Abstract
To determine the rate of and predicting factors for virologic failure among HIV-infected patients with persistent low-level viremia (PLV) under antiretroviral therapy (ART), a retrospective cohort study was conducted among HIV-infected patients who experienced PLV under ART. Persistent low-level viremia was defined as HIV RNA level at 50 to 1000 copies/mL for at least 2 consecutive visits. Of 68 patients, mean ± standard deviation age was 35.2 ± 9.0 years and 64.7% were males. Median (interquartile range [IQR]) CD4 count was 94 (26-264) cells/mm3 and baseline HIV RNA was 112 000 (1 090-461 500) copies/mL. During the median (IQR) follow-up period of 5.7 (3.4-10.3) years of ART, the rate of virologic failure was 38.2%. In multivariate analyses, only maximum amplitude of HIV RNA >400 copies/mL during PLV (hazard ratio = 5.668; 95% confidence interval, 1.888-17.014; P = .002) significantly predicted virologic failure. Patients with PLV >400 copies/mL are more likely to develop virologic failure and should be closely monitored. Interventional studies to prevent virologic failure in these patients are needed.
Introduction
HIV infection is still one of the important public health problems worldwide. In patients who receive antiretroviral therapy (ART), there is a significant decrease in HIV viral load (HIV RNA) and restoration of immune function.1 –4 The goal of ART is to reach and maintain complete virologic suppression.5,6 However, some patients have experienced episodes of transient detectable HIV RNA level (viral blips) and some other patients have developed persistent detectable HIV RNA level.7,8 Previous studies have shown that viral blips are not associated with virologic failure, while some studies have shown the association between persistent low-level viremia and virologic failure.9 –15
In clinical practice, the most appropriate management for patients with persistent low-level viremia is still uncertain. Complete viral suppression resulting from ART has been important for predicting long-term outcome. 16 Therefore, it is important to understand the association between persistent low-level viremia and virologic failure, especially in the resource-limited settings where options of ART are limited. If persistent low-level viremia is associated with virologic failure, any intervention or early switch therapy should be considered for long-term viral suppression. Conversely, if persistent low-level viremia is not associated with virologic failure, patients with persistent low-level viremia may be able to maintain ART regimen and not require any intervention or switch therapy. In resource-limited settings, the rate of and predicting factors for virologic failure in patients with persistent low-level viremia are unknown and some patients with persistent low-level viremia have never experienced virologic failure. The aim of this study was to identify the rate of and predicting factors for virologic failure in HIV-infected patients with persistent low-level viremia under ART.
Methods
A retrospective cohort study was conducted among HIV-infected patients who received ART between January 1, 1995 and December 31, 2012, at a medical school hospital in Bangkok, Thailand. Data were collected from medical records. Inclusion criteria were as follows: (1) an HIV-infected patient aged 15 years and older at initiation of ART (2) received ART for more than 1 year (3) had experienced low-level viremia (HIV RNA level at detectable level of 1000 copies/mL) at least 2 consecutive visits (4) had regular follow-up at infectious disease clinic. Data collected included demographic characteristics, underlying diseases, history of opportunistic infections, clinical presentations, classification based on Centers for Disease Control and Prevention (CDC), initial ART regimen, baseline CD4 count and HIV RNA, CD4 count, and HIV viral load at occurrence of persistent low-level viremia and last test of persistent low-level viremia. All tests for CD4 count, HIV RNA, and ART regimens were ordered by doctors in the infectious disease clinic.
Persistent low-level viremia was defined as HIV RNA level in the range from 50 copies/mL to 1000 copies/mL at least during 2 consecutive visits. Undetectable HIV RNA level was defined as <40 copies/mL or <20 copies/mL depending on HIV RNA assays. Virologic failure was defined as HIV RNA level of more than 1000 copies/mL. Patients were categorized into 2 groups: patients with and without virologic failure. Duration of ART was calculated from the duration from initiation of ART to the last follow-up in the nonfailure group and to virologic failure in the failure group. Duration of persistent low-level viremia was calculated from the occurrence of low-level viremia to the last test of HIV RNA that showed low-level viremia.
The data were analyzed by using SPSS software package version 16.0. The categorical data are presented as frequencies and percentages. Continuous data are presented as means and standard deviations (SDs) or medians and ranges for variables with or without normal distribution, respectively. Baseline characteristics were compared by using chi-square test for categorical variables and Student t test or Mann-Whitney U test for continuous variables. The proportion of patients free from virologic failure was estimated using Kaplan-Meier method and comparisons were made using the log-rank test. Rate of virologic failure in patient with low-level viremia was calculated by percentage of patients with virologic failure. Predicting factors for virologic failure in patients with persistent low-level viremia were assessed by univariate and multivariate Cox proportional hazard model analyses. The study had been approved by the Research Ethic Committee of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand.
Results
A total of 68 patients met the inclusion criteria. Mean ± SD age of all patients was 35.2 ± 9.0 years and 64.7% of patients were male. Half (50%) of patients had prior opportunistic infections. Median (interquartile range [IQR]) baseline CD4 count and baseline HIV RNA level at ART initiation were 94 (26-264) cells/mm3 and 112 000 (1090-461 500) copies/mL, respectively. Of the 68 patients, 26 were categorized as the virologic failure group and 42 as the nonfailure group. The patients’ characteristics were described and compared between the 2 groups as shown in Table 1. There were no differences in demographics, history of opportunistic infections, and CDC classification between the 2 groups. Neither baseline CD4 count nor baseline HIV RNA level differed significantly between the 2 groups.
Baseline Characteristics of 68 Patients with Persistent Low-Level Viremia.
Abbreviations: IQR, interquartile range; SD, standard deviation; ART, antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; d4T, stavudine; 3TC, lamivudine; ZDV, zidovudine; TDF, tenofovir; PLV, persistent low-level viremia; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; VDRL, Venereal Disease Research Laboratory.
Antiretroviral therapy regimens, immunologic response, and virologic response are shown in Table 1. Nonnucleoside reverse transcriptase inhibitor–based regimen was used as initial ART in 69.2% and 57.1% of patients in the virologic failure group and the nonfailure group, respectively (P = .023). Median duration of ART in the nonfailure group was significantly longer than that in the virologic failure group (6.5 versus 4.0 years; P = .021). There were no differences in CD4 count in each period of persistent low-level viremia between the 2 groups but HIV RNA level at the last test of persistent low-level viremia (449 copies/mL in the virologic failure group versus 108 copies/mL in the nonfailure group; P < .001) and maximum amplitude of HIV RNA level during persistent low-level viremia (632 copies/mL in the virologic failure group versus 227 copies/mL in the nonfailure group; P < .001) were different between the 2 groups.
Outcomes of patients with persistent low-level viremia were categorized into 3 groups: complete viral suppression, persistent low-level viremia, and virologic failure. The rate of virologic failure was 38.2% during a median (IQR) follow-up after initial ART period of 5.7 (3.4-10.3) years. In all, 22.1% of patients still had persistent low-level viremia and 39.7% had HIV RNA <50 copies/mL.
From Kaplan-Meier analysis, the median time to develop virologic failure is 11.5 years (95% confidence interval [CI], 8.116-14.843 years). When compared between patients with maximum amplitude of HIV RNA >400 and ≤400 copies/mL during persistent low-level viremia, the median time to develop virologic failure is significantly shorter in the former group (6.6 versus >15 years; log-rank test, P < .001; Figure 1).
Kaplan-Meier analysis of virologic failure between patients with maximum amplitude of HIV RNA ≤400 and >400 copies/mL during persistent low-level viremia.
In univariate analyses, HIV RNA >400 copies/mL at occurrence of persistent low-level viremia (hazard ratio [HR] 2.458; 95% confidence interval [CI], 1.137-5.314; P = .022), HIV RNA >400 copies/mL at the last test of persistent low-level viremia (HR 5.270; 95% CI, 1.787-15.542; P = .003), and maximum amplitude of HIV RNA during persistent low-level viremia >400 copies/mL (HR 4.443; 95% CI, 1.782-11.077; P = .001) significantly predicted virologic failure. Patients who were on successful ART >5 years also had a significantly lower risk of virologic failure (HR 0.050; 95% CI, 0.010-0.620; P = .031), as shown in Table 2. In multivariate analyses, only maximum amplitude of HIV RNA during persistent low-level viremia >400 copies/mL (HR 5.668; 95% CI, 1.888-17.014; P = .002) significantly predicted virologic failure.
Univariate and Multivariate Analysis of Factors Associated with Virologic Failure among 68 Patients with Persistent Low-Level Viremia.
Abbreviations: HR, hazard ratio; CI, confidence interval; PLV, persistent low-level viremia.
Discussion
In clinical practice, we found that some HIV-infected patients receiving ART had experienced transient detectable viremia, usually 50 to 400 copies/mL, and this low-level viremia has been persistent for a period of time in some patients. The rate of transient viremia and persistent low-level viremia in patients who received ART was 27.2% and 4.2%, respectively. 17 Predicting factors for virologic failure in this group are unclear. There is a cohort study showing that patients with persistent low-level viremia have significantly higher rate of virologic failure, that is, about 4-fold, than patients with sustained viral suppression. 13 In addition, patients with persistent low-level viremia tend to develop HIV drug resistance over time. 18
In the present study, we found that the rate of virologic failure in patients with persistent low-level viremia was 38.2%. In addition, 22.1% of patients still had persistent low-level viremia at the end of study. The rate of virologic failure in the present study is much higher than previous studies due to the much longer follow-up time, with a median of 6 years. Regarding the predicting factors for virologic failure among patients with persistent low-level viremia, the maximum amplitude of HIV RNA >400 copies/mL during persistent low-level viremia was the only significant predicting factor for virologic failure in multivariate analysis. Similarly, a previous study showed that patients with persistent low-level viremia at a level of more than 400 copies/mL were at worse prognosis than those with lower levels of detectable viral replication. 13
There were limitations in the present study. It is a retrospective cohort study and some data might be missing. HIV RNA assay was not regularly monitored in some patients. The study also has relatively small sample size. However, the results from the present study can provide important information for health care providers who encounter patients with persistent low-level viremia. According to the results of the present study, patients with persistent low-level viremia (especially more than 400 copies/mL) should be closely monitored and need frequent HIV RNA assay for the early detection of treatment failure.
In summary, the rate of virologic failure in patients with persistent low-level viremia is high. The maximum amplitude of HIV RNA >400 copies/mL during persistent low-level viremia was a significant predicting factor for virologic failure in patients with persistent low-level viremia. Patients with this factor should be closely monitored. Further study to determine optimal management for these patients is crucially needed.
Footnotes
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.