The hepatitis C cascade of care in people who inject drugs in Dar es Salaam, Tanzania

Summary The World Health Organisation has recently called for hepatitis C virus (HCV) elimination and has identified people who inject drugs (PWID) as a key population to scale‐up screening and linkage to care. This study reports the cascade of care for HCV in PWID attending the largest opioid substitution treatment (OST) clinic in Dar‐es‐Salaam, Tanzania. Between February 2011 and March 2016, HCV serology for all PWID registered at the Muhimbili National Hospital OST clinic, Dar‐es‐Salaam were obtained from records. In 2015, consecutive HCV‐seropositive PWID were invited to undergo a clinical evaluation including epidemiological questionnaire, liver stiffness measurement (Fibroscan) and virological analysis (HCV RNA viral load and genotyping). During the study period, 1350 persons registered at the OST clinic: all had a HCV serology including 409 (30%) positive results. Among the HCV‐seropositive individuals, 207 (51%) were active attenders and 153 (37%) were enrolled for clinical assessment: 141 (92%) were male, median age: 38 years (IQR 34‐41), and 65 (44%) were co‐infected with HIV; 116 patients (76%) had detectable HCV RNA, with genotypes 1a (68%) and 4a (32%); 21 (17%) had clinically significant fibrosis (≥F2) and 6 (5%) had cirrhosis (F4). None were offered HCV treatment. Chronic hepatitis C among PWID enrolled in the OST centre in Dar‐es‐Salaam is frequent, but its continuum of care is insufficient; integration of HCV diagnosis and treatment should form a part of OST intervention in PWID in Tanzania.


| INTRODUC TI ON
An estimated 71 million people are chronically infected with the hepatitis C virus (HCV) worldwide and each year between 400 000 and 700 000 deaths are attributable to this virus. 1,2 The World Health Organisation (WHO) has recently called for HCV elimination. 3 In its 2016-2021 global hepatitis plan, the WHO defined ambitious strategies to achieve 90% reduction in new HCV cases and 65% decrease in HCV-related mortality by 2030. 3 Intravenous drug use is a major driver of HCV spread worldwide and the WHO has clearly identified people who inject drugs (PWID) as a key population to target for HCV screening, prevention and care. 4 It is estimated that 10 million of 16 million PWID across the world are positive for HCV antibody. 5 In sub-Saharan African (SSA), the use of injectable drugs has been long considered as a minor issue in terms of the numbers of people involved. Globally, 8% of PWID are estimated to reside in sub-Saharan Africa. A recent influx of heroin has led to a rise in injecting drug use, which has been recognized as a growing concern in coastal East Africa. In particular, Kenya, Tanzania, Madagascar, Reunion, Seychelles and Mauritius have endured a sharp increase in local heroin use. Heroin trafficking follows the southern pathway, a network of mainly maritime routes originating from Afghanistan and Pakistan, traversing the Indian Ocean, before arriving in East Africa. 6 Hence, East Africa is a point of geographical significance and is widely considered the gateway for African narco-trafficking, with 90% of the imported heroin destined for distribution to both continental and global sites. In 2013, it was estimated that 22 tons of heroin passed through East Africa annually, with 2.5 tons being consumed locally. 7 Costing as little as USD$1 per "hit," it is estimated that 30 000-45 000 people who inject heroin in Tanzania. 8 Data on the burden of HCV among PWID in SSA are scarce. A study in Sénégal reported a high prevalence of HCV infection in drug users, but did not analyse the severity of the liver disease and furthermore, the drug users were mainly noninjectors. 9 In East Africa, there have been a handful of descriptive studies, restricted to assessing the seroprevalence of HCV infection, ranging from 28%-53% in Tanzania to 42% in Kenya. [10][11][12] Lack of access to HCV nucleic acid testing (NAT), is a major obstacle to identifying chronically-infected individuals encountered across resource-limited settings. 13 Similarly, evaluating the stage of liver disease is problematic. This study aimed to assess the severity of liver disease and cascade of care for HCV-infected PWID registered at one of the largest opioid substitution therapy (OST) clinic in Dar-es-Salaam, Tanzania, East Africa. We also determined the proportion of significant liver fibrosis or cirrhosis using liver stiffness measurement (LSM), as measured by ultrasound-based transient elastography, and assessed the diagnostic accuracy of APRI, Fib-4 and GPR using LSM as a reference test.

| Ethical consideration
The study received clearance from both Muhumibili University for Health and Allied Sciences (MUHAS) and the Tanzanian National Institute for Medical Research (NIMR) (NIMR/HQ/R8a/Vol.ix/2298) institutional review board panels. Participants were enrolled in the study after providing written consent.

| APRI, Fib-4 and GPR fibrosis scores
The following blood parameters were measured at the study enrol-

| Transient elastography
LSM was obtained in fasting patients using ultrasound-based transient elastography (Fibroscan ® 402, Echosens, Paris, France) and was performed by trained experienced operators according to the manufacturer's protocol. 18 Results were expressed in kilopascal (kPa) as the median value of 10 successful acquisitions. Failure was defined as no single successful measurement (valid shot = 0) and unreliable measurement was defined as IQR/LSM of >0.30 when LSM is ≥7.1 kPa. 19 To estimate fibrosis stage, we used the following cut-off values of Fibroscan ® in accordance with the WHO 2016 guidelines for HCV screening, care and treatment; ≥7.0 kPa for ≥F2 disease and ≥11.0 kPa for ≥F4 disease, respectively. 4

| Serological methods used to detect anti-HCV, anti-HIV Abs and HBsAg
Serology testing for anti-HCV, anti-HIV Abs and HBsAg were performed using the Abbott AXSYM ® system (Abbott Diagnostics, Chicago, Illinois) according to the manufacturer's instructions, at the MNH clinical chemistry department, Dar-es-Salaam.

| HCV RNA detection and quantification
HCV RNA was quantified using the Cobas Ampliprep/Cobas TaqMan HCV version 2 (CAP/CTM; Roche Molecular Systems Pleasanton, California), real-time polymerase chain reaction (RT-PCR) assay according to the manufacturer's instructions.

| HCV genotyping
Samples were analysed at Henri-Mondor Hospital (Creteil, France) for genotyping and HCV RNA confirmation. HCV genotypes and subtypes were determined by means of the reference method that is sequencing of the nonstructural 5B region of the HCV genome, followed by phylogenetic analysis, as previously described. 20

| Statistical analysis
The characteristics of the study participants were presented by me-

| Hepatitis C cascade of care
A total of 1350 PWID were registered at the OST clinic at MNH since its inception. All were offered and accepted to have screening for anti-HCV antibody, 409 (30%) tested positive, of whom 207 (51%) were active attenders, 131 (32%) had defaulted, 49 (12%) had died, 22 (5%) had been successfully discharged from the programme. As part of this research project between April and July 2015, 153 (74%) of consecutive active HCV-seropositive attenders were successfully linked to further clinical and virological evaluation. 116 (76%) were deemed to be HCV RNA positive and 21 (17%) were suspected to have significant fibrosis on the basis of high LSM values. None had access to any anti-HCV therapy. Figure 1 summarizes the cascade of care for HCV in this population.

| General characteristics
During the study timeframe, 153 consecutive PWID (median age

| Severity of liver fibrosis
The median noninvasive scores of liver fibrosis are indicated in Table 1

| Performance of biochemical scores using LSM as a reference
The performance of each biochemical score for correctly categorizing significant liver fibrosis or cirrhosis, using LSM as a reference, is summarized in Table 2. With the AUROC being below 0.60, the overall performance of these tests for the diagnosis of fibrosis and cirrhosis was not acceptable. To diagnose of clinically significant fibrosis (≥F2), the low cut-off APRI (<0.5) had the best sensitivity (73%), while a cut-off value at 2 had a poor sensitivity for the diagnosis of cirrhosis, but a very good specificity (95%). However, its utility is hampered by the fact that more than half of the resulting scores presided in the "grey zone," between the different cut-off values.

| D ISCUSS I ON
The diagnosis of HCV among PWID in Tanzania accessing the largest OST clinic is limited to serology testing on registration. Our study revealed that about a third had prior exposure to HCV, of whom half are regular attenders at the OST clinic. Of those not engaging in the clinic, 12% of patients are known to have died. In addition, close to a third of patients are reported as "defaulters." With the clinical outcomes not known for this group, it is conceivable that the true mortality rate could be higher.
Clinical evaluation from a sub-group of consecutive HCVseropositive PWID receiving OST, found that nearly half were coinfected with HIV and three-quarters were HCV viraemic, with genotypes 1a and 4a being identified. This is in line with the only other report of genotyping performed in PWID in East Africa (Kenya). 21 In addition, we found 17% of patients with significant liver fibrosis according to LSM including 5% with cirrhosis. At the time of writing, there has been no access to direct-acting antiviral (DAA) interferon-free therapy for PWID in Tanzania.
To our knowledge, this is the first study to provide a comprehensive screening and assessment cascade of care for HCV in PWID in Africa. There have been two previous studies estimating HCV seroprevalence among PWID in Tanzania, reporting a prevalence of 28% and 53%, respectively. 10,12 Both previous studies also confer our finding of a heavily predominant male population. 10,12 Although this may truly reflect that injecting drug use is more commonly practiced among men, the difference is likely to be exaggerated as women may represent a more marginalized and however, their utility in resource-limited settings has been poorly documented. To our best knowledge, our study is the first to report TA B L E 2 Diagnostic accuracy of APRI, Fib-4 and GPR using LSM as a reference in patients with chronic hepatitis C  34 The latter is an issue which has also been identified in a recent validation of APRI in HCV/ HIV co-infection in Cambodia. 35 Mathematical models have shown that scaling-up harm reduction services, through OST and NSPs, in combination with DAA therapy will help achieving HCV elimination in PWID. 36 In populations with escalating incidence of PWID, a failure to integrate harm reduction strategies into any proposed healthcare intervention can have a significant impact on HCV transmission, as evidenced by the recent "opioid crisis" in parts of North America. 37,38 In Tanzania, there are an estimated 50 000 PWID, with only 3000 engaging in a local OST programme. 10 Despite the existence of NSP in Dar-es-Salaam, 39 43 Although Tanzania is considered a pioneer in Africa for its OST programme, it is dependent on funding through the President's emergency plan for AIDS relief (PEPFAR).
Recent changes to the local healthcare agenda threaten to deprioritize the OST programme, while the well-publicised reduction of international foreign aid also poses a real risk to the existence of this once-acclaimed initiative.
Our study has some limitations: first, it reflects HCV-related