According to the Joint United Nations Programme on HIV and AIDS (UNAIDS), despite the tremendous progress on the prevention of HIV, there are still 36.9 million people living with HIV (PLHIV). A significant portion of PLHIV are not aware of their infection status, even when it develops into advanced HIV disease (AHD), due to prolonged asymptomatic phases after HIV infection.
Reduction in undiagnosed hiv infection in the european union/european economic area, 2012 to 2016.
In some countries, PLHIV are discriminated against by their communities, generating stigma that has a negative impact on seeking medical advice, which results in a higher risk of developing AHD.
Socio-economic Inequalities and HIV Writing Group for COHERE in EuroCoord Delayed hiv diagnosis and initiation of antiretroviral therapy: inequalities by educational level, cohere in eurocoord.
HIV testing history and access to treatment among migrants living with hiv in europe.
Furthermore, the effectiveness of antiretroviral therapy (ART) declines significantly after the patients develop AHD, causing not only greater health burden for PLHIV, but also greater financial burden for the patients and government.
Gender difference in advanced hiv disease and late presentation according to european consensus definitions.
This may result in difficulty reaching the “90–90–90” target to end AIDS in 2030; therefore, it is vital to identify groups at high risk for AHD.
In most countries, the HIV epidemic is sustained through the following transmission routes: men who have sex with men (MSM), heterosexual contact (HC), and injection drug user (IDU), with about one in three PLHIV developing AHD.,
Late presenters working group in COHERE in EuroCoord Late presentation for hiv care across europe: update from the collaboration of observational hiv epidemiological research europe (COHERE) study, 2010 to 2013.
Despite enhanced prevention efforts, many PLHIV in the modern era still have AHD at the time of diagnosis. One study suggested that CD4 cell counts among PLHIV at their first presentation to medical care did not increase significantly from 1992 to 2011 in developed countries,
IeDEA and COHERE Cohort Collaborations Global trends in CD4 cell count at the start of antiretroviral therapy: collaborative study of treatment programs.
Whether different transmission routes predispose to different risks for AHD is largely unknown; although several studies suggest that the risk of AHD differs among PLHIV depending on their HIV transmission routes, findings have been inconsistent.
Global epidemiology of hiv among female sex workers: influence of structural determinants.
Some studies suggested that criminalization of sex work, compulsory drug treatment, and homosexuality could lower the odds of access to HIV care among key populations.
Sexual stigma, criminalization, investment, and access to hiv services among men who have sex with men worldwide.
It is essential to understand the relationship between AHD and HIV transmission routes to prioritize prevention strategies and achieve early diagnosis, early linkage to care and early initiation of ART for key populations. Additionally, no systematic reviews have summarized the evidence regarding HIV transmission routes and AHD; therefore, this systematic review and network meta-analysis was conducted to summarize the pooled evidence.
Data extraction
An extraction information table was projected, and three researchers (Chen, Zeng, and Lyu) extracted data using the prepared table independently. Before the statistical analyses, four researchers (Jiang, Chen, Zeng, and Lyu) conferred about the details about the extraction and scrutinized the extraction table.
The following information was extracted: publication year, study period, region, continent, definition of AHD, median/mean age with an interquartile range (IQR)/standard error, study method, time lag (the time between the initial diagnosis of HIV and a CD4 count below 200 cells/μL or the diagnosis of AIDS), number of PLHIV/AHD for each transmission routes, and the number of male/female.
Methodological quality assessment
Two researchers (Chen and Zeng) evaluated the methodological quality of included cohort studies using the Newcastle-Ottawa scale (NOS) independently. The included cross-sectional and surveillance studies were assessed by the adaptive NOS updated by Herzog and colleagues.
was conducted to assess the risk of AHD associated with the MSM, IDU, HC transmission routes using crude data to estimate the odds ratio (OR). A random/fixed consistency model was selected according to the deviance information criterion (DIC). Additionally, a node-splitting analysis
Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis.
was conducted to evaluate potential inconsistencies, along with subgroup analysis to explore potential heterogeneity. A meta-analysis of single proportion was conducted to assess the prevalence of AHD internationally, and a trend chart was created to evaluate the tendency of the prevalence of AHD, based on locally weighted scatterplot smoothing (LOESS) regression.
Locally weighted regression: an approach to regression analysis by local fitting.
A map was plotted to illustrate the relationship between the prevalence of AHD and the level of economic development. Furthermore, the ecological linear regressions were conducted to explore the associations between the prevalence of AHD among PLHIV through different transmission routes and the potential factors including the level of economic development (gross domestic product per capita [PPP] adjusted by international dollars), time lag, regional policies regarding sex work, and compulsory drug treatment policies. Sensitivity analyses were conducted to test the robustness of the network meta-analysis and ecological linear regression. Sample size was weighted in all the above analyses.
The data analyses were conducted using R software (x64 3.5.1). The packages ‘dplyr’ and ‘reshape’ were used for data wrangling. Network meta-analysis, meta-analysis of single proportion, Egger/Begg-Mazumdar/Thompson-Sharp test and conventional/contour-enhanced funnel plots for publication bias,
Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry.
and the ecological linear regression were conducted based on ‘gemtc’, ‘meta’, ‘netmeta’ and ‘ecoreg’ respectively. Additionally, data visualization was based on software R (x64 3.5.1) and software Graphpad Prism v.8.0.2.263. The R packages ‘ggplot2’, ‘RColorBrewer’, ‘maps’ and ‘ggpubr’ contributed to trend chart and maps. The surface under the cumulative ranking curve (SUCRA) was generated using software Graphpad Prism v.8.0.2.263.
Result
After the removal of duplicates, we identified 3045 unique articles in the first stage. A preliminary screening of abstracts and titles was conducted, and 301 articles were screened for eligibility. Subsequently, 212 articles were excluded (71 articles did not study on AHD, 72 contained different definitions, three contained data errors, two were reviews, two were conference abstracts, one was a case series, 61 did not present the relationship between the selected transmission routes and AHD). We also retrieved an additional 12 articles from reference lists, and 101 articles were included in the final analysis (Fig. 1).
Fig. 1Flow diagram of search strategy and study selection.
The final 105 studies from 101 articles (15 cross-sectional studies from 15 articles and 25 cohort studies from 25 articles, respectively, 65 surveillance studies from 61 articles) included 1,297,872 PLHIV with 478,830 patients who developed AHD, and estimated the risk between AHD and the following transmission routes: MSM, IDU, and HC. The detailed characteristics of the included articles provided in the appendix A3 (pp 4–8).
A consistent random-effects network model for AHD and the three specific transmission routes was constructed for analysis. Fig. 2 illustrates the results of the network analysis with direct, indirect and network comparison estimates using raw data. Fig. 2 reveals that the PLHIV associated with HC had the highest risk of AHD, followed by those associated with IDU, with an OR of 0•56 (95% credible interval [CrI] 0•47–0•68), and MSM (OR=0•54, 95% CrI 0•46–0•63). On the basis of the node-splitting analysis, the P value of consistency among the three transmission routes was greater than 0•05, which suggested that the model was consistent and suitable to provide useful estimates. Also, we conducted a sensitivity analysis including high-quality studies assessed by NOS, which showed the consistent result that PLHIV infected via HC had the highest risk of AHD compared with those infected via IDU and MSM (see appendix A5 pp19).
Fig. 2Direct, indirect and network odds ratio for advanced HIV disease among people living with HIV through heterosexual contact (HC), injection drug users (IDU), and men who have sex with men (MSM)
A vs B: the latter (B) is the reference. P-value >0.05 indicates that accepting the null hypothesis of consistency between direct and indirect results.
Two conventional and contour-enhanced funnel plots showed that there was little risk of publication bias in the meta-analysis. Additionally, the results of Egger/Begg-Mazumdar/Thompson-Sharp tests were in accordance with the funnel plots, which suggested accepting the null-hypothesis of no publication bias due to non-statistical significance consistently (p>0•10) (see appendix A6 pp 20–24).
Since there were a relatively large number of studies from five continents, the heterogeneity of the estimates was predictably high; and the details are illustrated in the appendix A (pp 18). Subgroup analyses of the following potential factors were conducted: time lag, the level of economic development of regions, continent, prevalence of AHD, and study method. Generally, the ranking of the risk of AHD associated with the three transmission routes remained stable and HC had the highest risk of AHD compared with IDU and MSM (see appendix A8 pp 25–39).
Fig. 3 shows the temporal changes in the prevalence of AHD among the three specific transmission routes from 1992 to 2016. Compared to the prevalence of AHD associated with MSM and IDU, that associated with HC remained the highest during the period. Generally, the prevalence of AHD associated with HC did not change materially, while that associated with IDU and MSM witnessed a downward tendency, respectively. Recently, the prevalence of AHD associated with HC showed a slightly upward tendency, while that associated with MSM and IDU experienced a plateau and a decrease, respectively.
Fig. 3Temporal tendencies for the prevalence of advanced HIV disease among people living with HIV through heterosexual contact, injection drug use, and men who have sex with men.
Results from locally weighted scatterplot smoothing (LOESS) regression are based on all the included studies. 95% confidence intervals are illustrated as grey shaded areas. Years are estimated by the median year of study period.
Fig. 4 consists of two different maps; one is an epidemic map of the prevalence of AHD, and the other displays the level of economic development of regions in the included studies. The pooled prevalence of AHD among PLHIV in all of the included studies was 34•87% (95% confidence interval [CI] 33•30%−36•45%). There was a much higher prevalence of AHD (37•45%, 95% CI 35•35%−39•58%) in regions with lower PPP than in the regions with higher PPP (32•82%, 95% CI 30•38%−35•30%). PLHIV associated with other transmission routes, including but not limited to transfusion and unknown, were included to show the pooled prevalence of AHD in this figure.
Fig. 4Two world maps regarding gross domestic product per capita (PPP) 2009 adjusted by international $ (a) and the prevalence of advanced HIV disease (b)
PPP 2009 was adopted because the median year of study period for all the included studies is 2009. Due to data unavailable of PPP 2009 in China (Taiwan) from the World Bank, the area of China (Taiwan) filled with dark grey in the map (a).
Table 1 and Table 2 demonstrate the relationship between legislation and prevalence of AHD among PLHIV through different transmission routes. According to Table 1, there was a higher risk of AHD (crude OR [cOR]=1•30, 95% CI 1•27–1•33) in regions where sex work was criminalized than in those regions where sex work was legalized. Considering the potential bias due to the level of economic development and time lag, they were evaluated separately as well, revealing a lower risk of AHD in regions with higher PPP (cOR=0•91, 95% CI 0•89–0•93) and a higher risk of AHD in studies with time lag ≥ three months (cOR=1•90, 95% CI 1•85–1•96). After adjusting for the level of economic development and time lag, consistent results showed that there was a higher risk of AHD in criminalized sex work regions (adjusted OR [aOR]=1•21, 95% CI 1•18–1•25) than in legalized sex work regions. Similarly, after taking the level of economic development and time lag into consideration, those regions that criminalized compulsory commitment to care of substance misusers (CCC) had a higher risk of AHD (aOR=4•38, 95%CI 4•10–4•67) than those that did not criminalize CCC (Table 2). Results of sensitivity analyses indicated that the relation between criminal justice to sex work, CCC and AHD did not significantly change when the PPP in different year was adjusted in the multivariate model; and when studies with small sample size were excluded (see appendix A9-10 pp 40–43). The relationship between the criminalization of homosexuality and the prevalence of AHD among MSM was not analysed because homosexuality was criminalized in only two countries (Singapore and Malaysia) included in the study.
Table 1Relation between different sex work policies and prevalence of advanced HIV disease among people living with HIV through heterosexual contact.
Table 2Relationship between criminal justice legislation to the compulsory commitment to care of substance misusers and the prevalence of advanced HIV disease among people living with HIV through injection drug use.
Discussion
To our knowledge, this network meta-analysis is the first and most comprehensive synthesis of data examining the risk of AHD associated with different transmission routes. This is also the first study to explore the association between criminalization and the risk of AHD at the country/region level. Our findings indicated that PLHIV who acquired HIV through heterosexual contact had the highest risk of AHD, followed by those through IDU, and MSM. The prevalence of AHD decreased among the MSM and IDU transmission routes generally, but the trend among the HC transmission route seemed to slightly increase recently. Regions with criminalized sex work and CCC polices presented a higher risk of AHD than those regions without. These results reinforced the challenges in achieving the ambitious “90–90–90” target in 2020 and the end of AIDS in 2030: The prevalence of AHD remained high, especially among PLHIV who acquired HIV through heterosexual contact. More efforts should be made to facilitate early diagnosis among key populations.
There are several implications and considerations related to these findings. Our results revealed that the prevalence of AHD was high (34•87%) among PLHIV, which was consistent with that (one-third) estimated by UNAIDS. More than two out of every three PLHIV did not know their HIV status in 2016, resulting in late HIV diagnosis. Male gender, older age, low risk perception, lack of awareness about HIV and decreased HIV testing coverage were risk factors for a late HIV diagnosis.
Expanded hiv testing coverage is associated with decreases in late hiv diagnoses.
A previous study showed that even after adjusting for gender and age, late presentation for care was more common among individuals with low socioeconomic status than among those with high socioeconomic status,
Neighbourhood socio-economic position, late presentation and outcomes in people living with hiv in switzerland.
which aligns the fact that a higher prevalence of AHD was observed in regions with a lower level of economic development than in regions with a higher level of economic development in our study.
The varied risks of AHD among different transmission routes might depend on the current or past testing rate and the epidemic patterns.
Vital signs: human immunodeficiency virus testing and diagnosis delays – United States.
A previous study showed that MSM population had the highest possibility of undergoing a past HIV test in the last year, followed by individuals engaging in IDU and HC.
Late presentation of hiv infection among adults in new zealand: 2005-2010.
Another recent study indicated that gay/bisexual men were more likely to attend health services and underwent testing than women and heterosexual men because of the greater perceived risk, which could explain the lower risk of AHD among MSM.
HIV testing history and access to treatment among migrants living with hiv in europe.
Apart from variations in access to health services, the perception of risk of HIV among different groups or the establishment of programmes for HIV diagnosis for specific risk groups could result in different risks of AHD.
Clinical outcomes of patients infected with hiv through use of injected drugs compared to patients infected through sexual transmission: late presentation, delayed anti-retroviral treatment and higher mortality.
Moreover, PLHIV with IDU were more likely to have less access to healthcare and lower socioeconomic status, which was associated with late presentation.
Socio-economic Inequalities and HIV Writing Group for COHERE in EuroCoord Delayed hiv diagnosis and initiation of antiretroviral therapy: inequalities by educational level, cohere in eurocoord.
The decreasing trend in prevalence of AHD might be attributed to the global response, including the substantial rise in HIV testing in many countries, and early HIV treatment as prevention to reduce the HIV transmission.
The global response and unmet actions for hiv and sex workers.
However, this might not have been the case for sex workers and drug users. Limited ART coverage and retention might be due to the criminalization of sex workers, and called for a continuing investment in community and structural interventions so that this population could profit from the preventions and treatments that other key populations received.
The global response and unmet actions for hiv and sex workers.
The results from a national observational cohort in the Netherlands revealed that although the prevalence of late presentation decreased over time from 62% in 1996 to 42% in 2013, it did not decline significantly among individuals associated with heterosexual transmission;
Factors associated with presenting late or with advanced hiv disease in the netherlands, 1996–2014: results from a national observational cohort.
these results were in line with the trend of prevalence of AHD among PLHIV associated with HC in our study. The trend among PLHIV associated with IDU in our study was consistent with the results of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study from 2010 to 2013.
Late presenters working group in COHERE in EuroCoord Late presentation for hiv care across europe: update from the collaboration of observational hiv epidemiological research europe (COHERE) study, 2010 to 2013.
Stigma, discrimination, and criminalization remain obstacles for early diagnosis in key populations. A previous review showed that the criminalization of sex work increased the risk of sexual/physical violence, HIV/sexually transmitted infections (STIs), and unprotected sex among sex workers.
Associations between sex work laws and sex workers’ health: a systematic review and meta-analysis of quantitative and qualitative studies.
Moreover, an ecological linear regression analysis suggested that the legalization of some aspects of sex work might help reduce the HIV prevalence in sex workers.
National sex work policy and hiv prevalence among sex workers: an ecological regression analysis of 27 european countries.
The criminalization of sex work can force sex workers to work in isolation, disrupt peer support networks, increase their marginalization, and reduce their access to HIV services due to a fear of prosecution and moral judgement,
Associations between sex work laws and sex workers’ health: a systematic review and meta-analysis of quantitative and qualitative studies.
ultimately increasing the risk of AHD. Therefore, more efforts should be made to improve the health of sex workers and access to HIV services. Previous studies revealed that the compulsory treatment for drug dependence was not related to improved outcomes as a whole, with some studies revealing potential harms.
Mandatory addiction treatment for people who use drugs: global health and human rights analysis.
In the context of criminal justice to CCC, drug users might fail to seek care due to the threat of detainment within compulsory drug detention centres and the fear of being targeted by police,
The effectiveness of compulsory drug treatment: a systematic review.
potentially contributing to a late HIV diagnosis. Another systematic review showed that criminalization of drug use including forced detention as addiction treatment, had a negative effect on HIV prevention and treatment such as HIV testing and counselling programs in 85 of the 106 eligible studies, which could result in AHD.
HIV and the criminalisation of drug use among people who inject drugs: a systematic review.
Accordingly, UNAIDS has been advocating for the global adoption of public health alternatives to the criminalization and imprisonment to IDU.
The sensitivity analysis and subgroup analyses showed the stable rankings among the three transmission routes, which suggested the robustness of the network results. No publication bias was observed, which revealed the validity of our results. The sensitivity analyses also highlighted the stability of ecological linear regression when the analyses were conducted using PPP of different years and were restricted to studies with larger sample size.
There were several limitations in the current study. First, we used the crude number of individuals with AHD and the number of PLHIV from observational studies instead of randomized controlled trials, which were usually used for network meta-analysis. Confounding factors could impact the results of the network meta-analysis, as the adjusted risk estimates were not used for the pooled data.
Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis.
Second, no study conducted in Africa was included in the current study, which should be considered when interpreting our results. Third, the median year of study period
Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan africa, 2002-2013: a meta-analysis.
was used to present the temporal trend of AHD prevalence, which could result in some biases. Fourth, ecological analyses of country/region-level data to explore the relationships between criminalization and AHD among key populations could result in ecological fallacies.
National sex work policy and hiv prevalence among sex workers: an ecological regression analysis of 27 european countries.
In addition, sex workers were not equivalent to PLHIV associated with HC, although we examined the relationships between the criminalization of sex work and AHD among PLHIV associated with HC. The exclusion of studies without known legislation policies and specified time lag in the ecological linear regression and the change in sex work and CCC criminal justice over time could lead to biases and restrict the extrapolation of our results. Nevertheless, the effects of criminalizing sex work and CCC criminal justice on the prevalence of AHD remain an important topic of future research.
In conclusion, our findings indicated that the prevalence of AHD among PLHIV was high, and PLHIV associated with HC had the highest risk of AHD, followed by individuals who engaged in IDU, and MSM. The temporal trend of the prevalence of AHD justified the need to expand prevention campaigns and to maintain efforts to increase HIV testing in the heterosexual population. The positive association between criminalization and AHD suggest that more efforts should be made to improve access to HIV services, and attention should be focused on reducing structural inequalities, stigma, discrimination, and the exclusion on sex workers and drug users.
