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Increase in CD4 cell counts between 2 and 3.5 years after initiation of antiretroviral therapy and determinants of CD4 progression in India S Rajasekaran1, L Jeyaseelan2, K Raja1, S Vijila1, KA Krithigaipriya1, R Kuralmozhi11 Department of Pulmonary Medicine, Government Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, India 2 Department of Biostatistics, Christian Medical College, Vellore, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.58929
Background : Estimation of CD4 cell count remains the primary monitoring tool in assessing efficacy or failure of Anti Retroviral Therapy (ART) under national program conditions in India. Aims : To study the average trajectory of CD4 cell count after two years of initiation of potent ART and to find the determinants of CD4 progression over time. Settings and Design : A prospective cohort study under program conditions. Materials and Methods : Adult ART naïve patients, receiving drug regimens consisting of two NRTIs and one NNRTI were studied for CD4 progression. Laboratory monitoring included the baseline and follow-up CD4 cell count, hemoglobin level and absolute lymphocyte count estimation. The change in CD4 cell count, hemoglobin and bodyweight was calculated from the baseline to the latest follow up measurements. Statistical Analysis : Survival curve using Life table methods was plotted. Comparison between survival curves was done using Tarone-Ware statistics. Generalized estimating equation with exchangeable correlation structure was done to find the risk factors for CD4 progression. Results : Among 7,934 HIV positive patients in the ART program, one-year cohort of 714 adult patients who had completed two consecutive follow-up CD4 values were assessed. Those with baseline CD4 < 100 had cumulative probability of survival 85%, 82%, 82% and 82% at 12, 24, 36 and 42 months respectively. Those who had baseline CD4 count between 100-199 had cumulative probability of survival 96%, 93%, 92% and 90% at 12, 24, 36 and 42 months respectively (P< .001). Lower the CD4 count (< 100) lower the hemoglobin values. Conclusions : CD4 progression continues two years after ART in patients who had base level > 100 cells. Early initiation of ART is necessary before CD4 crashing to < 100 cells for increasing the survival function. Keywords: Anti retroviral therapy, determinants of CD4 progression, HIV
The Antiretroviral Therapy (ART), with the combination of potent antiretroviral medications, has become the standard of care for HIV-1 infection. [1] The primary mechanism of action of ART is the reduction of plasma HIV-RNA that in turn allows an increase in the CD4 cell count. However, some studies have shown that a plateau in CD4 cell gains after the second year of therapy. [2],[3],[4] The Department of Health and Human Services guidelines cite that one potential risk of delaying ART in HIV infected patients is that the damage to the immune system observed in persons with low CD4 cell counts could be irreversible. [5] The information on the plateau and the irreversible immune system has all been derived from several studies with patients with wide variety of virologic responses to ART. [6] Valdez et al, [7] report that CD4 lymphocyte raises during the second and third year were not significant. Kaufmann et al, [8] report that at 48 months 98% of subjects reached CD4 cell counts >200 cells/µl, 86% >350 cells/ µl, and 74% >500 cell/ µl. Similarly, Hunt and others [6] have reported that from year 3 to 4 of ART, mean CD4 gains were +89×10 6 , +86×10 6 , +95×10 6 and +88×10 6 in patients with pre therapy CD4 counts of <50×10 6 , 50×10 6 - 199×10 6 , 200×10 6 - 349×10 6 /l by year 4. They have also observed that the factors associated with increased CD4 cell count gains from month 3 to four years included lower pre-therapy CD4 cell count, younger age, female sex and infrequent low level viremia. Kaufmann et al, [8] reported that a higher nadir CD4 cell-counts and younger age were independently associated with greater increases in CD4 cell counts at 48 months. National ART Program in India was initiated on April 1, 2004 and completed five years of its existence. People Living with AIDS / HIV (PLHA) with CD4 cell counts <200×10 6 and those with CD4 cell counts >200×10 6 and with World Health Organization clinical staging IV is eligible to get free ART. This study was undertaken to characterize the duration of the CD4 cell increase observed for the 3½ years after ART was initiated in the National ART program at the Government Hospital of Thoracic Medicine (GHTM), Tambaram, Chennai, India. The primary objectives were to study the average trajectory of CD4 cell count after two years from initiation of potent ART and to find the determinants of CD4 progression over time.
GHTM, a tertiary care hospital with a history of providing care to tuberculosis patients since 1928, is the largest public HIV care center in India. The National AIDS Control Organization (NACO) has recognized it as a center of excellence, actively taking part in the country wide ART program since April 2004. GHTM, Tambaram, has electronic medical record system, named TB and HIV Hospital Information System (T/HIS), in existence since December 2001. Developed with the support of Centers for Disease Control and Prevention, Atlanta, USA, it allows longitudinal follow-up of all patients accessing care at GHTM. Patients are provided unique patient numbers and are tracked during the follow-up visits. Data collected at the outpatient counters, inpatient services, laboratory, integrated HIV counseling and testing (ICTC) and ART Center at the hospital are linked for more efficient analysis. The Institutional Review Board of GHTM has approved this analysis. There are no financial commitments involved other than expenditure incurred by the government. PLHA, who are eligible by NACO guidelines (2004), are enrolled in the ART Program. They receive their free treatment and clinical check-up during monthly visits to GHTM. The ART regimens consist of two Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Zidovudine (AZT) or Stavudine (d4T) and Lamivudine (3TC) and one Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI), Nevirapine (NVP) or Efavirenz (EFV). Zidovudine is the preferred NRTI, except for patients with anemia. Use of Efavirenz, in the place of Nevirapine, is largely limited to concomitant administration of Rifampicin, an anti-TB drug given to patients, who also have tuberculosis. Patients are being assessed every month clinically in addition to multiple counseling sessions, which address psychological readiness for treatment, drug adherence and follow-up support. Patients on ART are linked to a treatment guardian, such as a family member, friend or organization. For the purpose of this study, the adult ART naive patients with HIV, aged >14 years of age having baseline CD4 and two consecutive CD4 measurements after initiating ART (at the 6 and 12th months of follow up) have been included. Patients whose CD4 was measured beyond 6±1 months have been excluded (considered as missing value). Laboratory monitoring including the baseline and follow-up CD4 cell count was done by FACS Calibur (flow cytometry) every six months. All CD4 counts were performed at GHTM, Tambaram, with single platform flow cytometry using three-color antibody with CD45 gating. Bodyweight was recorded at every monthly visit. Patient's hemoglobin level (HB) and Absolute Lymphocyte Count (ALC) were measured every month during the first year and once in three months subsequently. The change in ALC, HB and bodyweight was calculated from the baseline to the latest follow-up measures. The baseline CD4 was defined as the CD4 cell count measured at the time of registration for ART. Baseline CD4 counts were categorized into three groups: 0-99, 100-199 and 200 cells/µl and more. These three categorizations, based on CD4 counts, signifying demarcation of treatment failure group (those with baseline CD4 count <100 never cross 100 CD4 count mark even after one year of treatment), upper limit of initiation of ART in patients with WHO clinical stages I, II and III disease (CD4 count 200) and the initiation of ART in patients with WHO clinical stage IV disease, irrespective of CD4 count (>200). The follow up CD4 counts were measured every 6 months. However, in the following analyses, the follow-up CD4 is considered, if it was measured at 6±1 months. The CD4 cell counts measured over time were analyzed using linear random intercept and random slope model for each category of baseline CD4 cell count. The dependent variables were defined as the difference between the baseline CD4 cell count and the CD4 cell counts observed between two and 3½ years after initiation of ART (repeated measures). The independent variable is the time at which that the CD4 cell counts were measured, that is from two years onwards. The intercept of these models reflect the amount of increase or decrease in CD4 cell count from baseline to two years after initiation of potent ART. The slope reflects the magnitude and the direction of the rate of change in CD4 cell counts between two and 3½ years after ART initiation. MLWIN software was used to analyze the above concept where the measurements per patient were used as the lowest level and the patient was used as the highest level. In order to analyze the determinants for CD4 cell counts progression over time, generalized estimating equation (GEE) was used. The dependent variables were CD4 cell counts measured from the baseline to 48 months. The independent variables were age, baseline CD4 (categorized into three groups), HB, ALC, bodyweight, previous history of anti tuberculosis treatment and WHO clinical staging at baseline. The GEE was done for males and females separately. GENMOD procedure in SAS software version 9.1 was used for GEE.
There were 17,772 HIV positive patients screened as on December 31, 2007. Of the screened, 7,934 patients were provided with ART from 2004. Of them 7,385 and 547 were adults and children respectively. Of the adults, 928 were ART naïve and registered within the first year of initiation of National ART Program. Of the 928 patients, 121 died and 78 lost to follow up or dropped out. However, 714 patients had minimum baseline and two consecutive follow-ups, CD4 cell counts which were defined as one-year cohort. The distribution of socio-demographic and baseline variables are presented in [Table 1]. Of the one-year cohort, 368 (51.5%) and 346 (48.5%) were males and females respectively. Nearly one-fourth of the patients were in the 15-29 years age group. Over two-third were between 30-44 years and 5.6% were aged 45 years and above, nearly two-third from rural areas. About 8.9% of them were unmarried and 13.5% divorced, separated or widowed; 17.3% of the patients were illiterate and nearly 14% studied up to higher secondary or more; 17.7% were involved in agriculture work and 40.5% were unskilled workers or drivers; 28.3% of the patients were housewives. The baseline CD4 cell count subgroups, <100, 100-199 and 200 and more, had 53.5%, 35.2% and 11.3% patients respectively. Over one-third of the patients had ALC <1000 count and 30.2% of the patients weighed ≤=40kg. 19.2% of the patients had HB less than 9gm/dl. Nearly 56% of the patients had previous anti-Tuberculosis treatment prior to initiation of ART. The cumulative survival probabilities for the adult naïve patients of first year cohort by baseline CD4 categories are presented in [Figure 1]. From the one-year cohort of 928 patients, there were 719, 651, 399 and 183 patients available at the end of 12, 24, 36 and 42 months respectively. Of them, the patients whose baseline CD4 was <100 had cumulative probability of survival, 85%, 82%, 82% and 82% at 12, 24, 36 and 42 months respectively. Patients with baseline CD4 between 100-199 had cumulative probability of survival 96%, 93%, 92% and 90% at 12, 24, 36 and 42 months respectively. Patients with baseline CD4 cell count >=200, had cumulative probability of survival, 92%, 90%, 90% and 90% at 12, 24, 36 and 42 months respectively. The survival rate over time for the CD4 cell count <100 category was significantly lower as compared to others (P<.001). 71% of 121 deaths occurred within the first six months of initiation of ART. The diagrammatic representation of median CD4 cell count from the baseline to 3½ years and the absolute and percentage change from median baseline CD4 cell count to two years and 3½ median cell count is presented in [Figure 2]. At two years, the absolute and percentage CD4 cell count change from the baseline median CD4 cell count for the patients whose CD4 cell counts were <100, was 393 and 819% respectively. At 3½ years, the absolute and percentage change from the baseline median CD4 was 512 and 1067% respectively for the same group of patients. The patients whose CD4 cell counts were 100-199 at the baseline at two years had absolute and percentage change 344 and 242% cell counts respectively. The absolute and percentage at change at 3½ was 570 and 401% cell counts respectively. For those patients, whose CD4 cell counts were 200 and more at the baseline, at two years, had absolute and percentage change 276 and 111% cell count respectively. The absolute and percentage at change at 3½ years for this group was 440 and 177% cell count respectively. The number of individuals observed past two years, the number of observations contributed by these patients from two to 3½ years, mean (SE) increase in CD4 cell count at two years and the mean slope (SE) between two to 3½ years and the P values for the slope (based on the random slope and random intercept model) is presented in [Table 2]. Based on the random intercept at two years, the patients whose CD4 cell count was <100, had mean increase in CD4 cell count 433(13). The mean slope for change in CD4 cell count from two to 3½ years was 6.4(0.8), which was statistically significant (P<.001). The patients, whose CD4 cell count was 100-199, had mean increase in CD4 cell count 368(15). The mean slope for change in CD4 cell count from two to 3½ years was 6.4(1.2), which was statistically significant (P<.001). The risk and protective factors for CD4 progression is presented in [Table 3] according to sex. Amongst the male patients whose CD4 cell count was less than 100, had significantly lower gain in cell counts -119 (95%CI: -169.7 to -68.3) as compared to patients whose CD4 cell count was 200 and more. The male patients whose HB was 9.1-11gm/dl had significantly higher cell counts, 45.1(9.6 - 80.6) as compared to patients whose HB was 11.1gm/dl and more. Similarly, the male patients with ALC less than 1200 count had significantly lower gain in CD4 cell count as compared to patients with ALC of 1800+ counts. The male patients who had undergone anti TB treatment prior to the ART, have significantly higher CD4 cell count 35.6 (3.9 to 67.4) as compared to male patients who did not (P=.02). The female patients with CD4 cell counts less than 100 had significantly lower gain in CD4 cell counts -67.8 (-114.2 to - 21.4) as compared to patients whose CD4 cell count was 200 or more. The female patients whose age was 30-44 had significantly lower CD4 cell count -44.5 (-81.9 to -7.1) as compared to female patients whose age was 15-29 years. The female patients whose ALC count was less than 1600 counts had significantly lower ALC counts as compared female patients, whose ALC count was 1800 or more.
The level of immune competence that can be reached in HIV infected individuals receiving ART is of major clinical significance as this helps the physicians continue or modify the ART treatment regimen. CD4 monitoring is important for early identification of patients who are more likely to have slow CD4 progression as they may have lengthy exposure to the risk of opportunistic infections. [8] Further, it is expensive to do viral load estimation for monitoring treatment response overtime in resource poor settings. In the ART program in India, the monitoring tool remains to be the estimation is CD4 cell counts, which is being done once in six months. This study focuses the relevance of base level characteristics influencing CD4 progression, even while the primary objective remained to study whether the CD4 increases after two years of ART. Among 7,934 PLHA enrolled on ART, the surviving cohort of 714 adult ART naïve patients registered during the first year of ART program formed the study population. Thus, this cohort provided an opportunity to study the CD4 progression over three and half years. This data represents poor and middle class patients, who seek care at public health facilities, where the ART services are available to them free of cost. While the focus of this presentation is on CD4 progression in patients on ART, an interesting observation was made on mortality. There were 928 adult naïve patients who were recruited within a year of the program. Of them, 89, 23 and nine died over a period of three-and-a-half years amongst patients whose baseline CD4 counts were <100, 100-199 and 200+ respectively. The higher mortality rate in the low CD4 category implied that the risk of dying is much higher in this group, if the ART was initiated late. The hazard of dying was much higher for this category patient within the first 6 months. However, if they survive for more than six months, the hazard of dying nearly remains constant, as in the other category of patients. Several authors have also reported various risk factors, including low CD4 count for mortality. [9],[10],[11],[12] Tarwater et al, [4] report that the increase of CD4 cell count in the first two years was sustained regardless of the CD4 cell count at which potent ART was initiated, however, the increase leveled off after two years. The best predictor of the level of CD4 cell increase was the suppression of viral load at the first year of ART initiation. Staszewski et al. also reported strong association between the extent of viral suppression induced by therapy and the rise in CD4 cell count. [13] Further, they found CD4 level was continue to rise even at 72 weeks of initiation of ART. Kaufmann et al.[8] and Hunt et al, [6] had also reported an increase in CD4 cell count even after two years. We also found that there was a significant increase in CD4 cell count even after two years of ART, especially in the subject whose CD4 count baseline was <200. Despite the increasing trend of CD4 cells in the baseline CD4 cell count ≥ 200 category, the statistical significance could not be achieved due to small number of patients in this group. As for the risk factors, we identified that males with lower CD4 cell count (<100), lower HB values, ALC count less than 1200 had among males had significantly slow CD4 cell progression even with ART. Amongst the female patients, lower CD4 cell count, 30-44 year age group with ALC count < 1600 were the risk factors for slow CD4 cell progression. Hunt et al[6] and Kaufmann et al, [8] report that the factors associated with increased CD4 cell count gains from month 3 to four years included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia. Based on the experience of our other studies, as the response to ART has been found to differ by sex, we analyzed the risk factors for males and females separately. [14],[15] This study is based on the data from the Government sponsored ART program, which serves mostly middle and low socioeconomic level PLHA and therefore the findings, can be generalized to these category of patients. As viral load estimation is not the routine procedure in the program, the association of viral load after controlling for the baseline characteristics could not be done. It is encouraging to learn that our patients CD4 cell count continue to increase even after two years significantly, in patients whose baseline CD4 cell count category was <100 and 100-199. Additional efforts are needed in patients with < 100 CD4 cell count with low hemoglobin and body weight to reduce the mortality during the initial six-month period. The program could rely on the inexpensive monitoring tools such as estimation of hemoglobin and ALC, as they are associated with CD4 progression.
We thank the Director General of NACO, New Delhi and the Director of Medical Education, Chennai for their constant support and encouragement.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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