annual and biannual CD4 monitoring were compared, the cumulative probability of confirmed CD4 <200 did not show a statistically significant difference. This suggests that less-frequent CD4 measurement does not miss important immunologic events in patients with viral suppression.
Less-frequent CD4 monitoring in virally suppressed patients also has some benefits. First, this would initiate potential cost savings. According to Hyle et al,9 reducing CD4 monitoring in stable patients from biannually to annually would save $10.2 million per year in United States. Another benefit is to reduce patient anxiety regarding transient declines in CD4, which can otherwise lead to additional testing. In this study, the cumulative probability of detecting a single CD4 <200 was lower when measured annually compared with biannually, indicating that less-frequent CD4 testing may be a reasonable management approach.
Meanwhile, the results of this study demonstrated that the risk of clinical failure during viral suppression was very low for all HIV-suppressed patients with baseline CD4 ≥200 cells per microliter. There were only 23 events during total 4057 patient-years without any case of death. This result is relevant to the results of previous studies. The ARTEMIS trial showed that the HIV-suppressed patients with CD4≥200 cells per microliter had lower risk of developing AIDS-defining events than patients with CD4 <200 cells per microliter or without viral suppression during 1 year of follow-up after initiating ART.26 Similarly, in a German HIV cohort study, patients who had viral suppression but CD4 <200 cells per microliter after 1 year of ART had significantly higher rates of AIDS progression than the patients with higher CD4 counts.27 In our study, the event rate of clinical failure was very low regardless of baseline CD4 once the value increased to >200 cells per microliter. Besides, the time to detect the occurrence of clinical failure would not be changed by CD4 measurement frequency. So, these results can also support less-frequent CD4 monitoring without concerns of missing the clue for clinical failure when CD4 is measured annually.
There were several limitations to our study. First, the definition of viral suppression was 2 consecutive viral load measurements of <400 copies per milliliter, which is based on the viral load testing thresholds over the history of the cohort. However, current testing platforms are able to test at levels of <20 or <50 copies per milliliter, meaning that patients without viral suppression by some standards may have been included in the analysis. Second, the observational nature of our database does not permit assessment of whether documented CD4 declines are related to specific events, medications, or other interventions.
Despite these limitations, this is the first multicenter analysis in the Asia-Pacific of the clinical utility of frequent CD4 monitoring in patients with viral suppression. And our primary end point is focused on the occurrence of confirmed CD4 <200, which might be more clinically meaningful than single CD4 <200. Furthermore, patients with baseline CD4 250–299 cells per microliter, who were not regarded as immunologically stable in previous studies, are demonstrated not to have additional risk of confirmed CD4 <200 during viral suppression. Finally, our study supports less-frequent CD4 monitoring by statistical analysis comparing 2 different CD4 testing intervals.
In conclusion, CD4 testing at 6-month intervals offered no benefit over annual testing in detecting confirmed CD4 <200 cells per microliter. Patients with baseline CD4 ≥250 cells per microliter had much lower risk of 2 consecutive CD4 <200 cells per microliter during viral suppression compared with patients with baseline CD4 200–249 cells per microliter. Therefore, annual CD4 monitoring in virally suppressed HIV patients with a baseline CD4 ≥250 cells per microliter may be sufficient for clinical management.
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The TREAT Asia HIV Observational Database is an initiative of TREAT Asia, a program of amfAR, The Foundation for AIDS Research, with support from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute, as part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA; U01AI069907), and the Dutch Ministry of Foreign Affairs through a partnership with Stichting Aids Fonds.
The TREAT Asia HIV Observational Database
C. V. Mean, V. Saphonn*, and K. Vohith, National Center for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; F. J. Zhang*, H. X. Zhao and N. Han, Beijing Ditan Hospital, Capital Medical University, Beijing, China; M. P. Lee*, P. C. K. Li, W. Lam, and Y. T. Chan, Queen Elizabeth Hospital, and K. H. Wong, Integrated Treatment Centre, Hong Kong, China; N. Kumarasamy*, S. Saghayam, and C. Ezhilarasi, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), YRGCARE Medical Centre, VHS, Chennai, India; S. Pujari*, K. Joshi, and A. Makane, Institute of Infectious Diseases, Pune, India; T. P. Merati*‡, D. N. Wirawan, and F. Yuliana, Faculty of Medicine Udayana University and Sanglah Hospital, Bali, Indonesia; E. Yunihastuti*†, D. Imran, and A. Widhani, Working Group on AIDS Faculty of Medicine, University of Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia; S. Oka*, J. Tanuma, and T. Nishijima, National Center for Global Health and Medicine, Tokyo, Japan; J. Y. Choi*, Na. S, and J. M. Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; B. L. H. Sim*, Y. M. Gani, and R. David, Hospital Sungai Buloh, Sungai Buloh, Malaysia; A. Kamarulzaman*, S. F. Syed Omar, S. Ponnampalavanar, I. Azwa, N. Huda, and L. Y. Ong, University of Malaya Medical Centre, Kuala Lumpur, Malaysia; R. Ditangco*, E. Uy, and R. Bantique, Research Institute for Tropical Medicine, Manila, Philippines; W. W. Wong*, W. W. Ku, and P. C. Wu, Taipei Veterans General Hospital, Taipei, Taiwan; O. T. Ng*, P. L. Lim, L. S. Lee, and P. S. Ohnmar, Tan Tock Seng Hospital, Singapore; P. Phanuphak*, K. Ruxrungtham, A. Avihingsanon, P. Chusut, and S. Sirivichayakul, HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; S. Kiertiburanakul*, S. Sungkanuparph, L. Chumla, and N. Sanmeema, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; R. Chaiwarith*, T. Sirisanthana, W. Kotarathititum, and J. Praparattanapan, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; P. Kantipong* and P. Kambua, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; W. Ratanasuwan* and R. Sriondee, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; V. K. Nguyen*, V. H. Bui, and T. T. Cao, National Hospital for Tropical Diseases, Hanoi, Vietnam; T. T. Pham*, D. D. Cuong, and H. L. Ha, Bach Mai Hospital, Hanoi, Vietnam; A. H. Sohn*, N. Durier*, B. Petersen, and T. Singtoroj, TREAT Asia, amfAR—The Foundation for AIDS Research, Bangkok, Thailand; D. A. Cooper, M. G. Law*, A. Jiamsakul*, and D. C. Boettiger, The Kirby Institute, UNSW Australia, Sydney, Australia. *TAHOD Steering Committee member; †Steering Committee Chair; ‡co-Chair.