The survival rates of HIV-infected adults treated with ART in this current study were lower compared to England and Wales [10, 11] and higher compared to Tanzania, Nepal and Ethiopia [12-14]. Comparing with China, a middle-income country, the survival rates in this study were lower in the first year of ART but became comparable with longer time on ART [15].
When a comparison with the previous Malaysian study was made, the current study had higher survival rates. This could be due to the use of ART in all patients in the current study, whereas the previous study included patients started with single- or double- or triple-drug regimens [5]. Another reason for low survival rates compared to other Malaysian study probably because the patients who were started ART were chosen based on specific selection criteria due to limited government subsidy prior to 2006 [6].
Further analysis was performed and found that 14 patients in this study who died within the first six months on ART had poor baseline characteristics. They were consisted of a higher percentage of patients with age older than 50 years old (six out of 14), anaemic (ten out of 14), low baseline CD4 cell count which was less than 50 cells/µL (11 out of 14) and had tuberculosis (eight out of 14), when compared to the entire study population. The similar was explained in a China study that poor baseline patient characteristics contributed largely to the worse survival. The authors suggested that early diagnosis and treatment within the first six months of ART were important for improving survival outcome in HIV-infected patients [16].
Anaemia, which was based on the baseline haemoglobin level, is a well-recognised predictor for survival among HIV patients. The result of this study was consistent with previous studies. An Ethiopian study reported that HIV patients with baseline haemoglobin level less than 11 g/dL had an increased hazard risk of 3.06 compared to their counterparts [8]. In Tanzania, moderate and severe anaemia were reported to increase the hazard risk by 7.50 and 9.20 times, respectively [12]. Neighbouring country Vietnam somehow reported a lower hazard ratio. HIV patients with lower baseline haemoglobin level of less than 10 g/dL had 1.9 times higher risk to die compared to those whom haemoglobin level was 10 g/dL and above [17]. A previous study in Malaysia showed the same inverse relationship between baseline haemoglobin level and mortality. The authors analysed baseline haemoglobin level as a continuous variable and concluded that the hazard risk decreased by 16% (with every increase of haemoglobin level by 1 g/dL [6].
Baseline haemoglobin level was not only predictive of long-term mortality, it was also significantly associated with early mortality during the first six months of ART. In the same study, for long term mortality risk beyond six months of ART, having persistent anaemia increased the risk by 4.9 times compared to no anaemia [18].
Although anaemia was known to increase mortality risk, the possibility of reverse causality should be considered. Anaemia at baseline could be due to HIV disease itself, particularly when the disease was at its advanced stage. Being a common haematologic complication in HIV-infected patients, the aetiologies of anaemia were multifactorial. Anaemia could occur due to bone marrow suppression, micronutrient deficiency, impaired erythropoiesis, systematic fungal and mycobacterial infection, malignancy, or association with chronic disease [19].
Anaemia which occurs as a result of co-infection may render a longer recovery time or lead to a poor prognosis of recovery. Thus, these patients have a higher mortality risk [17]. Fortunately, anaemia could be improved with ART initiation, but certain antiretroviral drugs like zidovudine was known to cause bone marrow toxicity leading to anaemia [20]. Therefore, it is important to monitor haemoglobin level periodically according to the national guidelines if zidovudine was the choice of drug in the ART regimen.
Another prognostic factor for HIV survival in this study was TB co-infection. The result of the current study was comparable with previous studies in countries across different regions including China, Ethiopia, Myanmar, and Iran [15, 21, 22, 23].
A Malaysian study involving HIV/TB patients looked further into the association of types of tuberculosis with mortality. When compared to extrapulmonary TB both smear positive pulmonary TB and smear negative pulmonary TB were not prognostic for a higher mortality [24]. The same result was reported in a study in Myanmar reporting that pulmonary TB was not found to be a predictor for death based on multiple Cox proportional hazards regression [22].
HIV and TB speed up each other’s disease progression, thus forming a lethal combination. TB is the leading cause of death among HIV patients [25, 26]. When it involves HIV patients co-infected with TB, the management becomes complicated because of the known drug-drug interactions between the drug used in HIV and TB treatment.
Antiretroviral drugs such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) are inducers or inhibitors of drug metabolising enzymes and anti-TB such as rifampicin is a potent inducer of metabolising enzymes and transporters. The consequences of the interactions include therapeutic failure and increased toxicity, which in turn could increase the mortality risk amongst HIV/TB co-infected patients. However, with the systematic approach in identifying and managing individual drug regimens, mortality rates in this group of patients could be reduced. WHO recommends starting ART in all HIV/TB co-infected patients regardless of their CD4 cell count. Being the most common co-infection among HIV patients, it is therefore important to collaborate HIV and TB care services for this group of patients [27, 28].
It was expected that CD4 cell count would be a significant predictor for HIV survival in this current study, but the results of multiple Cox regression showed the otherwise. This result could be explained by the small proportion of patients within the event group in this current study. A study in India showed that lower adherence to ART was observed among those with CD4 cell count less than 200 cells/µL, which could explain the higher mortality rates among those with low CD4 cell count [29]. However, adherence was not considered in this study which had also been a limitation of this study.
Strength and Limitation
This study was conducted at one of the biggest tertiary hospital under Ministry of Health Malaysia. Hence, the results can be applied to other hospitals in Malaysia as all under the Ministry of Health share the same system and support. All patients included in this study were treatment naïve, therefore the results are not confounded by previous ART. The mortality data was from reliable sources, i.e. the National Registration Department, adding to the quality of the current study.
Due to the retrospective design of the study, there was a high percentage of missing data for some of the variables of interest which were then excluded from survival analysis, such as baseline viral load and WHO clinical staging. This could cause bias in the assessment of progression to mortality. Besides, the current study did not include the factor regarding adherence to ART, which may have caused bias in identifying prognostic factors for HIV survival. This information was not included as it was not consistently recorded in medical records. Neither was the assessment of ART adherence standardised among different healthcare workers.