Rate of CD4 Decline and Factors Associated with Rapid CD4 Decline in Asymptomatic HIV-Infected Patients

Abstract

The accurate marker to assess the risk of disease progression in HIV disease is CD4 count. CD4 decline to <200 cells/mm³ prompts the patients to have risk of opportunistic infections. A retrospective cohort study was conducted in asymptomatic HIV-infected patients who had CD4 count >200 cell/mm³, were antiretroviral naive, and had ≥1-year follow-up. Eighty patients, with mean age of 36.4 (standard deviation [SD] = 9.1) years and 58.8% females, were analyzed. The mean (SD) baseline CD4 count was 423 (119) cells/mm³. During the median (IQR) time of 29.0 (14.1-49.6) months, 26.3% had CD4 declined to <200 cells/mm³. From Cox proportional hazard model, only baseline CD4 count <350 cells/mm³ was significantly associated with rapid decline in CD4 count (HR 4.208; 95%CI, 1.428-12.397; P = .009). Age, gender, comorbid disease, risk of HIV infection, duration of HIV diagnosis, and body weight were not associated with rapid CD4 decline. This indicates that asymptomatic patients with CD4 count <350 cells/mm³ are at priority for antiretroviral therapy in resource-limited settings.

Keywords

asymptomatic HIV CD4 decline risk factor resource-limited settings

Introduction

HIV infection is one of the major global health problems. Currently, the Joint United Nations Programed on HIV/AIDS reports that estimated number of people living with HIV in Thailand are about 440 000, and the estimated adult HIV prevalence is 1.1%.¹ Of these, approximately 150 000 patients have been treated with antiretroviral therapy (ART) under the National AIDS Program in Thailand. Since 2010, Thailand has revised its policy on initiating ART by increasing eligibility from a CD4 count of 200 to 350 cells/mm³.² The intention was to initiate ART earlier to improve efficacy and reduce AIDS mortality. In October 2014, the Thailand National Guidelines on HIV/AIDS Treatment and Prevention approved the goal of eradicating the threat of AIDS by extending ART to all HIV-infected patients regardless of CD4 count.³

Despite the increase in CD4 count threshold to 350 and including all CD4 count, HIV-infected patients initiating ART still have very low CD4 counts.^4
-6 Late presentation of patients to health care facility and deferring of treatment in asymptomatic patients are 2 major reasons for late initiation of ART in Thailand.⁷ Antiretroviral therapy is often deferred in some asymptomatic patients who are not ready to take ART, and the crucial timing to defer ART safely is not clear.

Two laboratory markers, CD4 count and HIV-1 viral load, are well-established prognostic markers of HIV disease progression.^8

-11 Of the 2, CD4 count is an accurate marker of the stage of HIV disease and risk of morbidity and mortality and recommended by all guidelines of HIV management to be a routine part of HIV clinical care. Decline in CD4 count to less than 200 cells/mm³ prompts the patients to have risk of opportunistic infections and to be classified as AIDS.

Although decline in CD4 count is well recognized for HIV disease progression, some uncertainties remain over the rate of CD4 decline and the factors associated with rapid decline in CD4 count. A full description of HIV natural history in terms of these data is important because these are used to guide clinical decisions such as timing of ART initiation and to estimate the duration of HIV infection. Currently, data of CD4 decline and factors associated with rapid CD4 decline in asymptomatic HIV-infected patients in Thailand are still not available. This study aimed to determine the rate of CD4 decline and factors associated with rapid decline in CD4 count in asymptomatic HIV-infected patients in Thailand.

Materials and Methods

A retrospective cohort study was carried out in asymptomatic HIV-infected patients who were cared at Ramathibodi Hospital, a medical-school hospital, during 2010 to 2014. All participants had documented HIV infection and met the following criteria: (1) greater than 15 years of age, (2) antiretroviral naive, (3) baseline CD4 count >200 cell/mm³, (4) had followed up for at least a year, and (5) scheduled for regular clinical and laboratory visits until the end of the study period. Patients were excluded if they had history of HIV-related symptom or opportunistic infection at baseline.

All patients were measured CD4 count every 6 months. Rapid CD4 decline was defined as CD4 declined to <200 cells/mm³ within 3 years. Baseline characteristics and possible associated factors, including age, gender, body weight, hepatitis B virus coinfection, hepatitis C coinfection, underlying diseases, baseline CD4 count, change in CD4 count, were retrieved from medical records. The study was approved by the institutional ethic committee.

All analyses were performed using an electronic database organized in SPSS version 16.0. Mean values (± SDs) and median values (with interquartile range, IQR) were used to describe the continuous data with and without normal distribution, respectively. Number of patients and percentage were used to describe categorical data. Time to CD4 count <200 cells/mm³ was estimated using Kaplan-Meier analysis. Factors associated with rapid CD4 decline were determined using Cox proportional hazard model. The results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). A P value at <.05 was considered statistically significant.

Results

Eighty patients were included in this study. Baseline characteristics of all patients are summarized in Table 1. Mean (SD) age was 36.4 (9.1) years and 58.8% were females. Twenty-one (26.3%) patients had comorbid disease. Mean (SD) baseline CD4 count was 423 (119) cells/mm³. The most common risk of HIV infection was heterosexual contact (90%). During a median (IQR) study time of 29.0 (14.1-49.6) months, 21 (26.3%) patients had CD4 count declined to <200 cells/mm³. From Kaplan-Meier analysis, median time to CD4 <200 cell/mm³ was >60 months (Figure 1) and the probabilities of CD4 decline to <200 cells/mm³ at 1, 2, 3, 4, and 5 years were 8.1%, 14.5%, 20.1%, 29%, and 38.8%, respectively.

Figure 1.

Kaplan-Meier analysis of time to CD4 <200 cell/mm³.

Table 1.

Baseline Characteristics of 80 Asymptomatic HIV-Infected Patients.

Characteristics	Values
Age, mean ± SD, years	36.4 ± 9.1
Gender, number of patients (%)
Male	33 (41.2)
Female	47 (58.8)
Comorbid diseases, number of patients (%)	21 (26.3)
Diabetes mellitus	2 (2.5)
Hypertension	3 (3.8)
Dyslipidemia	2 (2.5)
Others	14 (18.7)
Baseline body weight, median (IQR), kg	55.7 (50.0-63.0)
Risk of HIV infection, number of patients (%)
Homosexual	5 (6.2)
Heterosexual	72 (90.0)
Intravenous drug use	2 (2.5)
Blood transfusion	1 (1.3)
Duration of HIV infection, median (IQR), years	1.9 (0.6-15.6)
Baseline CD4 count, mean ± SD, cells/mm³	423 ± 119

Abbreviations: IQR, interquartile range; SD, standard deviation.

When patients were categorized according to the baseline, estimated time for 25% of patients with CD4 decline to <200 cells/mm³ in patients with baseline CD4 ≥350 versus <350 cells/mm³ was 48.4 versus 14.0 months (log rank test, P = .008; Figure 2). From univariate analysis, baseline CD4 count <350 cells/mm³ was significantly associated with rapid CD4 decline (HR 3.281; 95% CI 1.298-8.292; P = .012), and age <30 years had a trend associated with rapid CD4 decline (HR 2.381; 95% CI 0.994-5.703; P = .052). Gender, comorbid disease, risk of HIV infection, duration of HIV diagnosis, and body weight were not associated with rapid CD4 decline (P > .1). From multivariate analysis, only baseline CD4 count <350 cells/mm³ was significantly associated with rapid CD4 decline HR 4.208; 95% CI 1.428-12.397; P = .009] as shown in Table 2.

Figure 2.

Kaplan-Meier analysis of time to CD4 <200 cell/mm³ among patients with baseline CD4 ≥ 350 versus < 350 cells/mm³.

Table 2.

Univariate and Multivariate Analysis of Factors Associated with Rapid CD4 Decline.

Factors	Univariate			Multivariate
Factors	Hazard Ratios	95% Confidence Interval	P Value	Hazard Ratios	95% Confidence Interval	P Value
Age <30 years	2.381	0.994-5.703	.052	2.220	0.899-5.485	.084
Female gender	0.832	0.256-2.707	.760	-	-	-
Presence of comorbid disease	1.115	0.370-3.360	.846	-	-	-
Baseline body weight >50 kg	1.231	0.395-3.805	.719	-	-	-
Homosexual contact	1.428	0.157-13.018	.752	-	-	-
Duration of HIV infection >2 years	1.729	0.654-4.572	.270	-	-	-
Baseline CD4 <350 cells/mm³	3.281	1.298-8.292	.012	4.208	1.428-12.397	.009

Discussion

The present study has shown that one-fourth of asymptomatic HIV-infected patients had CD4 count decline to < 200 cells/mm³ within 3 years. Baseline CD4 < 350 cells/mm³ was independently associated with rapid CD4 decline. Age, gender, comorbid disease, risk of HIV infection, duration of HIV diagnosis, and body weight were not significantly associated with rapid CD4 decline.

The rapid decline in CD4 count in asymptomatic HIV-infected patients has been a concern in many resource-limited settings because ART is not available for all patients.¹² Factors associated with rapid CD4 decline has been demonstrated in previous studies. Meijerink et al¹³ have shown that a history of intravenous drug use is associated with a more rapid CD4 decline among HIV-infected patients in Indonesia. Rodríguez et al¹⁴ have studied in 2 cohorts of HIV-infected patients in the United States and demonstrated that higher presenting HIV RNA levels are associated with greater subsequent CD4 decline. The present study could not demonstrate these findings because of the much lower rate of intravenous drug use and lack of baseline HIV RNA data. According to the Thai HIV guidelines, HIV RNA is not recommended to test in antiretroviral-naive patients due to the constrained resources.^2,3

In resource-limited settings where ART is not available for all HIV-infected patients, CD4 count <350 cells/mm³ should be the critical cut point to provide ART. Baseline CD4 <350 cells/mm³ independently associated with rapid CD4 decline supports the prior Thai national guidelines in 2010 that ART should be initiated in HIV-infected patients with CD4 count of <350 cells/mm³.² Nevertheless, the recent new Thai guidelines in 2014 encourage starting ART in all patients regardless of CD4 count.³ In real-life clinical practices, some patients are not ready to take ART due to various reasons. In that case, ART should not be deferred until CD4 counts <350 cells/mm³.

We recognize some limitations in the present study. First, the nature of retrospective study resulted in the lack of some variables in some patients. Second, the sample size in this study is relatively small. In our setting, most of the patients presented to the hospital late, and baseline CD4 counts were <200 cells/mm³ and were excluded from the present study. Finally, the study patients in this study were enrolled from only a single site which is a tertiary care hospital. Nonetheless, the results from the present study provide the relevant information regarding rate of CD4 decline and factors associated with rapid CD4 decline in asymptomatic HIV-infected patients and could be useful for clinicians who care HIV-infected patients in resource-limited settings.

In summary, one-fourth of asymptomatic HIV-infected patients had CD4 count declined to <200 cells/mm³ within 3 years. Baseline CD4 <350 cells/mm³ was independently associated with rapid CD4 decline in asymptomatic HIV-infected patients. This finding indicates that asymptomatic HIV-infected patients with CD4 <350 cells/mm³ are at priority for ART in resource-limited settings.

Footnotes

Authors’ Note

The abstract is this study was presented at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Vancouver, Canada, 2015. Abstract MOPEB150.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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