Following HIV diagnosis, timely linkage to care, prompt initiation of ART when indicated, and maintaining good adherence to ART are critical for successful HIV treatment. Delayed linkage and poor retention in care have been associated with deleterious clinical outcomes including delayed ART initiation, high rate of ART failure, and worse survival (19
). The present analysis showed that the mortality rate and the risk factors for death were different over time after ART initiation. The first year mortality after ART initiation was about 2-fold higher than that of a period of 1-5 yr after ART initiation. During the first year after ART initiation, CDC clinical categories B or C on ART initiation and underlying malignancy were significant risk factors for death. The patients with clinical category C were about 22 times more likely to die than those with clinical category A. These findings are consistent with other studies that have shown that early mortality after ART initiation is related to the delayed treatment initiation due to late presentation to care (4
). Baseline CD4 cell counts ≤50 cells/µL was associated with early mortality in univariate analyses, however, it was not associated in multivariate models, probably because clinical staging was a better indicator of early death (26
). In addition, visit constancy to hospital was not associated with early mortality, suggesting that the patients with high risk opportunistic infections (OIs) for death remained increased risk for early death after ART initiation, even though they remained in good retention in care, before the full effect of therapy had not yet been obtained (9
Between 1 and 5 yr after ART initiation, poor retention in care, baseline CD4 cell counts ≤ 50 cells/µL on ART initiation, and HBV co-infection were significant risk factors for death. However, clinical category B or C on ART initiation which were risk factors for early mortality were not associated with mortality in 1-5 yr on ART, suggesting that patients with high risk OIs for death initially do not have persistently increased risk for death if they survive the first 12 months of ART (24
). In contrast, baseline CD4 cell counts ≤ 50 cells/µL on ART initiation was associated with mortality in 1-5 yr on ART, suggesting that severely immunosuppressed patients still have increased risk for death, even though they survive the first 12 month of ART (28
In the present study, we traced the patients initially categorized as lost in collaboration with local PHCs. Previous studies conducted in sub-Saharan Africa showed that survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced, due to high rates of death among patients lost to follow-up after ART (24
). In our study, of 92 patients initially categorized lost, 44.6% were confirmed dead after tracing, resulting in 12.5% increase of number of death after tracing.
In our study, we measured retention in care by hospital visit constancy during the observation period after ART initiation (19
). This measure is less detail to assess retention in care than appointment adherence, and is computationally more challenging (21
). The missed visit within an interval of interest cannot be measured and retention can be overestimated or underestimated by the timing of visit (18
). However, this measure is known to be preferable for research for longer observation periods, particularly relevant for patient starting ART, and is better accounts for loss to follow-up (LTFU) than other measures such as missed visit or adherence measure (21
). Previous studies have typically included only scheduled outpatient medical appointment for HIV care (19
). In this study, however, we included urgent care visit for HIV care to measure the retention because patients who returned to care after LTFU were frequently hospitalized via urgent care, and thereafter successfully retained in care if they survived.
In our study, suboptimal retention in care was common during 5-yr observation period. Among patients who survived more than 12 months after starting ART, 53.5% was regular clinic attendance, whereas 46.5% had various durations of LTFU. Our data showed that patients with ≤ 50% visit constancy were about 13 times more likely to die than those who attended hospital regularly during 5-yr observation period. The patterns of healthcare usage and the duration of LTFU among patients with LTFU were also considerably variable, and 49% of the patients with LTFU demonstrated a cyclical pattern of being in and out of care (32
), leading to measuring retention in care more complex in our study.
In addition, HBV co-infection was also independent risk factor for death between 1 and 5 yr after start of ART. HIV infection is associated with more rapid progression to cirrhosis or hepatocellular carcinoma (34
). HBV is the most common cause of cirrhosis and hepatocellular carcinoma in Korea, and the prevalence rate in twenties and over showed 7.6% in men and 3.4% in women (36
). In our study, the prevalence rate of HBV was 9% in men and 7.5% in women, and slightly higher than that of general population. Because tenofovir has not been available and other anti-HBV drugs, such as entecavir and adefovir have not been covered by public health insurance until end of 2011 in Korea, many HBV/HIV co-infected patients have been treated with lamivudine as monotherapy against HBV in their ART regimen. At present, there are few published data regarding the clinical outcomes of HBV/HIV co-infected patients treated with ART in Korea, and further studies are needed.
Although the mortality rate and the risk factors associated with mortality after initiating ART were different in these two time periods, the causes of death were similar over time on ART. AIDS-related death was more common and tuberculosis remained the most frequent OI associated with death in both time periods.
This study has some limitations. First, this study is an observational study, so we cannot rule out the presence of unmeasured confounding. Second, our study was conducted at a single center in the southeastern region of Korea, and the numbers of death are relatively small, therefore our findings may not be generalized to other region of the country. Third, there was the lack of detailed information about the reason that tuberculosis is the most frequent cause of death, reasons for LTFU after ART initiation, and some missing data on serology for hepatitis due to its retrospective design.
In summary, the mortality rate, cause of death, and risk factors associated with death in adults receiving ART in Korea were different over time after ART initiation. Late presentation to care with AIDS-defining OIs is an important risk factor for early death in the first year of ART, whereas poor retention in care, CD4 cell counts ≤ 50 cells/µL on ART initiation, and HBV co-infection are significant risk factors of late mortality. Different strategies to reduce mortality according to the time period after ART initiation are needed.