Infection with the Human Immunodeficiency Virus (HIV) remains one of the leading public health challenges in all of the countries in the world. Also, acquired immunodeficiency syndrome (AIDS) constitutes a great problem as the last and most severe stage of HIV infection, which develops within 7 to 10 years, if the infection is left untreated.
The estimation is that, in 2018, around 37.9 million people were living with HIV/AIDS worldwide, while 770,000 died as the result of AIDS-related diseases and conditions. In the previous decades, great efforts have been made to end the HIV/AIDS epidemic, which officially started a little over 38 years ago. According to the global 90-90-90 strategy of the United Nations Programme on HIV/AIDS – UNAIDS, it was planned that, by the year 2020, 90% of people living with HIV would be aware of their HIV positive status, that 90% of the people aware of their HIV positive status would be on antiretroviral (ARV) therapy, and that 90% of those on ARV therapy would have stable viral suppression . Globally, in the previous 8 years, there has been a 16% decrease in the number of newly infected HIV patients. Nevertheless, the world is still far from achieving the goal set for 2020, i.e. reducing the number of people newly infected with HIV below 500,000 .
In 2018, more than half (54%) of people newly infected with HIV, aged 15 – 49 were amongst the key populations and their partners – 18% were sex worker clients and sexual partners of other key groups; 17% were men who have sex with men (MSM); 12% were people injecting themselves with drugs; 6% were sexual workers; 46% were from the general population . In regions with a high prevalence of HIV infection, such as Eastern and Southern Africa, HIV was primarily present in persons from the general population, while in regions with a lower prevalence of HIV it was primarily present amongst persons from key populations and their sexual partners.
The estimation that a significant number of people in the world who are HIV positive are not aware of that fact is a cause for concern, with this percentage ranging from 30% to 50% in the European region. In the period between 1984 and the end of 2017, 3,664 HIV positive persons were registered in the Republic of Serbia, of whom 1,901 developed AIDS, and 1,110 died of AIDS. UNAIDS and WHO estimations indicate that, at the end of 2018, in Serbia, 3,000 (2,200 – 3,800) were living with HIV, of whom between 400 and 1,200 were not aware that they had been infected .
All the above stated indicates that, despite numerous new developments in virology and pharmacology, despite intensive efforts in therapy, early diagnostics and prophylaxis, HIV remains one of the greatest public health problems in the world, Serbia included. The aim of this paper was to analyze the trend regarding newly diagnosed persons infected with HIV, as well as those who had developed AIDS, and who had died of this disease, amongst men and women in Serbia, in the period between 2007 and 2017.
MATERIALS AND METHODS
Data on newly diagnosed HIV positive persons (hereinafter: HIV-infected persons), persons who had developed AIDS, and persons who had died of AIDS, were taken from the Reports on Infectious Diseases in the Republic of Serbia for the period between 2007 and 2017, which are annually issued by the Institute of Public Health of Serbia Dr Milan Jovanović Batut, and are available on the Institute’s website .
Data on infectious sexually transmitted diseases are collected as a part of epidemiological monitoring, which is organized and implemented by 24 different public health institutes, in cooperation with health institutions, and in keeping with the law. The Rulebook on Reporting Infectious Diseases defines the dynamics and method of delivering data collected as part of epidemiological surveillance. . At the Institute of Public Health of Serbia Dr Milan Jovanović Batut data are collected in the form of aggregated reports, on a weekly and monthly basis, with the exception of data on newly registered cases of anti-HIV antibody carriers and cases of patients developing or dying of AIDS, which are continuously reported by health institutions, via special individual report, to the Institute of Public Health of Serbia Dr Milan Jovanović Batut (Central Register of HIV-infected persons in the Republic of Serbia, as of 2002, and the Central Register of Persons Suffering from and Dying of AIDS in the Republic of Serbia, as of 1985). Within the annual reports from the 24 public health institutes in Serbia, which have mandates on the territories of the 25 districts, more detailed data are submitted regarding the sex and age of persons suffering from and dying of sexually transmitted diseases .
Based on the data obtained, age-specific and standardized rates of newly diagnosed HIV-infected persons were calculated, as well as age-specific and standardized rates of AIDS incidence and mortality rates of AIDS. Standardized rates were calculated via the direct method of standardization, while Segi’s world population was applied for the standard population . The trends of standardized incidence and mortality rates were calculated by means of the joinpoint regression analysis (Joinpoint Regression Program, Version 22.214.171.124. February, 2019; Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute), applying the method by Kim et al. . The average annual percent change (AAPC) was calculated by means of the joinpoint regression analysis. Years was set as an independent variable, while the appropriate age-specific, i.e. standardized rate was set as a dependent variable. The Grid Search method was applied . Additionally, 95-percent confidence intervals were calculated for each AAPC assessment, in order to determine whether the AAPC is different from 0. The comparability test was applied in order to compare two lines of regression. The main goal of the comparability test was to compare two sets of data on trends, whose mean functions were represented via joinpoint regression, i.e. to test whether the two mean values of the regression function were parallel (parallelism test) .
In Serbia, in the period between 2007 and 2017 there were 1,411 men and 148 women infected with HIV (Table 1). On average, 127 men and 13 women were infected with HIV, annually. The highest age-specific rates of newly diagnosed HIV-infected persons (per 100,000) were in the age group of 25 - 29 years (men – 11.8; women – 2.1) and the age group of 30 – 39 years (men – 8.6; women – 2.0). The average standardized rates of newly diagnosed HIV-infected persons were 4.3 times higher for men (3.4/100,000) than for women (0.8/100,000). A significant rise in rates of newly diagnosed HIV-infected persons, during the observation period 2007 – 2017, was registered in men, for the age groups: 30 – 39 years, amounting to 8.7% per year; 40 – 49 years, amounting to 9.6% per year; and 50 – 59 years, amounting to 15.4% per year; while in women no significant rise was registered in each of the different age groups. When all age groups are observed together, a significant rise in the standardized rate of newly diagnosed HIV-infected persons is apparent; in men, amounting to 7% per year, and in women, amounting to 22.1%, per year.
In Serbia, in the period between 2007 and 2017, 458 men and 77 women developed AIDS (Table 2). On average, 42 men and 7 women developed AIDS each year. The highest age-specific incidence rates for AIDS (per 100,000) were in the age groups: 40 – 49 years, (2.7 for men and 0.5 for women) and 30 – 39 years (2.6 for men and 0.4 for women). The average standardized incidence rates for AIDS were 4.5 times higher for men (0.9/100,000) than for women (0.2/100,000). A significant rise in AIDS incidence rates in men, during the observation period, was registered for the age groups: 30 – 39 years, amounting to 7.5% per year; 40 – 49 years, amounting to 7.2% per year; 50 – 59 years, amounting to 19.8% per year; as well as 4.9% per year for all ages combined. However, when age-specific rates are observed in women, a significant yearly decline is apparent, amounting to: -27.8%, for the age group of 30 – 39 years; -14.3%, for the age group of persons over 60 years; as well as -12.2%, for all ages combined.
In Serbia, in the period between 2007 and 2017, 171 men and 31 women died of AIDS (Table 3). On average, 16 men and 3 women died of AIDS each year. The highest mortality rates (per 1000,000) were in the age group of 40 – 49 years, for men (1.1), while in women they were the highest in the age groups of 30 – 39 years and 40 – 49 years (0.2). Average standardized AIDS-related mortality rates were four times higher for men (0.4/100,000) than for women (0.1/100,000). When the trends of age-specific and standardized mortality rates are observed, in men, there have been no significant changes in the past 11 years, while in women, a significant annual decline is visible, amounting to -25.8%, for the age group of 40 – 49 years, as well as -13.9%, for all ages combined.
According to the comparability test of rate trends of newly diagnosed HIV-infected persons, between the two sexes, as well as the AIDS incidence rates, in men and women, the trends were parallel (the final selected model did not succeed in rejecting parallelism, p = 0.221 for HIV; p = 0.093 for AIDS) (Figure 1, a and b). However, according to the comparability test, AIDS-related mortality rate trends, in men and women, were not parallel (the final selected model succeeded in rejecting parallelism, p = 0.037) (Figure 1, c). AIDS-related mortality rates in women decreased significantly by 13.9% per year, while in men there was no significant change in the whole observation period.
As to the modes of transmission, during the period between 2007 and 2017, in men newly diagnosed with HIV infection, unprotected anal sexual intercourse amongst men was the most common way of transmission (69.0%) (Figure 2); followed by heterosexual intercourse (13.9%), injection drug abuse (3.9%), transmission from mother to child (0.6%), and receiving coagulation factors and other blood products due to coagulation factor deficit (0.1%); while for 12.5% of men, the mode of transmission remained unknown. During the observation period, within the MSM population, a rising trend in the number of newly diagnosed HIV-infected men was apparent; while in the population of injection drug users, there was a falling trend. During the observation period, in women, the dominant pathway of transmission was unprotected heterosexual intercourse (75.7%); while there was 14.2% of female injection drug users (IDUs); mother to child transmission was present in 2.7% of the cases; and blood transfusion was the pathway of transmission in 0.7% of cases. For 6.1% of women the pathway of transmission was unknown.
In Serbia, in the period between 2007 and 2017, the average standardized rates (per 100,000) of HIV-infected persons were 3.4, for men, and 0.8, for women, i.e. they were 4.3 times higher in men than in women. In men, in the observation period, there was an average annual increase in the rate of HIV-infected persons of 7%, and in women this increase was 22.1%. The greatest average yearly increase (+15.4%) was in men aged 50 – 59 years, and in women, there was no significant change in any of the age groups.
Research in Romania was carried out with the aim of predicting, on the basis of data on the dynamics of AIDS between 2004 and 2016, the infection trends in Romania from 2017 to 2027. It was established that there was a significant rise, amounting to 71%, in the number of HIV-infected persons between 2004 and 2016, as well as that the number of AIDS patients increased by 60.3%. Also, despite the availability of medication, treatment and care for AIDS patients in Romania, only a negligible decrease in the number of people dying from AIDS occurred. The largest number of HIV infected persons was in the age group of 26 – 30 years, which coincides with the epidemiological situation in Serbia . It is interesting that in Spain, the highest rates of newly diagnosed HIV-persons were in persons under the age of 20 years, although their absolute number was small, while the next age group with the highest rates was the one from 35 to 39 years. Joinpoint analysis showed an increase in the rate of newly diagnosed HIV-infected persons in the period between 2000 and 2009, but stratification by modes of transmission showed that a rising trend was present only in the MSM population . According to the results of another study carried out in Spain, which followed the seroprevalence of the HIV infection and infection caused by the hepatitis C virus (HCV), in the period 2008 – 2012, HIV infection was more frequent in men, HIV and HCV infection rates were the highest in persons born between 1955 and 1970, and the peaks of these infections overlapped. The seroprevalence of the HIV infection increased with the year of birth for persons born before 1965 (53.4% per year), after which it decreased by 27.1% per year. As HIV and HCV have the same pathways of transmission, it is believed that the rise can be explained by the epidemic of injection drug abuse during the eighties of the 20th century, while in recent years, the main pathway of transmission has been sexual contact (more than 90% of newly HIV-infected persons). Consequently, the prevalence of HIV infection is on the rise in the younger population .
In a study by Li et al., the epidemiological situation regarding HIV infection and the development of AIDS, as well as AIDS-related mortality was analyzed in China, in the period between 2004 and 2011 . A continuous rise in the rate of newly diagnosed HIV-infected persons was determined. Mortality was efficiently controlled due to certain measures which were primarily directed towards therapy. Free testing was made available, as well as free therapy for economically vulnerable groups. Counselling and free antiretroviral therapy was provided for pregnant women infected with HIV. This study monitored rates in different regions of China. While the mortality rate at the level of the whole country is under control, in certain regions, such as Gansu and Ningxia, the mortality rate is on the rise. This is attributed to multiple factors, such as the unfavorable economic situation, poor access to health care in these regions, poor acceptance of testing, the large number of patients affected by the disease who are hiding their health status, and the presence of numerous opportunistic infections.
The number of newly diagnosed HIV-infected persons in the WHO European Region has risen by 22% in the last decade. The rate of newly diagnosed HIV infections has risen by 14% in the previous 10 years from 14.2 in 2009 to 16.2 in 2018. This increase is primarily the result of the rise in the number of HIV-infected persons in Eastern Europe. The comparison of the number of new diagnoses with the estimated number of new HIV infections over the past decade has shown that more people contracted HIV than was diagnosed, which indicates that the number of undiagnosed HIV-infected persons in the region is rising .
In Serbia, in the 11-year observation period, a significant rise in the incidence of AIDS amounting to 4.9% per year occurred in men, while in women a significant decline of 12.2% per year was registered. A study from 2017, which followed the trend of AIDS in Italy from 1999 to 2014, could provide explanations for the rise in men contracting the disease. It was noted that men are more frequently unaware of being infected, which is why they begin treatment later. The study offers several potential explanations. Firstly, women are more often offered testing, for instance during pregnancy. Secondly, it is possible that women more often access healthcare than men . This is also supported by data from Spain, where 56% of those tested were female, which is in keeping with recommendations for prenatal testing . In Serbia, the greatest rise in age-specific incidence rates in men was in the age group of 50 to 59 years, amounting to 19.8% per year. In Italy, also, it was established that it was more probable for people over 50 years to get tested late, as compared to people aged between 35 and 49 years . It is possible that older persons are less aware of the risk of being infected with HIV, since preventive measures and services are primarily directed towards the younger population. Also, social stigma and discrimination are more pronounced in older people, thus creating a barrier towards HIV testing, which is why certain diseases occurring in older patients are not recognized as indicative of AIDS, which can lead to later diagnosis ,.
In Serbia, in the period between 2007 and 2017, AIDS-related mortality rates in men were stable, while in women, a significant decline of 13.9% was registered. In women, the decline registered in the age group of 40 – 49 years was 25.8%. Since 1997, highly active antiretroviral therapy (HAART) has been available and free in the Republic of Serbia, i.e. all costs of treatment are charged to the Health Insurance Fund of the Republic of Serbia for all health insurance beneficiaries indicated for treatment. In Algeria, after the introduction of HAART, in 1998, a significant decrease in AIDS-related mortality occurred. The percentage of HIV-infected persons on therapy rose, reaching the highest value in 2010 (84%). Mortality rates dropped from 200.2, before the introduction of HAART, to 91.4, per 100,000. As of 2003, the mortality rate, according to the joinpoint analysis, decreased by 66.1% per year, only to start rising after 2006 .
In a study testing the trend of hospital admission, readmission, and the mortality of HIV infected persons, in the period between 1993 and 2013, at a university clinic in North-West Spain, a decrease of 49% in mortality from AIDS-related diseases was registered . In Brazil, in the period between 2000 and 2011, a significant drop of 1.7% per year in tuberculosis mortality rates was registered in persons with HIV/AIDS, with significant regional variations. The drop was significant for men (-2.4%), while the trend was stable for women. The decrease was significant for the age groups of 20 – 29 and 30 – 39 years. In the older age groups (50 – 59, 60 – 69, 70 – 79) a significant rising mortality trend was registered. Mortality in pediatric and younger adult age groups, as well as for the age group of 40 – 49 years remained stable during the observation period .
In Serbia, during the observation period, the most frequent mode of transmission of newly diagnosed HIV infection was noted in the MSM population (69% of infected persons). In the observation period, a rising trend of newly diagnosed HIV positive men was registered in the MSM population, while a decline was registered amongst the population of injection drug users. In women, during the observation period, the dominant pathway of transmission was unprotected sexual intercourse (75.7%). The MSM population constituted more than half of newly diagnosed HIV-infected persons in Western and Central Europe, which Serbia is a part of. Heterosexual intercourse (72%) and injection drug abuse (23%) remained the main pathways of HIV transmission in Eastern Europe .
The data from Italy indicating that almost two thirds of AIDS patients, who had become infected through sexual intercourse, were diagnosed late, is alarming. Heterosexuals had a particularly high risk of late diagnosis, as compared to injection drug users (IDUs). The assumption is that prevention programs do not pay enough attention to individuals with a low level of awareness regarding risky sexual behavior and, in that way, the probability of late HIV testing is increased .
Planned goals of the global UNAIDS 90-90-90 strategy have not as yet been achieved. Globally, in 2018, there were 79% of people living with HIV who were aware of their HIV positive status, 62% of people aware of their HIV positive status were on ARV therapy, and 53% of people on ARV therapy had viral suppression. It is estimated that, in Serbia, at the end of 2018, 3,000 persons were living with HIV, 2,597 (86.6%) of whom were aware of their HIV positive status, while 72.5% of diagnosed HIV-infected persons were on ARV therapy. Even after 2020, the 90-90-90 goals remain of utmost importance, indicating that additional efforts and investments need to be made in HIV testing and treatment programs, in order to end the AIDS epidemic by 2030.
A limiting factor in this study is the fact that in Serbia, just like in other countries in the world, newly diagnosed HIV-infected persons are only registered, without any definite knowledge as to how long the patients have been infected, i.e. when the infection was contracted. The trend of newly diagnosed cases of HIV infection depends on the stadium of the infection that persons are diagnosed in, as well as on the scope of testing for persons at increased risk of HIV infection; thus it does not reflect HIV infection incidence in the population, nor does it represent the overall prevalence of the HIV infection. Consequently, it is not clear whether the rise in the number of newly diagnosed HIV-infected persons is the result of an increase in the number of newly infected persons, or the result of more comprehensive testing, especially amongst key populations, which are at increased risk. The latest WHO recommendations require of Serbia, as well, to take such steps that would enable the first, most important one, and that is broad access to voluntary confidential counselling services and HIV testing, with parallel destigmatization and removal of discrimination towards people infected with HIV, as well as effective prevention of HIV infection transmission, especially in key populations at high risk of HIV.
For the observation period from 2007 to 2017, in Serbia, a significantly higher rate of newly diagnosed HIV-infected persons was registered for men than for women. The decline in the number of patients developing AIDS and in AIDS-related mortality was not simultaneously followed by a decrease in the number of newly diagnosed HIV-infected persons, which is why, with a prolonged life span, the total number of persons living with HIV is increasing, while the portion of people unaware of their HIV positive status represents a risk factor for further infection transmission. Public health measures need to primarily be directed towards the prevention of infection. It is necessary to work further on improving preventive measures, especially on educating the young population on the pathways of transmission and the risks, as well as on early detection of HIV-infected persons and timely treatment. It is important to increase the number of counselled and tested persons in the key populations, who are at a higher risk of HIV infection. Early diagnosis of the HIV infection and timely treatment contribute to the decrease in infection transmission in vulnerable populations.