Short Communication: Factors Influencing Time to CD4 + T Cell Counts >200 Cells/mm 3 in HIV-Infected Individuals with CD4 + T Cell <50 Cells/mm 3 at the Time of Starting Combination Antiretroviral Therapy

Abstract

We evaluated factors influencing time to CD4⁺ T cell counts >200 cells/mm³ in HIV-infected individuals with CD4⁺ T cell <50 cells/mm³ starting combination antiretroviral therapy (cART). We included a total of 29 patients on successful cART for more than 1 year. In a logistic regression model, higher pre-cART CD4⁺ T cell counts were significantly associated with shorter time to CD4⁺ T cell counts >200cells/mm³ in HIV-infected individuals with baseline CD4⁺ T cell <50 cells/mm³. In survival analysis, patients having higher pre-cART CD4⁺ T cell counts, especially 40–49 cells/mm³, were at significantly higher risk of achieving CD4⁺ T cell counts >200 cells/mm³.

Introduction

S urvival in human immunodeficiency virus (HIV)-infected individuals has improved with the introduction of combination antiretroviral therapy (cART).^1,2 However, late diagnosis of HIV infection still contributes to poor medical outcomes and the continuation of viral transmission.^3
–5

Of the immunologic markers, the CD4⁺ T cell levels are not only comprehensively used for initiating HIV therapy and prophylaxis for opportunistic infections,^6,7 but also are an important criterion for categorizing HIV-related clinical conditions.^8,9 HIV-infected patients with CD4⁺ T cell counts <200 cells/mm³ are at risk for developing Pneumocystis infections.⁷ In particular, CD4⁺ T cell counts <50 cells/mm³ are predisposing factors for all opportunistic infections (OIs) including Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) infections.⁷ Thus, in HIV-infected individuals, to prevent opportunistic infections it is important that CD4⁺ T cell counts are increased to >200 cells/mm³ as soon as possible.

However, to our knowledge, little is known about factors influencing time to CD4⁺ T cell counts >200 cells/mm³ in HIV-infected individuals with baseline CD4⁺ T cell counts <50 cells/mm³ at the start of cART.

Materials and Methods

A retrospective case-control study was conducted at an urban hospital in Seoul, South Korea. HIV-1-infected persons, who started cART between 1996 and 2010, were aged 18 years or older at treatment initiation, had CD4⁺ T cell counts <50 cells/mm³ at the time of starting cART, and had sustained virological suppression (HIV RNA<400 copies/ml) over 1 year of cART were eligible for this study. Patients who had any treatment interruption for more than 1 month were excluded. CD4⁺ T cell counts of each individual were evaluated every 3 months (within a window of±1 month). The pre-cART CD4⁺ T cell counts were mostly measured when the treatment was started.

During this study, 593 HIV-infected patients were retrospectively analyzed. Among these patients, death and follow-up loss were 31 and 265, respectively. Also, the study included nine treatment-naive patients. The study included 288 patients who started cART as well, and 75 of these 288 patients had interruptions of treatment or virological failures. Among 222 patients who had maintained a suppressed viral load over 1 year after initiating cART were 29 HIV-infected patients who had CD4⁺ T cell counts <50 cells/mm³ at the time of starting cART. All enrolled patients were initially treated with cART at CD4⁺ T cell counts <50 cells/mm³ due to late diagnosis of HIV infection.

The following variables were assessed: age at therapy initiation (years); gender; reported route of infection; prior acquired immunodeficiency syndrome (AIDS) diagnosis at cART initiation; hepatitis B or C coinfection; tuberculosis (TB) coinfection during the follow-up; antiretroviral therapy (ART) regimens [two nucleoside analog reverse transcriptase inhibitors (NRTIs)+nonnucleoside reverse transcriptase inhibitor (NNRTI), two NRTIs+protease inhibitor (PI), or other combination] at cART initiation; CD4⁺ T cell count (cells/mm³), CD8⁺ T cell count (cells/mm³), and HIV viral load (copies/ml) at cART initiation. The Centers for Disease Control and Prevention (CDC) classification was determined for each individual.¹⁰ The most severe CDC category recorded was listed as the clinical status.

We estimated duration (months) from the initiation of cART to the date of test reporting CD4⁺ T cell counts >200 cells/mm³ in each individual. Patients were then categorized into two groups depending on the median time to increase from CD4⁺ T cell counts <50 cells/mm³ to >200 cells/mm³ after starting cART. One group was deemed the slow increase group as its interval times were more than the median time and the other group was deemed the fast increase group as its interval times were faster than the median time. Pre-cART CD4⁺ T cell counts were mostly measured when cART was started. Even though pre-cART CD4⁺ T cell counts were measured within 2 weeks before initiating cART in eight patients, there were four cases of the slow increase group and four cases of the fast increase group.

To evaluate predictors of slow increase, we performed logistic regression analyses. Variables with a p-value of <0.1 in the univariate analysis were included for the multivariate analysis. We also evaluated outcomes of CD4⁺ T cell count >200 cells/mm³ following cART initiation using a survival analysis method. The survivor function for CD4⁺ T cell count >200 cells/mm³ was compared using Cox proportional hazard models. Time was calculated from the initiation of cART and ended at the time of reporting CD4⁺ T cell counts >200 cells/mm³. The final multivariate model included all covariates that remained significant at the 0.10 level (two sided). The analyses were performed using SPSS (version 18).

Results

A total of 29 patients who fulfilled the inclusion criteria were identified. The median age was 50 (range, 35–75) years, and 96.6% (28/29) of the subjects were male. The most common exposure category was men having sex with men (MSM) (44.8%), followed by heterosexual contact (10.4%). These 29 patients had achieved an absolute level of CD4 counts of 200 cells/mm³ and had a median interval time of 12 (range, 3–42) months up to >200 cells/mm³ of CD4⁺ T cell counts after cART. Slow (n=15) and fast (n=14) increase groups had median interval times of 18.3 and 3.5 months, respectively.

The demographic and clinical characteristics of each group are shown in Table 1. Compared with patients who exhibited a fast increase in CD4⁺ T cell counts, patients who showed a slow increase had significantly lower pre-cART CD4⁺ T cell counts. Only the slow increase group had TB coinfections. In the multivariate analysis, lower pre-cART CD4⁺ T cell count was significantly associated with the slow increase of CD4⁺ T cell counts >200 cells/mm³ (odds ratio 0.873; 95% confidence interval 0.781–0.975; p=0.016) (Table 2).

Table 1.

The Demographic and Clinical Characteristics of HIV-Infected Individuals with CD4 ⁺ T Cell <50 Cells/mm ³ at the Start of Combination Antiretroviral Therapy

Variables	Slow increase group N=15, n (%)	Fast increase group N=14, n (%)	Total N=29, n (%)	p-value
Male gender	14 (93.3)	14 (100)	28 (96.6)	1.000
Age at starting cART, median, years (range)	47 (35–79)	51 (35–75)	50 (35–75)	0.323
Mode of transmission
Homosexual contacts	8 (53.3)	5 (35.7)	13 (44.8)	0.462
Heterosexual contacts	2 (13.3)	1 (7.1)	3 (10.4)	1.000
Unknown and others^a	5 (33.3)	8 (57.1)	13 (44.8)
Pre-cART CD4⁺ T cell count, median (IQR), cells/mm³	14 (6–18)	28 (6–47)	17 (10–29)	0.032
Pre-cART VL, median (IQR), log₁₀ copies/ml	5.36 (4.72–5.69)	5.31 (3.88–6.30)	5.34 (4.82–5.34)	0.921
Pre-cART CD8⁺ T cell count, median (IQR), cells/mm³	370 (197–456)	493 (279–748)	413 (222–664)	0.076
Initial cART regimen
PI plus 2 NRTIs	7 (46.7)	6 (42.9)	16 (55.2)	0.837
NNRTI plus 2 NRTIs	8 (53.3)	8 (57.1)	13 (44.8)	0.837
TB coinfection at starting cART	3 (20.0)	0 (0.0)	3 (10.3)	0.224
HBV coinfection at starting cART	0 (0.0)	2 (14.3)	2 (6.9)	0.224
CDC stage at starting cART
B3	3 (20.0)	1 (7.1)	4 (13.8)	0.598
C3	12 (80.0)	13 (92.9)	25 (86.2)	0.598

Unknown and others: 12 unknown and 1 blood product.

HIV, human immunodeficiency virus; cART, combination antiretroviral therapy; IQR, interquartile range; VL, viral load; PI, protease inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; TB, tuberculosis; HBV, hepatitis B virus; CDC, Centers for Disease Control and Prevention.

Table 2.

Multivariate Analysis of Time to CD4 ⁺ T Cell Counts >200 Cells/mm³ After Combination Antiretroviral Therapy in HIV-Infected Individuals with Baseline CD4 ⁺ T Cell <50 Cells/mm³

Variables	Slow increase group N=15	Fast increase group N=14	Odds ratio (95% CIs)	p-value
Age at starting cART (per 1 year increase), median, years (range)	47 (35–79)	51 (35–75)	1.045 (0.948–1.152)	0.375
Pre-cART CD8⁺ T cell counts (per 100 cells/mm³ increase), median (IQR), cells/mm³	14 (6–18)	28 (6–47)	0.888 (0.657–1.201)	0.442
Pre-cART CD4⁺ T cell counts (per 1 cell/mm³ increase), median (IQR), cells/mm³	370 (197–456)	493 (279–748)	0.873 (0.781–0.975)	0.016

cART, combination antiretroviral therapy; IQR, interquartile range; HIV, human immunodeficiency virus; CIs, confidence intervals.

We also evaluated the factors associated with the time to the increase of CD4⁺ T cell counts >200 cells/mm³ since cART initiation in Cox proportional hazard analysis. In the multivariate model, patients having a higher pre-cART CD4⁺ T cell count, especially those whose baseline count was greater than 40 cells/mm³, had a significantly higher rate of CD4⁺ T cell counts >200 cells/mm³ (adjusted hazard ratio 6.633; 95% confidence interval 1.121–39.230; p=0.037) (Table 3).

Table 3.

Cox Proportional Hazards Analysis of an Increase of CD4 ⁺ T Cell count >200 Cells/mm³ Following Combination Antiretroviral Therapy Initiation

Variables	Median time to event (months)	n (%) of events (CD4 >200 cells/mm³)	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
Age at starting cART, years
≤50	10.5	15 (51.7)	1		1
50>	9.7	14 (48.3)	0.897 (0.418–1.924)	0.78	0.874 (0.374–2.041)	0.756
Mode of transmission
Homosexual contacts	10.9	13 (44.8)	1		—	—
Heterosexual contacts	11.7	3 (10.4)	1.362 (0.378–4.912)	0.637	—	—
Pre-cART CD4⁺ T cell count, cells/mm³
<10	17.4	7 (24.1)	1		1
10–19	11.7	12 (41.4)	1.001 (0.380–2.640)	0.998	0.990 (0.374–2.618)	0.983
20–29	8.3	3 (10.3)	2.404 (0.591–9.789)	0.221	2.234 (0.511–9.753)	0.285
30–39	9.7	5 (17.2)	3.594 (0.980–13.180)	0.054	3.538 (0.963–12.996)	0.057
40–49	2.7	2 (7.0)	6.25 (1.102–35.461)	0.039	6.633 (1.121–39.230)	0.037
Initial cART regimen
PI plus 2 NRTIs	10.5	13 (44.8)	1		—	—
NNRTI plus 2 NRTIs	13.1	16 (55.2)	0.774 (0.365–1.638)	0.503	—	—

cART, combination antiretroviral therapy; HR, hazard ratio; CIs, confidence intervals; VL, viral load; IQR, interquartile range; PI, protease inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor.

Discussion

The CD4⁺ T cell count is an important determinant of disease stage and prognosis in HIV-infected individuals.^8,9 According to Lee et al., the proportion of individuals with a late diagnosis defined by a CD4⁺ T cell count <200 cells/mm³ at the time of diagnosis increased annually from 2000 to 2007 in South Korea.¹¹ Late diagnosis, especially CD4⁺ T cell count <50 cells/mm³ at the time of diagnosis, results in delayed treatment, increasing OIs, and an increased risk of transmission.^3
–5 Thus, there is still a high risk of mortality in HIV-infected individuals due to late diagnosis.^3
–5

The factors that affect the extent of the increase of CD4⁺ T cell counts in patients receiving cART have been studied. Some have reported that the baseline CD4⁺ T cell count influences the rate of immune reconstitution,^12,13 whereas others have found no evidence of such an association.^14,15 However, to our knowledge, little is known about HIV-infected individuals with pre-cART CD4⁺ T cells <50 cells/mm³, which was a predisposing factor of all OIs including MAC and CMV infections. To the best of our knowledge, our study represents the first report regarding factors influencing time to reach CD4⁺ T cell counts >200 cells/mm³ in HIV-infected individuals with CD4⁺ T cell counts <50 cells/mm³ at the time of starting ART.

In this study, pre-cART CD4⁺ T cell counts were significantly associated with time to CD4⁺ T cell counts >200 cells/mm³ in HIV-infected individuals with CD4⁺ T cell counts <50 cells/mm³ at the time of starting cART. In other words, the lower the pre-cART CD4⁺ T cell counts among patients with CD4⁺ T cell counts <50 cells/mm³, the slower was the increase of CD4⁺ T cell counts >200 cells/mm³.

Also, we evaluated the impact of pre-cART CD4⁺ T cell counts in patients with CD4⁺ T cell counts <50 cells/mm³ at the time of achieving a CD4⁺ T cell count >200 cells/mm³ using survival analyses. Compared to those who started with a CD4 of 0–10 cells/mm³, a pre-cART CD4⁺ T cell count of 40–49 cells/mm³ showed a higher rate of achieving a CD4⁺ T cell count >200 cells/mm³. Moreover, pre-cART CD4⁺ T cell counts of 30–39 cells/mm³ showed a tendency to be greater in achieving CD4⁺ T cell counts >200 cells/mm³ (p-value=0.057). Therefore, in late diagnoses, especially for CD4⁺ T cell counts <40 cells/mm³, we need to immediately consider cART and be more aware of OIs and viral transmission during cART. However, the results of this study are based on a small sample size, so if more samples are added, more precise statistical significance can be identified.

Also, in our study, TB was observed in three patients in only the slow increase group and none in the fast increase group. However, there was no significant association between TB and time to CD4⁺ T cell counts >200 cells/mm³, although several studies showed that TB influenced the increase of CD4⁺ T cell counts during cART.^16,17

Our study has several limitations. First, our results were not applicable to females with HIV infection. Gender is a very important epidemiological variable but in our data, women comprised only 3%, so we did not consider gender in our data analysis. This is due to the fact that HIV-infected women in Korea are rare (only about 9%) and our study did not have enough women.¹⁸ Second, the sample size was small. However, we have enhanced the power by subdividing the group with smaller categories. A multicenter study is under progress for more concrete results. Third, as in all retrospective studies, there is a potential for bias and inaccurate data collection. Further prospective studies, with larger patient populations involving multiple centers, are necessary to ascertain the relevant influencing factors accurately. Fourth, although CD4⁺ T cell counts of each individual were evaluated every 3 months in the two groups, the time to achieve a CD4⁺ T cell count >200 cells/mm³ is likely to be affected by interval censoring because of a window of±1 month. Lastly, we used a single CD4⁺ T cell count for each time point, and “the regression to the mean” could bias our results.

In conclusion, the pre-cART CD4⁺ T cell count was significantly associated with time to CD4⁺ T cell counts >200 cells/mm³ in HIV-infected individuals with CD4⁺ T cell counts <50 cells/mm³ at the start of cART. Therefore, in late diagnoses, especially for CD4⁺ T cell counts <40 cells/mm³, we need to immediately consider cART and be more aware of OIs and viral transmission during cART.

Footnotes

Acknowledgments

This study was supported by a faculty research grant of Yonsei University College of Medicine for 2011(6-2011-0115), the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2011-220-E00015), and a grant by the Chronic Infectious Disease Cohort (4800-4859-304-260) from Korea Centers for Disease Control and Prevention. Statistical advice was reviewed by the statistician Hye Sun Lee, M.S., at the Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea.

Author Disclosure Statement

No competing financial interests exist.

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