Hepatitis C virus infection status and associated factors among a multi-site sample of people who used illicit drugs in the Amazon region

The hepatitis C virus (HCV) infection causes acute and chronic liver disease and may lead to cirrhosis, liver failure or hepatocellular carcinoma [1]. Globally, it is estimated that there are approximately 100 million persons with serological evidence of active or non-active HCV infection, and that HCV causes about 700,000 deaths each year [2]. Most cases of acute infection are asymptomatic and remain undiagnosed [3]. Currently highly effective pharmacotherapeutic (direct-acting antiviral) treatment options for HCV are now available [4]. Spontaneous clearance of HCV can occur within 12 months of infection in 15–45% of infected individuals, in the absence of treatment [5]. HCV infection does not result in long-term immunity and reinfection after effective treatment or clearance has been reported [6]. In epidemiological scenarios with high prevalence of HCV, multiple exposures may result in infections with HCV of more than one distinct genotype in the same person [7].

Illicit drug use – especially by injection and sharing non-sterile or shared injection equipment – is a main risk factor for transmission of HCV [8]. Many people who used illicit drugs (PWUIDs) infected with HCV are asymptomatic and/or unaware of their infection, and the continuation of risk activities that contribute to further transmission and an increase in the incidence of HCV [9]. Estimates indicate that there are about 16 million individuals who inject drugs worldwide, and unsafe use or sharing of drug paraphernalia (mainly syringes/needles used for drug injecting) is the main agent of virus transmission among users [10, 11]. As many as 10 million people who inject drugs may be HCV-infected worldwide, reflecting the strong association of these risk activities with the easy spread of the virus [10, 12].

Brazil is one of the emerging economies where the use of mostly stimulant drugs, such as cocaine – used intranasally (powder) or smoked (crack-cocaine and its related forms - merla or oxi) – has increased significantly in the last two decades [13‐15]. Although uncommon, the use of injectable cocaine has been documented also [13, 16, 17]. There are several reasons for the high rate of cocaine-products used in Brazil: geographic proximity and un-secured borders with the world’s largest cocaine producers (Peru, Colombia and Bolivia), a young population combined with increases in wealth in the last decade, and the extensive availability combined with the cheap price of cocaine in Brazil (one crack ‘stone’ selling for three Reais, equivalent to US$ 1) [15, 18].

Elevated rates of HCV infection have been reported in epidemiological studies with PWUIDs in different Brazilian regions (2 to 29%) [19‐23]. In the Amazon region (Northern Brazil), studies with PWUIDs have indicated a higher prevalence of HCV infection (28 to 37%), highlighting the elevated potential for the acquisition and transmission of HCV in this risk population [16, 17, 24, 25]. HCV genotype 1 is predominant among HCV-infected PWUIDs. Several risk factors for HCV infections have been reported: age (≥ 35 years), tattoos, domestic re-use of needles or syringes for medical procedures, injecting drug use, sharing of drug paraphernalia, daily and lengthy drug use histories (> 3 years). However, all studies done with PWUIDs were conducted with small samples and with limited geographic coverage [16, 17, 24, 25].

The vast Amazon region in Northern Brazil is a relatively isolated and socio-ecologically diverse environment, with only limited infrastructure and public services. In the Amazon region, studies have already identified the high use of illicit drugs among adolescents and the high prevalence of HBV and HCV infections among PWUIDs [17, 26, 27]. In this context, this study assessed a sample of 1666 PWUIDs in the Amazon region (Northern Brazil), collecting relevant epidemiological information on HCV infection and related risk factors and outcomes towards improved understanding of HCV transmission pathways and intervention needs in this particular risk population and socio-geographic context.

This study identified important characteristics of the study population of PWUIDs in the Amazon region of Northern Brazil and, specifically, associations with HCV infection status in this vulnerable group. The sample was predominantly composed of men, non-white, young, poor, unmarried, heterosexual and limited education levels. Moreover, some PWUIDs have indicated involvement with sex work, illicit drug trafficking, and the criminal justice system. This information is consistent with findings from other studies in Brazil [13, 18, 21, 29, 30]. Some studies have indicated that socioeconomic marginalization contributes to an increased risk of morbidity and mortality among PWUIDs [30, 31]. The strong association between HCV infection and involvement with drug trafficking may represent an example of socioeconomic marginalization contributing to increase the health risks of the PWUIDs. The role of these in the specific study sample requires further examination, which should be done in the future.

Crack and cocaine (used mainly non-injection) were the main illicit drugs consumed by study participants. However, many users may be considered poly-drug users, including some of them reporting - occasional - injection drug use at some point in life. Daily drug use and sharing of drug use equipment were characteristics common for most of the study participants. These findings corroborate information provided in other epidemiological studies conducted with PWUIDs in Brazil, including from the Amazon region [16, 17, 19‐21, 24‐27, 29, 30].

The estimated prevalence of HCV infection in the Amazon region’s general population ranges from 1 to 3%, based on the diagnostic methods used, with higher rates being recorded in different sub- or risk groups (e.g., older ages, indigenous) [22, 32‐34]. HCV prevalence estimates from previous studies have been multifold higher among PWUIDs, ranging from 28 to 37%, compared to general populations [16, 17, 23‐25]. The present study confirmed the high prevalence of HCV infection (36.6%) among PWUIDs in the Amazon region, reinforcing the need for effective control and prevention measures. The predominance of genotype 1 was observed among PWUIDs, but frequency of the genotype 3 was elevated relative to other risk population in the Amazon region, such as patients with chronic hematologic diseases (recipients of multiple blood transfusions) and patients undergoing hemodialysis [35, 36]. Most HCV infections in the Amazon region consist of genotype 1, whereas genotype 3 is found mostly among PWUIDs [16, 17, 24, 32, 35‐37]. The rapid spread of genotypes 1 and 3 (and specifically subtypes 1a and 3a), in different geographic areas over the past decades, has been a consequence of efficient transmission through unsafe blood transfusion products and injecting drug use [38‐40].

This study is a first in describing HCV infection status (i.e. active and non-active) in a multi-site PWUIDs population in the Amazon region in Northern Brazil. Among 577 PWUIDs infected with HCV, 193 (33.4%) presented with HCV spontaneous clearance. The multivariate analysis suggested spontaneous clearance status to be strongly associated with origin (Amazonian-born) and non-white (e.g., Black or Indigenous) of the participants. The contemporary population of Northern Brazil is comprised of a heterogeneous socio-ethnic mixture of indigenous Brazilian natives combined with migratory populations of Caucasians and Blacks of diverse origins [41]. Likely, a predominance of indigenous descent, and associated genetic factors, is a variable behind this strong association of socio-ethnic origin with HCV spontaneous clearance. Genetic ancestry analysis markers were not used in this study, but related finding have also been detected in other studies, including native/indigenous people in North America [5, 42]. In Canada, a study conducted with PWUIDs found that Indigenous/Aboriginal status was a factor associated with HCV spontaneous clearance [42]. The understanding of factors that promote or prevent the generation of protective immunity is potentially crucial for the development especially of improved prevention (e.g., a possible HCV vaccine) and/or treatment tools for HCV infection; further studies are needed from a clinical and virological perspective on these issues.

HCV infection status was associated with several risk factors in this study, most of which have previously been identified by other studies in Brazil [17, 19‐21, 24, 43]. The presence of tattoos and older age (> 30 years) are characteristic known to be associated with HCV infection in PWUIDs and Amazonian blood donors [16, 17, 24, 25, 28, 32]. Longer histories (> 12 years) of illicit drug use was the characteristic most strongly associated with HCV infection status, implying extended opportunity for and exposure to repeated key risk behaviors facilitating the acquisition of HCV and other pathogens, such as: sharing of drug use equipment, and injection drug use [16, 17, 19‐21]. The active involvement with drug trafficking as a risk factor likely provides quick and easy access to a greater number of different drugs (e.g., injectable cocaine) as well as riskier use methods (e.g., drug injecting), and so provides increased risk pathways to HCV transmission. Moreover, those newly infected with HCV can continue to transmit HCV to other users through the shared use of non-injection equipment (i.e., crack smoking paraphernalia). The possibility of HCV transmission by shared non-injection equipment has been demonstrated by studies in several countries, including studies in the Amazon region [24, 43‐46]. Recently, the presence of HCV-RNA in paraphernalia for crack-cocaine consumption (pipes and aluminum cans) was detected among samples from the Amazon region [46]. Studies have suggested that the risk of HCV transmission by shared non-injection paraphernalia would be modulated by the presence oral wounds and types of paraphernalia (i.e., sharp or heat-intensive materials) used [44‐46].

Sexual transmission of HCV is still controversially discussed, but considered possible [47]. Sexual transmission of HCV has been more commonly recorded in men-who-have-sex-with-men featuring high sexual (e.g., HIV) and drug use risks status [48]. Other studies have indicated the possibility of sexual transmission of HCV among PWUIDs with sexually transmitted infections (STIs), especially with the presence of oral and/or genital wounds [49, 50]. High levels of syphilis and HCV-HIV co-infection among PWUIDs have been documented previously in the Amazon region [17, 24, 29, 51]. These dynamics likely are involved in the associations of unprotected sexual intercourse with HCV infection status in the present study sample. An evaluation of HCV co-infections with other pathogens such as HBV, HIV, HTLV and T. pallidum in the present sample – confounded by poor health care resources and infrastructure in the study region – will be carried out separately to further examine this comprehensive epidemiological-virological picture.

The present study has a number of possible limitations. One limiting factor was the age limit criterion (18 years) applied for eligible participants, since many PWUIDs report an onset of illicit drug use at ages < 18 years. Second, the restriction of the study to the municipalities of the Amazon region renders the study sample not necessarily representative of the PWUIDs population in Northern Brazil more generally. In addition, although snowball sampling has been found to be adequate for quasi-representative sampling in hidden populations, could have been used to improve representativeness. As the interview data are self-reported, some information, such as drug use or sex-related risks behaviors, may contain response or recall bias. Screening for HCV infection was based on EIA, recent infections may present a small concentration of anti-HCV antibodies, not yet detected by EIA, and therefore may have been diagnosed as negative. Finally, the cross-sectional design of the study limits its capacity to establish causality.

The present study is the first epidemiological examination of HCV infection (active or non-active) status and related risk factors among a large, multi-site sample of PWUIDs in the Amazon region. High levels of HCV infection – predominantly genotype 1 and associated drug use intensity, sexual risks and social marginalization – as well as spontaneous clearance were identified. The results, despite the context of an underdeveloped health care structure, emphasize the urgent need for improved HCV prevention and care services for marginalized drug users in the Brazilian Amazon region, yet also for improved understanding of HCV transmission risks and especially those factors facilitating spontaneous clearance for HCV in the study’s target population.