Effect of AIDS-defining events at initiation of antiretroviral therapy on long-term mortality of HIV/AIDS patients in Southwestern China: a retrospective cohort study

Since the first case of the human immunodeficiency virus (HIV) infection was reported in 1981, 36.9 million people have been infected with HIV; the worldwide mortality rate of HIV/AIDS patients was 23.8% in 2017 [1]. As of August 31, 2018, 841,478 living HIV/AIDS patients and 259,200 deaths had been registered in China, with mortality rate of 23.55% [2, 3]. Guangxi, a province in Southwestern China, has the second highest number of reported HIV cases in the country, with 703,000 survivals and 40,500 deaths by 2017. The mortality rate (34.3%) was also higher than the national average mortality rate (23.8%) during the same period [4]. In China, the National Free Antiretroviral Treatment Program (NFATP) began in 2002 and was scaled up in 2003. The “Treat for All” policy was implemented in 2016, and HIV positive individuals would be treated after diagnosis of HIV regardless of their CD4⁺ cell count [5‐7]. However, research showed that 45.1% patients were in the advanced stages of AIDS when they were diagnosed [8], which might be the main reason for the high mortality rate in HIV positive individuals, even when they are on ART.

ART can significantly improve the prognosis of HIV infected people, and reduce the spread of HIV, which is more conducive to improving the prognosis and quality of life of patients [9]. At present, anti HIV drugs can be divided into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), fusion inhibitors and entry inhibitors. Then, the most widely used drugs are the first three categories in China. NRTIs mainly contains zidovudine (AZT), stavudine (D4T), lamivudine (3TC), tenofovir (TDF) and abacavir (ABC) et al.; NNRTIs mainly contains nevirapine (NVP), delavirdine, efavirenz (EFV) and etravirine et al.; and PIs mainly contains lopinavir (LPV), saquinavir, ritonavir and indinavir. In this study, the patients mainly used three kinds of antiviral treatment schemes: 2NRTIs + 1NNRTI, 2NRTIs + 1PI and single or the combination of two drugs.

By 2017, 542,000 people living with HIV/AIDS (PLHIV) had received ART in China [2]. Research showed that ART also can effectively reduce mortality, delay the progression of the disease, prolong the development of non-AIDS-defining events (non-ADE) to ADE, reduce complications, and prolong lifespan [10]. However, ART-treated patients still face a higher mortality risk and lower quality of life than the general population [11‐14]. Many studies have shown that a low CD4⁺ cell count, older age, male gender, clinical stage III/IV disease, low body mass index (BMI), and signs/symptoms of AIDS are independent factors related to death among patients on ART [4, 15‐19], indicating that patients with ADE may have higher mortality. A study in Italy suggested that patients with ADE should be treated within 30 days after ADE diagnosis. However, only 43% of ADE patients in Italy received treatment [20]. A recent study also found that the presence of AIDS-defining disease at HIV diagnosis was one of the factors related to high mortality [21].

So far, a number of studies have assessed in the relationship between ART and ADE, focusing on the relationships between ART [22‐24], quality of life [25], cytomegalovirus infection [26], and the effect of the timing of ART on survival [27]. However, most studies in the field have explored the impact of ART on ADE. A retrospective study showed that 57% of patients with advanced HIV disease had opportunistic infections, and the majority were diagnosed when they had developed ADE [28]. Late diagnosis and delayed treatment of HIV infection contribute to the development of opportunistic infections, such as pneumocystis pneumonia, Talaromyces marneffei infection, etc. In Guangxi, a recent retrospective study revealed that 70.2% of newly diagnosed HIV cases from 2012 to 2016 had a late presentation, and 45.1% had advanced HIV disease [29]. Most patients with late presentation, advanced HIV disease, or ADE have relatively low CD4⁺ cell count or develop AIDS symptoms.

Comprehensively, we speculate that the high mortality rate of HIV/AIDS patients in Guangxi, China may be due to the high proportion of ADE in the ART population. Therefore, in this study, we aimed to evaluate the effect of ADE on the mortality rate of HIV/AIDS patients who were on ART, providing a basic understanding of the relationship between ART and ADE from a perspective different from those of previous studies.

In this study, the prevalence of ADE in HIV/AIDS patients at ART initiation was 16.86%, which was roughly consistent with the data of previous studies in other countries or regions; for example, a report from France showed that 16% of patients with newly diagnosed HIV were ADE [31]. Our study also showed that even when individuals were on ART, the mortality of patients with ADE was significantly higher than that of those without ADE, which was consistent with some previous studies: a large multi-centre cohort study showed that non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE [32], and this multiple is a little higher than that of this study; a research showed that HIV controllers experience non-ADE, albeit at lower rates than patients who do not spontaneously control the virus [33]. While in this study, disseminated mycosis, recurrent severe bacterial pneumonia, herpes zoster, extra-pulmonary tuberculosis, and candidiasis of the oesophagus were the top causes of death by ADE.

Previous studies have shown that patients with a late diagnosis of HIV infection had a higher risk of mortality than those with an early HIV diagnosis [34], and universal ART among late presentation patients reduced mortality by just 10% [35]. Late presentation is defined well as, a patient diagnosed with the first CD4⁺ cell count < 350/μL, or a patient with AIDS-defining illness regardless of CD4⁺ cell count during diagnosis [8, 36, 37]. In this study, the median CD4⁺ cell count in the ADE group was 29.00 cells/μL (IQR: 12.00–116.50), and 96.05% of patients with ADE had late presentation, demonstrating that most of patients with ADE were in an advanced stage of HIV/AIDS. And studies showed that low CD4⁺ cell count (baseline CD4 count ≤ 50 cells/μL) was related to treatment failure [38, 39], a lower CD4⁺ cell count was always associated with a higher risk of a new AIDS events or death [40].

A delay in the diagnosis of patients with ADE postpones HIV care and the administration of ART, which further reduces the possibility of achieving viral suppression. In addition, even on ART, most of the patients with ADE at advanced HIV/AIDS stages may also have failed immunological recovery, thus increasing the risk of morbidity and mortality.

A number of studies have shown that early diagnosis and treatment at a higher CD4⁺ cell count without ADE could benefit patients in terms of preserving immune function and reducing the risk of mortality [20, 41, 42]. However, many HIV-infected people were unaware of their infection status. In the United States, 15% of HIV/AIDS patients were unaware of their HIV infection status [43], and only 40% of the adult population had undergone HIV testing [44]. HIV screening, especially in HIV high risk populations including men who have sex with men (MSM), female sexual workers (FSW), and bisexuals may be valuable for earlier diagnosis [45]. Therefore, to reduce HIV transmission and improve the effect of ART, HIV infection needs to be diagnosed as early as possible. Our study found that patients aged from 40 to 65 years, following sexual transmission, with previous non-use of cotrimoxazole, and a low baseline CD4⁺ cell count tended to have a higher risk of death. Therefore, increasing active HIV testing coverage and frequency should be implemented in high-risk populations. Once HIV infection is confirmed, ART should be provided immediately, which is expected to reduce the incidence of ADE and thus reduce mortality.

The study had a large sample size and long-term investigation, so that the study has a certain representative of ART outcomes in Guangxi and Southwestern China. In addition, this data collection began in 2004, and the cohort was well followed-up through the whole NFATP period in China, which can fully evaluate the impact of ADE on mortality for patients on ART. Several limitations of our study should also be mentioned. Firstly, this study is a retrospective cohort study, and the subjects were from a city in Guangxi, which may lead to a loss of access bias and selection bias. However, the large sample size (HIV/AIDS patients may come from other places in Guangxi or the country) may reduce these biases to some extent. Secondly, many patients in this study had no viral load data at the initiation of ART, and we could not assess the impact of viral load on treatment outcomes. Thirdly, our analysis did not include surveys of patient compliance with medication.

In conclusion, in the era of ART, it is still common for patients with initial ART to have ADE. Even on ART, these patients have a higher risk of death than those without ADE. Currently there is no cure for HIV/AIDS, and we should further promote voluntary testing and improve people’s awareness of early diagnosis to reduce late presentations, especially those with ADE.