Hepatitis C Treatment in People With HIV: Potential to Eliminate Disease and Disparity

Abstract

Access to direct acting antivirals (DAAs) may be associated with reductions in hepatitis C virus (HCV) viremia prevalence among people with human immunodeficiency virus (PWH). Among 3755 PWH, estimated HCV viremia prevalence decreased by 94.0% from 36% (95% confidence interval [CI], 27%–46%) in 2009 (pre-DAA era) to 2% (95% CI, 0%–4%) in 2021 (DAA era). Male sex, black race, and older age were associated with HCV viremia in 2009 but not in 2021. Injection drug use remained associated with HCV viremia in 2009 and 2021. Targeted interventions are needed to meet the HCV care needs of PWH who use drugs.

Among 3755 people with HIV, availability of direct acting antivirals (DAA) was associated with a reduction in HCV viremia prevalence from 36% in 2009 (pre-DAA era) to 2% in 2021 (DAA era) and changes in characteristics associated with HCV viremia.

The availability of oral direct acting antivirals (DAA) with proven effectiveness for hepatitis C virus (HCV) cure has made it possible to eliminate HCV not only at the individual level, but also potentially at the population level [1]. People with human immunodeficiency virus (PWH) are at increased risk of HCV infection due to shared modes of transmission and once infected are at increased risk for chronicity and accelerated liver disease progression to liver failure, liver cancer, and death [2, 3]. Additionally, the existing infrastructure for HIV care linkage and engagement on which HCV care and treatment can be layered has contributed to enthusiasm for HCV microelimination among PWH. This enthusiasm has been buoyed by reports of progress towards HCV microelimination in PWH in some regions of the world [4, 5]. However, these studies have largely reported experience in predominantly male, white populations and with less data on populations from the United States where black populations are disproportionately impacted by HIV and HCV.

In these analyses, we sought to understand changes in HCV viremia prevalence and associated sociodemographic characteristics of PWH in the oral DAA era compared to the pre-DAA era in a cohort of PWH. We hypothesized that the prevalence of HCV viremia would have decreased significantly from the pre-DAA to the DAA era and that this decrease in prevalence would be associated with changes in sociodemographic characteristics of those with HCV viremia.

METHODS

Study Setting

The Johns Hopkins HIV Clinical cohort includes people with HIV receiving care at the John G. Bartlett Specialty Practice in Baltimore, Maryland who provide written informed consent to share their medical data. The clinic serves a predominantly minority, urban population. HCV testing and care is provided within the HIV practice in which clinicians, nurses, and social workers work as multidisciplinary teams to provide care to defined groups of patients. HIV providers test for HCV as part of routine clinical care and refer infected patients to the colocated viral hepatitis clinic or prescribe HCV treatment themselves. Patients are supported in HCV care by their dedicated HIV nurse and a clinical pharmacist from the co-located pharmacy [6]. Oral DAA regimens became available to patients in routine care (ie, outside clinical trials) in late 2014. Maryland Medicaid imposed restrictions on DAA access for PWH who used substances until 2016 and restriction based on fibrosis stage until 2018 [7].

Study Sample

The Johns Hopkins HIV Clinical cohort has previously been described [8]. Briefly, data include demographics collected at enrollment into care, and clinical and laboratory data abstracted from the electronic medical record (EMR). Some cohort participants contribute biological specimens to a repository for supplemental research projects. For this analysis, our study sample was all PWH in the cohort who were in care (defined as attending at least 1 HIV primary care visit) in at least 1 calendar year from 2009 to 2021. Participants were included in the study sample for calendar years in which they attended at least 1 HIV care visit. This resulted in a study sample of 3755 PWH. The Institutional Review Board of the Johns Hopkins University School of Medicine approved the research study.

Outcome

Our outcome was HCV viremia, defined as HCV RNA >43 IU/mL (selected for concordance with the limit of detection for pre-DAA era clinical HCV RNA test results) using the last available HCV RNA test result in each given year. Because patients do not get an HCV RNA test every year, we made the following assumptions about HCV viremia values when they were not available: first, patients with a negative HCV antibody test in a year or no HCV test ever were assumed to not have HCV viremia. Second, if patients did not have an HCV test result for earlier study years, HCV viremia status was assigned to earlier years based on the first-available HCV test result (this affected <3% of observations). Third, because we assumed that HCV infections were chronic and unlikely to spontaneously clear, we carried-forward HCV viremia status for years with no updated HCV viremia laboratory test until evaluation for HCV treatment. To validate our assumptions, we performed additional HCV RNA testing on a random sample of stored research samples.

Covariates

Patient self-reported birth sex, birth year, race, ethnicity, and probable route(s) of HIV acquisition (defined as heterosexual sex, injection drug use [IDU], and being a man who has sex with men [MSM]) at enrollment is recorded in the EMR. Years in care was calculated based on time between patients’ date of enrollment into the cohort and the start of each study year. We characterized patients based on their most recent CD4 cell count from the study year or the year prior, and on their most recent HIV load from the 2 years prior to the study year; viral loads above 400 copies/mL and missing viral loads were classified as unsuppressed. The proportion of missed visits in the prior year was calculated as the number of HIV primary care visits that were missed without rescheduling or cancelling divided by the number of scheduled visits. We included an indicator for having a high proportion of missed visits if ≥50% of visits were missed. Recent cocaine, nonprescribed opioid, or hazardous alcohol use was determined through review of the EMR for clinical diagnoses, problem lists, progress notes, and toxicology screening by trained abstractors every consecutive 6 months [9].

Statistical Analysis

We characterized the study population in each year with respect to sociodemographic and biomedical characteristics, and according to the prevalence of HCV viremia based on clinical test results, results of HCV RNA testing of stored research samples, and using a measurement error correction called multiple imputation for measurement error (MIME) [10]. (Additional details are available in the Supplementary Material.) We also fit logistic regression models on the study samples from 2009 and 2021 to assess factors associated with HCV viremia in the pre-DAA (2009) and DAA era (2021) time periods and tested whether the associations between covariates and HCV viremia changed between the 2 periods.

RESULTS

There were 3755 PWH who contributed a median of 6 (interquartile range [IQR], 3–11) years of follow-up time, comprising a total of 24 795 person-years. From 2009 to 2021, the number of patients in care in the clinic in any 1 year ranged from 1656 (2013) to 2127 (2017). Across the study period, 63%–65% were male, 75%–77% were black, 53%–56% reported heterosexual sex as a likely route of HIV acquisition, 9%–13% had recent cocaine use, 5%–9% had recent nonprescribed opioid use, 11%–14% had recent hazardous alcohol use, and median age increased from 47 years in 2009 to 57 years in 2021. (Supplementary Table 1).

Based on clinical samples, the proportion of the cohort who were classified as having HCV viremia per year was 25%–29% in 2009–2014 and dropped in subsequent years to 16% in 2015, 9% in 2016, 7% in 2017, and 3% in 2021 (n = 50 of 1925 people had HCV viremia). After correcting for possible measurement error using MIME, the prevalence of HCV viremia in the cohort was estimated to have decreased by 94%, from 36% (95% confidence interval [CI], 27%–46%) in 2009 to 2% (95% CI, 0%–4%) in 2021 (Figure 1).

Figure 1.

Estimated proportion of each study population (all people with HIV in care or subset who ever tested HCV antibody positive) who had HCV viremia each year in the cohort with pointwise 95% confidence intervals, 2009–2021. Abbreviations: HCV, hepatitis C virus; PWH, people with human immunodeficiency virus.

There were 1153 people who ever tested HCV antibody positive, contributing a median of 6 (IQR, 3–11) years of follow-up. This subsample had a higher proportion of men, older patients, black patients, people who likely acquired HIV through IDU, and patients with recent alcohol and substance use (Supplementary Table 2). After correcting for possible measurement error, the prevalence of HCV viremia in this subcohort was estimated to have decreased by 92%, from 76% (95% CI, 69%–83%) in 2009 to 6% (95% CI, 1%–11%) in 2021 (Supplementary Table 2 and Figure 1).

When comparing correlates of HCV viremia in the pre-DAA (2009) and DAA eras (2021), history of IDU was the strongest correlate in both periods (odds ratio [OR], 17.1; 95% CI, 6.83–42.9 in 2009 and OR, 23.9; 95% CI, 9.63–59.3 in 2021). Comparing the pre-DAA to the DAA era, male sex was associated with HCV viremia (OR, 2.31; 95% CI, 1.00–5.31) in 2009 whereas in 2021 it was not (OR, 0.71; 95% CI, .37–1.35; P for interaction = .02; Table 1). In 2009, black patients had 2.50 times the odds of HCV viremia (95% CI, 1.28–4.90) compared to non-black patients, whereas in 2021, black race was not associated with HCV viremia (OR, 0.94; 95% CI, .42–2.13). Likewise, in 2009, a 5-year increase in age was associated with a 28% higher odds of HCV viremia (OR, 1.28; 95% CI, 1.11–1.49), whereas in 2021, age was not associated with HCV viremia (OR, 1.06; 95% CI, .88–1.26).

Table 1.

Correlates of HCV Viremia in the Pre-DAA (2009) and DAA (2021) Eras Among People With HIV Who Attended ≥1 HIV Primary Care Visit in Each Year

	Patients Categorized as HCV Viremic		Odds Ratios for HCV Viremia (95% CI)
	2009	2021	2009	2021	P a
No.	499	50
Male	350 (70)	30 (60)	2.31 (1.00–5.31)	0.71 (.37–1.35)	.02
Age, years (OR per 5 y)	50 (46–55)	59 (53–65)	1.28 (1.11–1.49)	1.06 (.88–1.26)	.08
Black race	428 (86)	42 (84)	2.50 (1.28–4.90)	0.94 (.42–2.13)	.06
HIV infection risk factor
MSM	54 (11)	4 (8)	…	…	…
IDU	370 (74)	42 (84)	17.1 (6.83–42.9)	23.9 (9.63–59.3)	.60
Heterosexual	264 (53)	25 (50)	0.80 (.41–1.56)	1.00 (.55–1.80)	.62
On ART	455 (91)	50 (100)	…	…	…
Years in HIV care	6 (2–9)	14 (11–19)	1.00 (.90–1.11)	0.96 (.93–1.00)	.48
Prior year, missed ≥50% visit	146 (29)	10 (20)	1.61 (.56–4.66)	0.83 (.39–1.77)	.32
HIV RNA <400 copies/mL	308 (62)	40 (80)	1.06 (.56–1.99)	0.47 (.21–1.03)	.11
Recent substance use
Cocaine	95 (19)	12 (24)	1.78 (.59–5.35)	1.62 (.65–4.05)	.88
Nonprescribed opioids	71 (14)	7 (14)	1.16 (.42–3.25)	0.80 (.29–2.19)	.60
Hazardous alcohol	66 (13)	8 (16)	2.47 (1.06–5.78)	1.77 (.73–4.27)	.60

Data are in columns 1 and 2 are row (%) excepted when indicated with * presented as median (IQR).

Statistically significant values are highlighted in bold.

Abbreviations: ART, antiretroviral therapy; CI, confidence interval; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, injection drug use; MSM, men who have sex with men; OD, odds ratio.

^a P for test of the null hypothesis that OR in 2009 and in 2021 are the same.

DISCUSSION

In this large urban cohort of PWH, we demonstrate significant reduction in HCV viremia prevalence from 36% in 2009% to 2% in 2021. Importantly, the prevalence among anti-HCV–positive PWH declined from 92% to 6%, revealing the impact of HCV DAA treatment. In contrast to the pre-DAA era, as of 2021, there are no differences in HCV viremia prevalence by sex, age, or race. These data demonstrate the potential of highly effective oral DAA in improving individual-level health through elimination of viremia and advancing HCV equity across groups. HCV elimination efforts in this cohort of PWH have benefited from the infrastructural support provided by the Ryan White HIV/AIDS Program, which has prioritized addressing HCV infection as a major comorbidity among PWH thus providing resources in Ryan White funded clinics like ours to support testing and treatment for HCV [11].

However, these findings are in contrast to the larger group of people with HCV infection in the United States, where disparities persist. Specifically, according to the Centers for Disease Control (CDC) in 2021, there were higher HCV infection rates among people 20–39 years old and among men compared to women [12]. Racial inequities in access to HCV treatment exist, particularly among Medicaid recipients with lower treatment rates observed in black Americans and American Indians/Alaskan natives compared to non-Hispanic whites [13]. These inequities in curative treatment are reflected in persistent inequities in HCV-related death with a mortality rate 3.4 times for American Indians/Alaskan natives and 1.7 times for blacks compared to non-Hispanic whites [12].

Our data also demonstrate persistent disparity in HCV outcomes for PWH who use drugs. In both the pre-DAA and DAA era, history of IDU was the strongest corelate of HCV viremia. There are several factors, including injection drug use as the strongest risk factor for HCV infection acquisition and lower rates of HCV treatment uptake among people who use drugs including in this cohort that could contribute to our finding of higher HCV viremia in people who use drugs in the DAA era [14, 15]. Another factor contributing to higher burden of active HCV infection among people who inject drugs (PWID) in our cohort could be reinfection.

Our study has several strengths, including a description of factors associated with HCV viremia over several years spanning the pre-DAA and DAA era in a large cohort of PWH with HCV RNA results extracted from routine clinical testing and the availability of nonclinical samples to validate assumptions on HCV RNA status. Our study is, however, limited by utilizing data from a single clinical site. We also anticipate higher rates of mortality among PWID, which may have contributed to reduction in HCV viremia prevalence in the cohort. The substantial reduction in HCV viremia among PWH who are HCV antibody positive, however, strongly suggests HCV treatment as a major driver in the reduction of HCV viremia prevalence.

Overall, we observed a 94% reduction in HCV prevalence in our predominantly minority cohort of PWH to a viremia prevalence of 2%; similar to that in the general US population. These data provide support for HCV elimination programs that provide access to DAAs and government-funded comprehensive care programs such as those funded by the Ryan White Act in the United States. However, PWH who use drugs remain at increased odds of HCV viremia. Targeted efforts are needed to meet the HCV prevention and treatment needs of people who use drugs.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all Supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Notes

Author contributions. O. F. N. contributed conceptualization and writing the original draft. C. L. contributed conceptualization, formal analysis, and writing. A. F. and J. K. performed acquisition of data, and reviewing and editing the manuscript. R. M. and G. C. contributed acquisition of data, funding acquisition, and reviewing and editing the manuscript. C. S., S. M., D. T., and M. S. contributed conceptualization, and reviewing and editing the manuscript.

Financial support. This work was supported by the National Institutes of Health (grant numbers K01 AA028193, U01 DA036935, K24DA034621, K08MH118094, R01MD018539, and K24 AA027483).

Data and code availability. Data and code are available upon request.