Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Antiretroviral therapy (ART) is now recommended worldwide for all people living with HIV (PLHIV), regardless of their CD4 cell count [1]. However, barriers to ART access for PLHIV do exist, with important differences among countries, especially according to socio-economic levels and organization models of national healthcare systems [2]. These disparities can affect the probability of reaching the “90–90-90” target fixed by UNAIDS for 2030 (90% diagnosed individuals of all PLHIV, 90% treated patients, and 90% PLHIV achieving viral suppression) [3].

Even in high income countries, social determinants are known to be a driving force of health inequalities [4]. In the setting of HIV infection, demographic and socioeconomic factors can limit the access to testing, treatment, and retention in care and, consequently, reduce survival of PLHIV [5]. Entering the era of universal ART for all HIV people living with HIV, we can hypothesize that these factors could have an even greater impact on disparities in ART access compared to past years.

In 2015, the proportion of people newly diagnosed with HIV and presenting with < 200 cell/μL CD4 was 36.6% in Italy, whereas proportion of people with CD4 < 350 cell/μL was 54.5% [6]. In a previous study from the ICONA (Italian Cohort Naïve Antiretrovirals) cohort, among socio-demographic factors, migrant status was already demonstrated to be associated with barriers to ART initiation and with increased risk of treatment failure compared to natives [7]. However, other social or behavioral determinants, including gender [8, 9], poor education [10, 11], unemployment [12], social exclusion within special population groups, e.g. people who inject drugs (PWID), need to be considered [13].

Moreover, also in people accessing ART and adhering to therapy, lifestyle differences can affect chances to respond to ART, occurrence of side effects and co-morbidities in PLHIV [14].

Aim of our study was to determine if social determinants influence ART access, outcome and retention in care of PLHIV in spite of a context of public healthcare. The knowledge of factors which define the “social vulnerability” can allow to allocate resources and plan for interventions in order to reduce disparities which impact survival of persons living with HIV.

The ICONA Foundation Study is an observational cohort of people living with HIV who are antiretroviral naïve at the time of enrolment. This cohort was set up in January 1997 and currently consists of over 14,000 patients from 50 Italian infectious disease reference units. Demographic and socio-behavioral data, initiation and discontinuation dates of each antiretroviral drug, HIV-viral load and CD4 cell count every 3–6 months, AIDS defining diseases according to Centers for Disease Control and Prevention (CDC) criteria as well as non-HIV related diseases and death are recorded for all enrolled participants. Further details are available at http://​www.​fondazioneicona.​org/.

In the present study, all ART naïve PLHIV of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The following socio-demographic characteristics were retrieved and analyzed for their potential association with the study endpoints: age, gender (male, female), risk factor for HIV infection [heterosexuals (HS), men who have sex with men (MSM), people who inject drugs (PWID)], educational level, occupational status and residency area. Taking into account the structure of the Italian education system, and according to the UNESCO/International Standard Classification of Education standard classification (ISCED) [15], the educational level was categorized into four categories: primary school (corresponding to ISCED 0); junior secondary school (ISCED 1); high secondary school (ISCED 2–3); tertiary school (university and similar) (ISCED ≥4). The occupational status was classified into seven categories as follows: full-time worker, temporary employed, self employed, unemployed, student, retired, housewife (defined as women only managing household affairs without having paid employment). The residency area was categorized in Northern, Central and Southern Italy.

Patients who did not attend visits for ≥18 months were defined as lost to follow-up.

Socio-demographic factors are an important cause of health inequalities, even in high income countries adopting universal health care systems [5]. In Italy, both HIV testing and ART are free of charge for all individuals, independently on disease stage, work conditions or other economical issues. Data from the national health institute demonstrated a satisfactory framework of the HIV treatment cascade in our country, which appears to be very close to WHO targets, showing that in 2014 92% of people diagnosed with HIV were in ART treatment, 87.7% of whom with suppressed HIV viremia [6]. According to changes in international and national guidelines, which progressively suggested to start ART at higher CD4 count overtime, our data demonstrate that, for patients enrolled in the ICONA cohort, time to ART initiation significantly decreased from more than 3 years in 2002–2006 up to 0.2 years in the last 4 years. In this context, we aimed to evaluate if social determinants do still play a role in access and response to antiretroviral therapy in PLHIV.

Herein, we limited our analysis to native Italian people in order to avoid that confounding factors related to the status of migrant could influence our results, including language barriers and cultural differences. In a previous paper, however, including patients enrolled in the ICONA cohort as well, an increased risk of both delayed access to ART and virological failure was already demonstrated in migrants living with HIV [7]. Moreover, only patients enrolled in ICONA during a relative recent period (2002–2016) were included in the present study, in order to take into account exclusively modern (and highly potent) antiretroviral regimens.

The results of our analysis clearly evidenced that, even in a country with universal health care coverage as Italy, several social determinants, including female gender, PWID as a risk factor for HIV transmission, low educational level and unemployment, significantly impact both ART access and outcomes. It should be underlined that these variables are also strictly interconnected to each other: in fact, females, PWID and residents in Southern Italy also presented the lowest level of education and the highest rate of unemployment. Although the public health system is freely assured throughout the country since 1978, after a constitutional reform voted in 2001, budget and organization of health services are under regional control. Therefore, many differences in health services may exist among different Italian areas. Based on historical reasons, Northern, Central, and Southern Italy are quite different from an economic and social point of view, with a North-to-South gradient, being in general Northern regions the most industrialized areas of the nation.

First, a risk of late presentation was demonstrated for all the above mentioned categories, which was particularly evident for people aged more than 50 years, which is in line with national and international reports [6, 16]. Similarly, older patients started ART with significantly lower CD4 cell number compared to younger subjects and, in parallel, they presented significantly longer time to ART initiation since the first anti-HIV positive test. People > 50 years old had the same mode of HIV acquisition of younger people, but they may be less aware of their HIV status. Moreover, HIV testing is probably less recommended by health care providers in this group than in young adults [17]. However, old people need to be recognized as a high risk group as they present poorer immunologic response compared with younger patients, with higher mortality rates [18]. In our study, ART initiation was more likely with increasing age, even after adjustment for CD4 count. No significant association between age and achievement of viremia suppression on ART after 1 year was demonstrated. Older patients were associated with a more recent year of ART initiation, which was conversely associated with lower risk of discontinuation. From the multivariable analysis, however, after adjusting for year of ART initiation, older age was related to a higher risk of therapy discontinuation, probably due to a higher frequency of side effects and co-morbidities in this patient group. The type of drug ART regimen could also be a possible explanation, as older individuals were more frequently on a protease inhibitor-based regimen (42% compared to 25% in patients aged > 30 years, data not shown).

If female gender is a risk factor for late presentation, delayed therapy initiation and poor ART response is controversial in literature [19‐21]. In fact, several aspects might contribute to confound results from different cohorts, also depending on the chosen endpoints [19]: firstly, early diagnosis of HIV infection in women is favored by screening programs for HIV during pregnancy; secondly, lower HIV-RNA levels have been observed in women compared to males [20] which could justify better response rates to ART. Finally, regarding the association of gender and mortality for PLHIV, it should be taken into account that women have an overall higher life expectancy compared to men, at least in Western countries. Moreover, in PLHIV, a lower incidence of non-AIDS events in women compared to males has been described [22]. In our study, after controlling for other variables including pregnancy status and HIV viremia levels, females resulted more at risk of delayed ART initiation and therapy discontinuation, even if no differences in response rates to the first year of ART were evidenced. The status of housewife, however, was not associated with the same endpoints in our analysis; on the contrary, they presented a lower rate of therapy discontinuation. No data regarding this association in literature are available to our knowledge.

Among the different risk group categories for HIV acquisition, as expected, people who inject drugs presented a delay in initiation of ART and inferior virological response to therapy; our results are in agreement with the paper of Lesko et al. [13] who demonstrated as PWID, even in recent years, spent a significantly larger amount of time not on ART compared with non-PWID or, when on ART, not virally suppressed, thus greatly contributing to HIV transmission. On the contrary, MSM, who became the most represented group in the last years (52%), initiated ART at significantly higher CD4 levels than other risk groups; however, MSM resulted more frequently at risk of ART change / interruption compared to other groups.

The economic status of PLHIV is always hard to be determined. Educational level and occupational status, however, can be considered good proxies of such condition [5]. We demonstrated that the educational level has a crucial role of in influencing both access and response to ART in our country. This finding extend previous observations in Italy [23] and in other European countries [24‐26], and are in agreement with recent multi-cohort data from the COHERE [10, 11]. In addition, the relationship between occupational status and ART access and outcomes was also analyzed. Very few studies [12, 27] have addressed this point to date, as this information is not registered in the most part of the cohorts enrolling HIV patients. In France [27], a global indicator of social vulnerability including education, employment, and housing stability and comfort, after adjustment for lifestyle factors, psychosocial characteristics (depression, drug using) and known biomedical factors, was associated with mortality in PLHIV. Moreover, unemployment was associated with a reduced sustained virological suppression (e.g. undetectable viral load for ≥6 months) [12]. In our analysis, unemployment was associated with all three endpoints (a longer time to ART initiation, lower chances to reach a suppressed HIV viremia, and higher risk of discontinuation). It must be underlined that work conditions, although considered an excellent proxy of economic status, may change during patient’s life and cannot be considered as an independent variable as a poor health status could also cause job loss. However, as only the first year ART response was investigated in the present study, and the occupational status was registered at entry in the cohort, our results can be considered reliable.

Among lifestyle factors, smoking was not associated with any of the study endpoints in our analysis [14]. All results were adjusted for smoking and pregnancy status. However, other behavioral and clinical factors, including alcoholism or depression, were not targeted in our analysis but could have indirectly influenced our results. In particular, the inclusion of mental health outcomes as part of the ICONA database in the future would be suitable. A high percentage of missing data regarding educational level could have introduced some biases, representing an important limitation of our study. A major limitation is also the lack of information regarding the presence of transgender people in our cohort. In fact, even if sexual orientation and gender identity should be reported the ICONA database, no transgender cohort participants were registered among patients fulfilling inclusion criteria in our study, which seems to suggest that this information was under-reported by clinicians [28, 29].

In conclusions, notwithstanding median time to ART start decreased from 3.3 to 0.2 years from 2002 to 2016, socio-demographic factors still contribute to important disparities in ART initiation, outcome and durability in PLHIV from Italy. Therefore, a deeper evaluation of socio-economic determinants, possibly using a standardized approach, is needed on one side; on the other side, welfare interventions aiming to reduce the social inequality for fragile populations such as PWID, women, old people, patients with low educational level and unemployed, along with migrants, would indirectly improve the cascade of care for PLHIV. Moreover, it should be underlined that relatively few complete national data regarding continuum of care are available in Italy as in other countries, with wide variation in reporting procedures [30]. Nowadays it becomes more and more important to use consistent and accurate methods for tracking progress towards the achievement of WHO 90–90-90 targets.