Incidence of Tuberculosis Among HIV/HCV Coinfected Patients Receiving Hepatitis C Treatment with Pegylated Interferon And Ribavirin In Georgia

Summary

Treatment of hepatitis C is necessary for ensuring higher life expectancy among HIV/HCV co-infected patients. However antiviral treatment for chronic HCV infection with Pegylated interferon (PEG-IFN) and Ribavirin (RBV) is associated with a variety of side effects. In Georgia up to 22% of HIV-infected patients were found to have active Tuberculosis (TB) and 22.4 to 32.6% had latent TB. The objective of our study was to describe characteristics and outcomes of TB during chronic hepatitis C treatment with PEG-IFN and RBV in Georgia.

A retrospective study was conducted among HIV/HCV coinfected patients receiving antiviral treatment for chronic HCV infection at the Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia from December 2011 to May, 2015.

A total of 420 HIV/HCV co-infected patients received HCV therapy with PEG-IFN and RBV during study period. Six of 420 patients developed TB while receiving PEG IFN + RBV therapy. These patients were on Antiretroviral treatment. Baseline HIV RNA load was <34 copies/ml and CD4⁺ cell counts >350 cells/mm³. No opportunistic infections were observed in all cases.

Three of 6 patients had a previous positive tuberculin skin test (TST) result and had completed isoniazid chemoprophylaxis several years before TB diagnosis. In 2 patients TST was not performed. Only one patient had experienced a previous episode of TB and had completed the anti-TB therapy 1 year before hepatitis C treatment. In all patients TB was diagnosed during the PEG IFN + RBV therapy. Hepatitis C treatment was immediately stopped in all patients. The incidence rate of TB was 1.4 cases per 100 person-years (95% CI=0.58-2.97).

Our study emphasizes the necessity of screening for latent TB prior to the initiation of chronic hepatitis C treatment with PEG IFN and RBV.

Highly Active Antiretroviral Treatment (HAART) revolutionized the care of HIV-infected patients and caused significant reductions in HIV-associated morbidity and mortality, including many of the opportunistic infections [1, 6, 8]. In the era of effective antiretroviral therapy (ART), chronic liver diseases has become more prevalent among HIV-infected persons and is the second most common cause of death in HIV-infected patients [2, 4, 11, 12]. Despite the use of ART, patients coinfected with HIV and hepatitis C virus (HCV) have higher rates of chronic liver disease complications (cirrhosis, hepatocellular carcinoma and liver failure) compared with patients with HCV monoinfection [18].

Successful treatment of hepatitis C is necessary for ensuring quality of life and higher life expectancy among HIV/HCV co-infected patients. However it represents a significant challenge because of multiple safety concerns, including potentially serious drug interactions with ART.

The main goal of HCV treatment is cure, defined as undetectable levels of HCV RNA 12-24 weeks after completion of therapy, also referred to as sustained virologic response (SVR). Until recently, a combination of Pegylated interferon (PEG-IFN) and Ribavirin (RBV), given for at least 24 weeks, was standard of care for chronic hepatitis C. Efficacy of this combination averaged 50-55% and was associated with clinically significant adverse reactions [19]. Hematological toxicities including leucopenia occurring during IFN therapy frequently induces a decrease of CD4⁺ cell count in HIV/HCV coinfected patients [7, 16]. Multiple studies also showed a higher risk of developing bacterial infections in HCV-infected patients receiving hepatitis C treatment with IFN [7, 14, 17, 20].

Although cellular immunodeficiency is associated with a higher incidence of various infections, Tuberculosis (TB) has rarely been reported during HCV treatment with a combination of IFN and RBV [9].

Hepatitis C is a serious health problem in Georgia. Population-based survey conducted in the capital city of Tbilisi found high – 6.7% prevalence of HCV infection in adult general population [15]. Georgia has developed strong human and technical capacity for providing high quality diagnostic and treatment services for hepatitis C. Since 2011, for the first time in Eastern Europe, all HIV/HCV co-infected patients in Georgia have access to free antiviral treatment for hepatitis C. This is the first instance in the country when specific population group receives free hepatitis C treatment in accordance with international standards.

Despite a relatively low prevalence rate, the HIV/AIDS epidemic remains a significant public health concern in Georgia. Since the detection of the first case of HIV in 1989, the rate of new HIV diagnoses in the country has been increasing steadily [4].

Georgia also belongs to high TB burden countries. Up to 22% of HIV-infected individuals were found to have active TB in Georgia [5].

Therefore, the main objective of this study was to describe the characteristics and clinical outcomes of TB in HIV/HCV coinfected patients receiving hepatitis C treatment with PEG-IFN and RBV and calculate incidence rate of TB in this cohort.

Material and Methods

A retrospective study was conducted among HIV-infected patients receiving combination therapy with PEG-IFN and RBV from December 2011 until May 2015 at the Infectious Diseases, AIDS and Clinical Immunology Research Center (IDACIRC), Tbilisi, Georgia, which is the country’s referral institution for HIV/AIDS diagnosis, treatment, and care. All acid-fast bacilli (AFB) smear microscopy and culture tests were performed at the National TB Reference Laboratory in Tbilisi, Georgia.

Medical chart data abstraction was performed to collect information on patient socio-demographic factors and medical history. Clinical characteristics measured included opportunistic infections at baseline visit, HIV stage before HCV treatment, baseline CD4⁺ cell count, baseline HIV RNA level, ART regimens, HCV genotypes, duration of HCV treatment, SVR after HCV infection treatment, Tuberculin skin test (TST) result, latent TB infection (LTBI) treatment, site of TB. The incidence of TB was defined as the number of HIV-infected patients with incident active TB per 1000 patient-years of follow-up.

Definitions of TB

The diagnosis of TB was defined as either presumptive or definitive. A diagnosis of presumptive pulmonary TB was determined by a consistent clinical picture of more than 30 days, presence of AFB mycobacteria in sputum, bronchoalveolar lavage or other sterile specimen, lack of response to standard antibiotic therapy and/or successful response to standard anti-TB treatment in one month. A diagnosis of definitive TB was determined by a consistent clinical picture and positive culture for isolation of M. Tuberculosis [10].

Results and their discussion

A total of 420 HIV/HCV coinfected patients received HCV treatment with PEG-IFN and RBV at the IDACIRC from December 2011 to May, 2015. Six of 420 patients developed TB during HCV treatment. The incidence rate of TB in the study cohort was 1.4 cases per 100 person-years (95% CI=0.58-2.97). All 6 patients were on ART and had baseline HIV RNA level below 34 copies/mL. No opportunistic infections were observed in all cases.

Three of 6 patients had a previous positive TST result and had completed Isoniazid prophylactic therapy (IPT) several years before TB diagnosis. In 2 patients TST was not performed. Only one patient had experienced a previous episode of TB and had completed anti-TB treatment one year before initiation of HCV antiviral treatment. Four patients developed TB within 12 weeks of HCV treatment. TB was diagnosed in remaining 2 patients after 24 weeks of HCV treatment. Therapy with PEG-IFN and RBV was stopped in all 6 patients who developed TB. SVR was not achieved in those two patients who developed TB after 24 weeks of HCV treatment. HIV and HCV baseline clinical and laboratory characteristics, HCV treatment and TB characteristics are summarized in table 1.

Table 1.

Socio-demographic, clinical and laboratory characteristics of HIV/HCV co-infected patients who developed TB after receiving HCV treatment with Pegylated Interferon and Ribavirin; (N=6).

	Patient
Variable	1	2	3	4	5	6
Sex	Male	Male	Female	Male	Male	Male
Age, years	38	41	37	30	40	39
HIV transmission route	IDU	IDU	Heterosexual	IDU	IDU	IDU
HIV stage before HCV treatment	II	I	II	II	I	II
HIV RNA level at baseline, copies/mL	<34	<34	<34	<34	<34	<34
CD4+ cell count at baseline, cells/mm3	431	513	356	457	516	497
HIV treatment	TDF/FTC/EFV	TDF/FTC/RTG	TDF/FTC/ LPV/RTV	TDF/FTC/EFV	ABC/3TC/EFV	TDF/FTC/EFV
HCV treatment	Pegylated IFN/RBV	Pegylated IFN/RBV	Pegylated IFN /RBV	Pegylated IFN/RBV	Pegylated IFN/RBV	Pegylated IFN/RBV
HCV genotype	3a	1b	2a/2c	1b	1b	3a
Previous history of TB	N/A	N/A	N/A	N/A	2009	N/A
Previous TST result	Positive	Positive	N/A	Positive	Not performed	Not performed
Latent TB infection treatment	6 month of Isoniazid therapy	6 month of Isoniazid therapy	No	6 month of Isoniazid therapy	No	No
HCV treatment duration at time of TB diagnosis, in weeks	8	27	4	25	7	10
Site of TB	Pulmonary	Pulmonary	Pulmonary	Pulmonary	Lymph nodes	Pulmonary
Microbiological findings	Positive TB GeneXpert assay result	Positive results of bacilloscopic examiniation and culture of sputum sample	Positive results of bacilloscopic examiniation and culture of sputum sample	Positive TB GeneXpert assay result	Positive results of bacilloscopic examiniation and culture of sputum sample	Positive result of culture of sputum sample
SVR	Not performed	No	Not performed	No	Not performed	Not performed

Note: IDU – injection drug user; HCV- hepatitis C virus; TDF-tenofovir; FTC- emtricitabine; EFV- efavirenz; RTG- raltegravir; LPV-lopinavir; RTV-ritonavir; ABC- abacavir; 3TC-lamivudine; IFN-interferon; RBV-ribavirin; NA-not available; TB-tuberculosis; TST-tuberculosis skin test; SVR- sustained Viral Response.

The present study is the first cohort study to date in Georgia, evaluating TB incidence and describing characteristics of TB among HIV/HCV coinfected patients receiving PEG-IFN and RBV combination therapy. After analyzing data on HIV/HCV coinfected patients receiving antiviral treatment for HCV infection, we can conclude that TB may complicate treatment with PEG-IFN and RBV.

In our study incidence of TB during antiviral therapy for hepatitis C was 1.4 cases per 100 person-years (95% CI=0.58-2.97). Our incidence was higher to the incidence of TB (0.7 cases per 100 person-years [95% CI=0.19-1.78]) in a cohort of HIV/HCV coinfected patients receiving IFN-based hepatitis C treatment at three outpatient HIV/AIDS clinics in Madrid, Spain[14].

The observed high incidence of TB during HCV treatment with PEG-IFN and RBV reflects the high prevalence of TB in Georgia and the increased risk of disease in immunocompromised patients.

Although our incidence of TB was lower than TB incidence in HIV-infected patients not receiving ART (4.7 cases per 100 person-years; [95% CI= 3.94–5.59]) reported in Multicentre, hospital-based cohort study of patients presenting to 10 Spanish hospitals [13].

Because of the limitations due to a small sample size, we were restricted to examine association between risk factors and incidence of TB during antiviral treatment for chronic hepatitis C.

We found that three of six patients who developed TB during PEG-IFN and RBV treatment had LTBI test result with the TST and had completed IPT. However, occurrence of TB after IPT as documented by our study has also been reported [14]. LTBI diagnosis and treatment is a key component of the WHO Three I’s Program - Isoniazid preventive treatment (IPT), intensified case finding (ICF) for active TB, and TB Infection Control (IC), which represents as one of the major public health strategies to decrease the impact of TB on HIV-infected patients [3].

Due to scarcity of data on the long-term benefits of LTBI treatment in settings with high TB prevalence, further studies are required to determine optimal strategies. As mentioned above 3 patients in our study had completed IPT several years before TB diagnosis. Therefore considering IPT among HIV/HCV coinfected patients soon after exposure to IFN-based treatment can be considered as a reasonable strategy to avoid complication of hepatitis C treatment due to TB reactivation.