AIDS incidence trends at presentation and during follow-up among HIV-at-risk populations: a 15-year nationwide cohort study in Taiwan

HIV-related mortality and morbidity rates have substantially decreased because of global efforts to improve access to antiretroviral therapy [1, 2]; however, high acquired immunodeficiency syndrome (AIDS) incidence, especially during the early phase of the HIV care, remains challenging. Although global campaigns encourage earlier HIV testing, substantial numbers of HIV-infected individuals do not enter healthcare systems until later stages, even when AIDS-defining events occur [3–5].

AIDS incidence is associated with higher HIV-related morbidity and mortality rates [5–8], higher HIV transmission rates to sexual partners [9, 10], increase health expenses [7, 11], and impaired immunological response to highly active antiretroviral therapy (HAART) [12]. Therefore, ongoing surveillance to monitor AIDS incidence trends at presentation and during follow-up and the characterization of the associated risk factors is essential. AIDS incidence at presentation indicates late presentation of HIV [3–5], whereas AIDS incidence during follow-up is related to access to HAART, thresholds of initiation of HAART, regimens of HAART, and adherence to HIV care. Therefore, a better understanding of AIDS incidence trends at presentation and during follow-up would help improve patient care and optimize public health strategies aimed at further decreasing HIV-related morbidity and mortality.

Since the first HIV case in Taiwan was reported in 1984, a total of 33,423 cases were reported until the end of 2016. Of these, 15,418 patients (46.1%) developed full-blown AIDS [13]. Taiwan has implemented several important interventions for various HIV-at-risk populations to combat the HIV epidemic [13]. These include free HAART and anonymous voluntary counseling and testing (VCT) for HIV among at-risk populations since 1997, harm-reduction programs among intravenous drug users (PWIDs) since 2005, and an HIV case management program since 2007. However, little is known regarding AIDS incidence trends at presentation and during follow-up among the various HIV-at-risk populations in Taiwan [14–16].

In this nationwide cohort study, we employed data from the Taiwan Centers for Disease Control (TCDC)-operated Notifiable Diseases Surveillance System (NDSS) and Taiwan National Health Insurance Research Database (NHIRD) (reference period: 1998–2012) to analyze AIDS incidence trends at presentation (thus reflecting issues of late presentation of HIV) and during follow-up (thus reflecting issues of access to HAART, thresholds of initiation of HAART, regimens of HAART, and adherence to HIV care) among various HIV-at-risk populations over five cohort periods.

Although HAART has significantly altered the natural history of HIV infection in the cART era [1, 2], 27.4% patients still developed AIDS during the cohort periods, with a majority (73.6%) developing at HIV presentation. These findings indicate that in Taiwan, AIDS continues to pose a major threat to HIV patients, especially soon after diagnosis. Our study also revealed disparities in AIDS incidence trends in various HIV-at-risk populations. The disparities can be primarily explained by the different HIV-exposure-related sociodemographic factors and the influence of the adopted HIV prevention strategies; this knowledge will help prioritize resource reallocation for HIV diagnosis and the HIV-care continuum according to various targeted populations (Table 1, Fig. 3). The HIV epidemic in Taiwan is similar to that in other countries of the Asia-Pacific and North American regions [3, 4, 20, 21], where gbMSM are the predominant HIV transmission groups, and AIDS at presentation remains common. Therefore, this Taiwanese study’s findings should be of interest globally.

The late presentation (LP) of HIV is detrimental at both the individual [5–8] and general population levels [9, 10]. Different definitions have been adopted to indicate the LP of HIV, such as “a CD4 cell count of < 350 cells/μL or AIDS-defining event at the first follow-up [3]” or “a CD4 cell count of < 200 cells/μL or an AIDS-defining event within 3 months of HIV diagnosis [4]”. The lack of a standardized definition of LP makes it difficult to draw precise comparisons of the prevalence data reported from different studies. After using “a CD4 cell count of <200 cells/μL or AIDS incidence in ≤3 months of HIV diagnosis” as a definition of LP (i.e., as the definition of AIDS incidence at presentation in the present study), the present study found a lower proportion of HIV patients with LP (20.2%) than that reported from other Asia-Pacific countries in the TREAT Asia HIV Observational Database (TAHOD) (72%) [4], China (27.3%) [3], and European countries [COHERE (33.2%)] [5]. The lower prevalence of LP in the present study compared with that in TAHOD may be attributable to a nationwide program of free anonymous VCT adopted in Taiwan since 1997 and enrollment of low-income countries in TAHOD, which is limited to health care access and health literacy. Even though the overall LP prevalence in Taiwan seems to be lower than that in other countries, HIV prevention and care in various HIV transmission groups remains a problem in Taiwan.

Similar to worldwide trends [3, 4, 20, 21], our study revealed that gbMSM has been emerging as the predominant HIV-transmission route, accounting for 78.2% new-HIV-infection cases in period 5. Furthermore, the trend of increasing LP among gbMSM in Taiwan showed no obvious signs of decline/reversal (Fig. 3). Therefore, reduction in the HIV epidemic and LP in gbMSM should be prioritized in Taiwan’s HIV prevention strategies. TCDC has adopted a wide range of HIV prevention programs among HIV-at-risk populations, especially the gbMSM population. A nationwide program of free anonymous VCT through a clinical service delivery model was initiated at several hospitals, community health centers, and nongovernmental organizations in 1997. The number of visitors who received VCT has increased steadily, and the percentage of new-HIV-infection cases through VCT increased from 9.0% in 2004 to 30.0% in 2010, after which it has plateaued [22]. In addition, TCDC also established gbMSM community health centers, employed services of online opinion leaders, and promoted VCT outreach services at saunas and pubs. Even though gbMSM have access to a broad range of free HIV services and organized community structures in Taiwan, the rising trend of LP in the gbMSM population indicates that HIV-at-risk gbMSM have been unaware/unwilling to receive HIV testing until late stages of HIV. Therefore, an integrated approach should be urgently employed to overcome HIV testing barriers in high-prevalence areas. These barriers include redressal of low risk perception [23], stigma and fear of discrimination [24], concerns about confidentiality [25], and possible structural barriers that contribute to poor HIV testing access in areas other than Taipei and among low-income population groups (Table 2). Taipei is the capital of Taiwan and has ample resources for HIV prevention and treatment [26].

Our study revealed that heterosexual contact is the second most common HIV-transmission route in Taiwan, accounting for 15.5% new-HIV-infection cases in period 5. Although the contribution of heterosexuals for HIV transmission is lower than that of gbMSMs, the findings reveal significantly higher LP prevalence among heterosexuals than in gbMSMs [adjusted OR (95% CI), 1.54 (1.40–1.70)] and an upward trend of LP among heterosexuals (P for trend < 0.001); this warrants a critical rethink of the HIV prevention strategies for both heterosexuals and gbMSMs in Taiwan. The finding of higher LP prevalence among heterosexuals in the present study is consistent with findings from other studies [5, 27], and may be attributable to the lower HIV testing rates among heterosexuals [28]. One explanation for this is the particular history of the HIV epidemic in Taiwan. Because HIV transmission in Taiwan has occurred predominantly within gbMSMs since 2008, HIV prevention and HIV-education strategies have long been shaped around gbMSMs. HIV prevention campaigns aimed at heterosexuals have either been lacking or were subsumed within the broader prevention campaigns focused primarily on other sexually transmitted infections. Other explanations include a lower risk perception and concerns regarding confidentiality [4, 29]. In addition, the rapid network and community-driven response to HIV prevention strategies among gbMSMs is not readily transferable to heterosexuals because of the wide diversity of sociodemographic variables (i.e., polyamory and commercial sex workers) of the HIV epidemic among the heterosexuals [20, 30]. Therefore, implementation of evidence-based population-specific prevention strategies is critical for achieving early HIV diagnosis in heterosexuals. In 2016, TCDC launched a program to distribute HIV home-based and self-testing kits to nongovernmental organizations, health stations, and to heterosexual and gbMSM communities. The high uptake and acceptance of these strategies among heterosexuals holds promise for increasing the uptake of HIV testing services among heterosexuals [31].

Taiwan experienced a major HIV epidemic among PWIDs during 2003–2008, and then a substantial reduction in HIV infection in PWIDs because TCDC launched harm-reduction programs in August 2005 [14]. Consequently, only 3.2% (77/2406) of new-HIV-infection cases were attributed to PWIDs in Taiwan in 2016 [14, 32]. In contrast to some Asian and European studies [4, 5], PWIDs were not identified as a major LP risk group in our study (Table 2). A possible cause of the discrepancy may be the predominance of the HIV CRF07_BC strain among PWIDs in Taiwan, which is characterized by slow immunological progression [33, 34]; another reason could be the legal implementation of an active surveillance for prison inmates since 1991 with resultant early diagnoses of HIV in PWIDs [15, 35].

Consistent with relevant studies, the present study also identified old age as an LP risk factor [4, 36] (Table 2). These results are likely attributable to changes in risk-related behavior (i.e., decreased condom use) and lower HIV-risk perception among older people, which resulted in a higher proportion of diagnosis during hospitalization [37]. Moreover, primary physicians may not consider the possibility of HIV infection among the older population because of masking by multiple comorbidities [38], variations in HIV symptom manifestation [39], and underestimation of HIV-risk transmission behaviors [40]. Effective HIV prevention education for early HIV diagnosis in older populations rests in part on countering the misconceptions about HIV transmission risk and on enhancing the awareness of healthcare providers.

Mathematical models suggest that universal HIV testing followed by immediate treatment can decrease HIV incidence at the population level [41]. Although active surveillance programs among specific populations in Taiwan have been consecutively adopted since 1988, anonymous VCT has been a strategic priority for HIV testing among the sexual contact population since 1997. However, testing according to the perceived HIV transmission risk and willingness to undergo HIV testing among the sexual contact population likely contributes to the increasing LP prevalence in HIV-at-risk populations (Fig. 3a). HIV-screening implementation as part of routine care or implementation of opt-out testing in both healthcare and nonhealthcare settings may help increase HIV testing rates, destigmatize it, and improve healthcare access for new-HIV-infection cases [42, 43]. However, routine HIV-screening approaches in HIV-at-risk populations without permission, except in specific situations, are prohibited by law in Taiwan. Therefore, an integrated approach to scale-up current VCT strategies tailored to HIV-at-risk populations is urgently required to increase HIV testing coverage among the sexual contact and older populations and among those who reside outside of the Taipei area (Table 2). This integrated approach should include education to increase HIV-risk perception, eliminate stigma and discrimination, and adopt a flexible approach to HIV testing, including peer-based [44] or home-based HIV testing services [31], and indicator-guided HIV testing by healthcare providers [45, 46].

Another valuable finding of the present study is the disparity in AIDS incidence trends during the follow-up period among the various HIV-at-risk populations in the five cohort periods (Fig. 3). The higher AIDS prevalence during follow-up in the sexual contact population than among PWIDs in Taiwan may be attributable to the higher LP prevalence in the sexual contact population (Table 2) which may result from low risk perception, stigma and discrimination, concerns about confidentiality, and uneven distribution of resource for HIV prevention as mentioned above, and be intrinsically linked to HIV-1 genetic diversity in Taiwan. Serotype B is the predominant strain in the sexual contact groups, whereas CRF_07 BC is the major strain in PWIDs [33], which is characterized by slower immunological progression compared with those in serotype B [33, 34]. Several crucial strategies have been implemented to increase the HIV-care continuum in Taiwan, including access to free HAART since 1997, initiation of HAART at higher CD4-count thresholds (CD4 < 200 cells/mm³ in 2006, < 350 cells/mm³ in 2010, < 500 cells/mm³ in 2013, and in all patients, regardless of CD4 count, in 2016), an HIV case management program since 2007, and the employment of a single tablet regimen (STR) in HAART since 2016. We believe that AIDS prevalence during the follow-up period can be decreased substantially with HAART initiation for all patients and with STR implementation.

However, unlike in the sexual contact population, the rapid increase in AIDS incidence trends during the follow-up period among PWIDs (P for trend < 0.001) should be cautiously monitored (Fig. 3b). This increasing trend among PWIDs may be attributable to suboptimal adherence to HAART among prison inmates [47], a higher rate of HIV-care discontinuity [48–50], and deferral of HAART by physicians [51]. Considering the sharp decrease in adherence to ART after release of incarcerated PWIDs [52], treatment of addiction and HIV infection at imprisonment and after release is critical for improving the continuity of post-release care [53]. We also identified chronic kidney disease as a risk factor for AIDS during the follow-up (Table 3). These results are likely attributable to the defective immune system through both immune activation and immune suppression [54], which might result in the reactivation of Mycobacterium tuberculosis or other AIDS-defining opportunistic infections [55–57]. In summary, given the diversity of care needs of the various HIV-at-risk populations, identification of the modifiable factors associated with AIDS incidence after linking to the HIV care is vital to better customize the HIV-care strategies for HIV-at-risk populations in Taiwan.

The major strength of the present study was its nationwide scope and population-based design combined with the long and nearly complete follow-up. The population-based design minimized selection and referral biases. The findings are critical for public health policies with regard to AIDS control, and may be generalized to Asia-Pacific and North American countries, which face similar HIV epidemics. However, the study had some limitations. First, the data used was limited to data reported to TCDC and NHIRD by primary physicians. Second, whether unmasking of the type of opportunistic illnesses after HAART contributed to AIDS incidence after HAART was not ascertained.

The results revealed that 27.4% patients developed AIDS during the cohort periods, with a majority developing at presentation, which reinforces the importance of identifying HIV infections as early as possible. The disparities in AIDS incidence trends at presentation and during follow-up in various HIV-at-risk populations can be explained by different sociodemographic variables associated with HIV exposure and the influence of the adopted HIV prevention strategies. These results suggest an urgent need for more active offering of HIV testing among sexual contact groups, with different policies tailored for gbMSMs (increased risk perception, removal of stigma and discrimination, protection of confidentiality, and elimination of structural barrier to HIV testing) and heterosexuals (implement of HIV home-based and self-testing kits). After linking to the HIV care, differentiated care for specific populations is required to better customize HIV-care strategies, especially for PWIDs (increased adherence to HIV care and HAART, especially after release, and increase willing of prescription of HAART by physicians).