Abstract
Background:
HIV/HCV co-infection predisposes to accelerated liver damage and increased both liver-related and unrelated morbidity and mortality in patients with HIV infection.Objectives:
The aim of this study was to evaluate the prevalence of HCV infection, seropositivity, risk factors and genotype distribution among treated HIV positive patients. Furthermore, the occurrence and causes of deaths were analyzed.Patients and Methods:
Adult HIV-1 infected patients, with at least one antiHCV result, treated in one of Polish HIV/AIDS reference centers, participated in this cross-sectional study.Results:
Four hundred and fifty seven patients with a median age of 38 years (ranged 23 - 72), and predominantly male (76.6%) were enrolled in the study. Anti-HCV antibodies were detected in 325 individuals (71.1%). HCV RNA was detected in 207 of the 233 patients tested (88%). The HCV genotype analysis (n = 193) demonstrated almost equal distribution with slight genotype 1 domination as 37.3%, mainly 1b, followed by genotypes 3 as 32.1% and 4 as 30.6%. No association was found between HCV genotype and route of HIV acquisition. In univariate analysis, higher HCV seropositivity was related to male sex, intravenous drug use (IDU), mode of HIV transmission, history of drug and alcohol abuse and imprisonment. In multivariate analysis, only being injection drug user (P = 0.0001), imprisonment (P = 0.310) and younger age at the HIV diagnosis per each year (P = 0.025) were identified as risk factors for HCV infection. Sixty three deaths were reported; no association was found between HCV seropositivity and death prevalence.Conclusions:
HIV/HCV co-infection is an important medical problem in North-Eastern Poland. A history of incarceration and younger age at HIV diagnosis were additional to IDU risk factors for HCV seropositivity in this cohort.Keywords
Human Immunodeficiency Virus Hepatitis C Virus Prevalence Genotypes Poland
1. Background
Highly active antiretroviral treatment (HAART) has resulted in a shift in the causes of morbidity and mortality to non-HIV related causes (1, 2). Liver disease is now a leading cause of death in patients with HIV (PLHIV, people living with HIV), mainly due to chronic hepatitis C (2-4). The prevalence and incidence of both human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) have increased in Poland in the recent years (5-10). There were 18646 officially registered HIV cases between 1985 and 31st December 2014 (11). HCV infection incidence was 5.58 per 100,000 in 2011, with a marked increase in deaths reported in 2011 (9). Shared transmission routes are responsible for the high rate of co-infection, increasing both the complexity of disease management and the public health burden (3).
The prevalence of HIV/HCV coinfection varies greatly across the world, from as low as 0.9% in Istambul, Turkey up to above 90% in Russia, Bielarus, Ukraine, Latvia, Estonia (12, 13). Polish data regarding HIV/HCV coinfection prevalence and genotype distribution are scarce and fragmentary (14-17). No studies are available regarding the risk factors of HCV infection among people living with HIV (PLHIV).
2. Objectives
The aim of this study was to analyze the prevalence of HCV infection based on anti-HCV serology and HCV-RNA and HCV genotype distribution in a group of PLHIV from one of the Polish HIV/AIDS reference centers located in north-eastern Poland. Risk factors associated with HCV infection and causes of death in our cohort were also studied.
3. Patients and Methods
Study participants were recruited from adult, HIV-1 infected patients, treated in HIV/AIDS outpatient clinic of medical university teaching hospital in Bialystok, north-eastern Poland, (Table 1) one of 17 HIV/AIDS reference centers in the country. A total of 836 patients were eligible for the study and 457 were enrolled. The main inclusion criterion was at least one anti-HCV test result available. No exclusion criteria were applied. Prospective data collection was started from 2008 for all patients on initial attendance and retrospectively for those who had their first visit prior to 2008 and was conducted until the end of December 2013. The collected clinical and epidemiological parameters included age, gender, ethnicity, duration of HIV infection, mode of HIV transmission [sexual: hetero- or homosexual, injecting drug use (IDU), mixed-sexual and IDU or unknown], history of incarceration, mental disorders and alcohol abuse, HBs seropositivity, date and cause of death. All patients were Caucasian. No data regarding the length and numbers of incarcerations were analyzed. The nadir CD4 T lymphocyte count, measured by flow cytometry, was collected. The study was approved by Medical University of Bialystok ethical committee.
| Variables | Study Group | HIV/HCV Coinfection | HIV Monoinfection | P Value |
|---|---|---|---|---|
| Number of patients | 457 | 325 (71.1) | 132 (29.9) | |
| Age, y | 38.0 (23 - 72) | 37.0 (23 - 57) | 41.0 (23 - 72) | 0.04 |
| Gender, male | 350 (76.6) | 264 (81.2) | 86 (65.1) | 0.0002 |
| Age at HIV diagnosis, y | 29.1 (14 - 64) | 26.0 (14 - 51) | 33.5 (17 - 64) | < 0.0001 |
| Length of HIV infection, y | 10 (0 - 26) | 11.3 (1 - 26) | 7.0 (0 - 21) | < 0.0001 |
| Nadir CD4, cells/µL | 199 (4 - 1176) | 199 (4 -1174) | 199.5 (4 - 886) | 0.2826 |
3.1. Serological Analysis
Anti-HCV antibodies and HBs antigen were measured at the baseline evaluation of all HIV positive individuals with commercial serological assays (Architect, Abbott).
3.2. Molecular Tests
HCV-RNA was analyzed using RT PCR. Cobas Ampli Prep and Cobas Taqman (Roche Diagnostics) were used with lowest detection limit of 11 IU/mL. HCV genotypes were determined using Versant HCV (Bayer Diagn, Germany).
3.3. Deaths Analysis
The analysis of deaths was based on clinical and autopsy data, where available. Information for patients who died in our center is complete. Where patients died at home or at other medical institutions, their family was contacted and asked to provide all the available data regarding patient’s death.
3.4. Statistical Methods
The data was analyzed with Statistica PL software (Statsoft, USA), using Mann-Whitney, Fisher and chi2 tests. In the multivariate model, the following factors were included; age at first positive HIV Western Blot, heterosexual route of HIV transmission, HBs seropositivity, history of incarceration, injecting drug use, alcohol misuse and psychiatric disorders.
5. Discussion
Four hundred and fifty seven patients, with a median age of 38 years [range 23 - 72], predominantly males, 76.6% were studied. Anti-HCV antibodies were detected in most, 325/457 (71.1%). The highest seroprevalence was found in the 30 - 40 year old group as 81%. Our study group can be considered as an example of an "old" HIV cohort with IDU as the predominant means of HIV acquisition, 264/457 (57.8%). However, the proportion of MSM among new HIV diagnoses increases each year, both in our center and the country as a whole, Table 3 (18). The 71.1% anti-HCV seropositivity detected in our cohort is very high. The EuroSIDA cohort study reported an average 33% HCV seropositivity across Europe with significant regional variations (13). The highest prevalence was detected in eastern and southern Europe, where co-infection rates were about 50%. The highest and less variable seroprevalence was seen among IDUs from all participating countries, reaching 70 - 100% (Table 4). A recent Turkish study confirmed that HCV seropositivity was strongly related to IDU (12). This observation is in line with our analysis, which revealed IDU as a risk factor for HCV seropositivity.
HCV seropositivity Among PLHIV in Selected Central and Eastern European Countries, According to (13, 19) a
| Country | Patients of Known HCV Serostatus | IDUs of Known HCV Serostatus | HCV-Seropositive Patients Who Acquired HIV via Injection Drug use, % | ||
|---|---|---|---|---|---|
| Total, No. | HCV Seropositive, % | Total No. | HCV Seropositive, % | ||
| Poland b | 484 | 61.2 | 255 | 96.1 | 82.8 |
| Belarus b | 47 | 70.2 | 31 | 96.8 | 90.9 |
| Lithuania b | 80 | 51.3 | 39 | 94.9 | 90.2 |
| Russia b | 93 | 25.8 | 17 | 100.0 | 70.8 |
| Ukraine b | 122 | 71.3 | 82 | 97.6 | 92.0 |
| Latvia b | 93 | 66.7 | 64 | 87.5 | 90.3 |
| Estonia b | 80 | 56.3 | 38 | 94.7 | 80.0 |
| Moldova | 448 | 50.7 | - | - | - |
Since 2000 the sexual transmission of HCV between MSM has been of increasing concern (20-22). Epidemics of acute hepatitis C infections and multiple re-infections have been reported (20-23). We did not diagnose any acute hepatitis C among the study patients; however, the study design was cross-sectional and HCV incidence data is not available. Cases of acute hepatitis C in HIV positive MSM have recently been found in Warsaw, the capital and Krakow [unpublished, personal communications -Dr. E. Firląg-Burkacka, Dr. M. Bociaga-Jasik].
A recent analysis of 14651 HCV genotypes in the general population in Poland between 2003 - 2012 revealed a predominance of GT1 as 79.4%, followed by GT3 as 13.8% and GT4 as 4.9% (14). Locally in north-eastern Poland, the proportion of GT3 and GT4 were significantly higher as 23% and 8.6%, respectively (14). However, the proportions of GT3 and GT4 were even higher in earlier analysis, conducted between 2002 and 2006, reaching 34.1% and 15.5%, respectively (15, 24). HCV G3 was the major genotype seen among Polish prisoners (16). International EuroSIDA analysis, comprising eastern European countries, including Poland also reported higher proportions of HCV GT3 as 40%, GT4 19% and GT1 as 40% (25). The percentage of patients with replicating HCV in our study was higher than that seen in the EuroSIDA survey as 88.8% versus 77% (25).
Our study identified a history of imprisonment as an independent risk factor for HCV infection among PLHIV, consistent with an earlier study of IDUs in the community (26). The dynamics of blood borne infections, HBV, HCV and HIV, the history of illicit drug use and imprisonment are closely intertwined. Several European studies reported higher HIV and HCV prevalence and incidence in prisons (26-30). Polish data are summarized in Table 4. A cross-sectional study in French prison inmates showed 2.9% HIV and 4.8% HCV prevalence, which was six times higher than the general population, with 2.5% of inmates having viremic hepatitis C (27). In Spain, among 2377 prisoners, 117 HCV seroconversions were detected, giving an incidence of 1.17/100 patient/years (29, 30). The incidence was higher among cases with HIV co-infection (8.34/100 patient/years (py)) and IDUs without methadone replacement treatment during follow-up (6.66/100 py) (29). All potential routes of HCV transmission can occur in prison such as sharing of contaminated injection equipment, unsafe sexual contacts, unsafe skin penetrations (piercing, tattooing, sharing razors and blood-sharing rituals); however, this period of obligatory isolation may provide conditions for optimal adherence during chronic hepatitis C treatment.
Recent studies indicated that the prevalence and total number of patients with anti-HCV has increased from 2.3% (95% uncertainty interval [UI]: 2.1% - 2.5%) to 2.8% (95% UI: 2.6% - 3.1%) and from more than 122 million to more than 185 million between 1990 and 2005 (31, 32). In the general population in Poland, HCV antibodies were detected in 1.9% of over 26000 adults; HCV-RNA was detectable in 31% of seropositive individuals (33).
Our study results showed a decrease in HCV prevalence in HIV infected individuals from 85.2% to 53.2% in those diagnosed before 2005 compared to those diagnosed in 2005 or later. This is in line with other European observations (17, 34, 35). In the Swiss HIV cohort, HCV incidence has decreased among IDUs, remained stable amongst heterosexuals and increased 18 fold in MSM between 1998 and 2011. In MSM, a history of inconsistent condom use and a history of syphilis predicted HCV seroconversion (33). Similar observations were made in the French national survey, demonstrating a decrease in the overall prevalence of HIV-HCV co-infection from 22 - 24% to 16 - 18%. This prevalence decreased from 93% to 87% among injecting drug users, while it increased from 4% to 6% among MSM during 2003 - 2012 (34).
We did not observe any difference of mortality rate between HCV seropositive and seronegative patients. However, the total number of deaths recorded was 63 and in 13 the cause of death was not determined. Data shows that HCV serostatus does not affect HIV1 disease progression; however, liver related deaths are more frequent among co-infected patients (13, 36). Besides the accelerated progression of liver damage caused by HCV replication in HIV infected individuals, HCV increases liver-related mortality and risk of renal insufficiency in HIV infected individuals (19, 37, 38).
Study limitations include its cross-sectional design and single center data analysis. However, our results complement the scarce information currently reported on the Eastern Europe HIV/HCV epidemics. In conclusion, HIV/HCV co-infection is an important medical problem in North-Eastern Poland, requiring relevant attention and curative and preventive measures.
Acknowledgements
References
-
1.
Weber R, Ruppik M, Rickenbach M, Spoerri A, Furrer H, Battegay M, et al. Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med. 2013;14(4):195-207. [PubMed ID: 22998068]. https://doi.org/10.1111/j.1468-1293.2012.01051.x.
-
2.
van der Helm J, Geskus R, Sabin C, Meyer L, Del Amo J, Chene G, et al. Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997. Gastroenterology. 2013;144(4):751-760 e2. [PubMed ID: 23266560]. https://doi.org/10.1053/j.gastro.2012.12.026.
-
3.
Rockstroh JK, Peters L, Grint D, Soriano V, Reiss P, Monforte A, et al. Does hepatitis C viremia or genotype predict the risk of mortality in individuals co-infected with HIV? J Hepatol. 2013;59(2):213-20. [PubMed ID: 23583272]. https://doi.org/10.1016/j.jhep.2013.04.005.
-
4.
Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166(15):1632-41. [PubMed ID: 16908797]. https://doi.org/10.1001/archinte.166.15.1632.
-
5.
Niedzwiedzka-Stadnik M, Rosinska M. [HIV and AIDS in Poland in 2010]. Przegl Epidemiol. 2012;66(2):315-23. [PubMed ID: 23101224].
-
6.
Niedzwiedzka-Stadnik M, Rosinska M. HIV and AIDS in Poland in 2011. Przegl Epidemiol. 2013;67(2):267-72. [PubMed ID: 24040731].
-
7.
Rosinska M, Zielinski A. Recent increase in HIV rate by age, cohort, period analysis of surveillance data suggests changes in HIV epidemiology in Poland. Cent Eur J Public Health. 2011;19(3):123-7. [PubMed ID: 22026282].
-
8.
Rosinska M, Radziszewski F, Stepien M. [Hepatitis C in Poland in 2010]. Przegl Epidemiol. 2012;66(2):287-92. [PubMed ID: 23101218].
-
9.
Rosinska M, Parda N, Stepien M. Hepatitis C in Poland in 2011. Przegl Epidemiol. 2013;67(2):247-51. [PubMed ID: 24040726].
-
10.
Cornberg M, Razavi HA, Alberti A, Bernasconi E, Buti M, Cooper C, et al. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int. 2011;31 Suppl 2:30-60. [PubMed ID: 21651702]. https://doi.org/10.1111/j.1478-3231.2011.02539.x.
-
11.
HIV infections in Poland. Epidemiological reports. Available from: http://www.pzh.gov.pl/page.
-
12.
Aydin OA, Yemisen M, Karaosmanoglu HK, Sargin F, Gunduz A, Ceylan B, et al. Low Prevalence of Hepatitis C Virus Infection Among HIV-Positive Patients: Data From a Large-Scale Cohort Study in Istanbul, Turkey. Hepat Mon. 2014;14(8). ee18128. [PubMed ID: 25337142]. https://doi.org/10.5812/hepatmon.18128.
-
13.
Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis. 2005;192(6):992-1002. [PubMed ID: 16107951]. https://doi.org/10.1086/432762.
-
14.
Panasiuk A, Flisiak R, Mozer-Lisewska I, Adamek A, Tyczyno M, Halota W, et al. Distribution of HCV genotypes in Poland. Przegl Epidemiol. 2013;67(1):11-6. [PubMed ID: 23745369].
-
15.
Chlabicz S, Flisiak R, Lapinski TW, Kowalczuk O, Wiercinska-Drapalo A, Pytel-Krolczuk B, et al. Epidemiological features of patients infected with HCV genotype 4 in Poland: Epidemiology of HCV genotype 4 in Poland. Hepat Mon. 2011;11(3):191-4. [PubMed ID: 22087142].
-
16.
Tyczyno M, Halota W, Nowak W, Pawlowska M. Distribution of HCV genotypes in the populations of inmates in polish prison potulice and patients hospitalised in bydgoszcz. Hepat Mon. 2014;14(5). ee14559. [PubMed ID: 24910703]. https://doi.org/10.5812/hepatmon.14559.
-
17.
Grabczewska, E, Pawłowska, M, Halota, W. Epidemiological aspects of HCV/HIV co-infections. HIV AIDS Rev. 2003;2/3(4):123-6.
-
18.
Niedzwiedzka-Stadnik M, Pielacha M, Rosinska M. HIV and AIDS in Poland in 2012. Przegl Epidemiol. 2014;68(2):283-9. [PubMed ID: 25135516].
-
19.
Peters L, Grint D, Lundgren JD, Rockstroh JK, Soriano V, Reiss P, et al. Hepatitis C virus viremia increases the incidence of chronic kidney disease in HIV-infected patients. AIDS. 2012;26(15):1917-26. [PubMed ID: 22781222]. https://doi.org/10.1097/QAD.0b013e3283574e71.
-
20.
Urbanus AT, Van De Laar TJ, Geskus R, Vanhommerig JW, Van Rooijen MS, Schinkel J, et al. Trends in hepatitis C virus infections among MSM attending a sexually transmitted infection clinic; 1995-2010. AIDS. 2014;28(5):781-90. [PubMed ID: 24832014]. https://doi.org/10.1097/QAD.0000000000000126.
-
21.
Orsetti E, Staffolani S, Gesuita R, De Iaco G, Marchionni E, Brescini L, et al. Changing characteristics and risk factors of patients with and without incident HCV infection among HIV-infected individuals. Infection. 2013;41(5):987-90. [PubMed ID: 23703287]. https://doi.org/10.1007/s15010-013-0465-4.
-
22.
van de Laar T, Pybus O, Bruisten S, Brown D, Nelson M, Bhagani S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology. 2009;136(5):1609-17. [PubMed ID: 19422083].
-
23.
Ishikane M, Watanabe K, Tsukada K, Nozaki Y, Yanase M, Igari T, et al. Acute hepatitis C in HIV-1 infected Japanese Cohort: single center retrospective cohort study. PLoS One. 2014;9(6). ee100517. [PubMed ID: 24945812]. https://doi.org/10.1371/journal.pone.0100517.
-
24.
Chlabicz S, Bonifatiuk I, Radziwon P. Prevalence of hepatitis C virus antibodies among blood donors in north-eastern Poland. Hepatol Res. 2005;33(3):206-10. [PubMed ID: 16266823]. https://doi.org/10.1016/j.hepres.2005.09.001.
-
25.
Soriano V, Mocroft A, Rockstroh J, Ledergerber B, Knysz B, Chaplinskas S, et al. Spontaneous viral clearance, viral load, and genotype distribution of hepatitis C virus (HCV) in HIV-infected patients with anti-HCV antibodies in Europe. J Infect Dis. 2008;198(9):1337-44. [PubMed ID: 18767985]. https://doi.org/10.1086/592171.
-
26.
Arain A, Robaeys G, Stover H. Hepatitis C in European prisons: a call for an evidence-informed response. BMC Infect Dis. 2014;14 Suppl 6:S17. [PubMed ID: 25252822]. https://doi.org/10.1186/1471-2334-14-S6-S17.
-
27.
Semaille C, Le Strat Y, Chiron E, Chemlal K, Valantin MA, Serre P, et al. Prevalence of human immunodeficiency virus and hepatitis C virus among French prison inmates in 2010: a challenge for public health policy. Euro Surveill. 2013;18(28). [PubMed ID: 23870097].
-
28.
Saiz de la Hoya P, Marco A, Garcia-Guerrero J, Rivera A, Prevalhep study G. Hepatitis C and B prevalence in Spanish prisons. Eur J Clin Microbiol Infect Dis. 2011;30(7):857-62. [PubMed ID: 21274586]. https://doi.org/10.1007/s10096-011-1166-5.
-
29.
Marco A, Gallego C, Cayla JA. Incidence of hepatitis C infection among prisoners by routine laboratory values during a 20-year period. PLoS One. 2014;9(2). ee90560. [PubMed ID: 24587394]. https://doi.org/10.1371/journal.pone.0090560.
-
30.
Treso B, Barcsay E, Tarjan A, Horvath G, Dencs A, Hettmann A, et al. Prevalence and correlates of HCV, HVB, and HIV infection among prison inmates and staff, Hungary. J Urban Health. 2012;89(1):108-16. [PubMed ID: 22143408]. https://doi.org/10.1007/s11524-011-9626-x.
-
31.
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-42. [PubMed ID: 23172780]. https://doi.org/10.1002/hep.26141.
-
32.
Martinez-Rebollar M, Mallolas J, Perez I, Gonzalez-Cordon A, Lonca M, Torres B, et al. [Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients]. Enferm Infecc Microbiol Clin. 2015;33(1):3-8. [PubMed ID: 25124489]. https://doi.org/10.1016/j.eimc.2014.05.013.
-
33.
Flisiak R, Halota W, Horban A, Juszczyk J, Pawlowska M, Simon K. Prevalence and risk factors of HCV infection in Poland. Eur J Gastroenterol Hepatol. 2011;23(12):1213-7. [PubMed ID: 22002000]. https://doi.org/10.1097/MEG.0b013e32834d173c.
-
34.
Wandeler G, Gsponer T, Bregenzer A, Gunthard HF, Clerc O, Calmy A, et al. Hepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic. Clin Infect Dis. 2012;55(10):1408-16. [PubMed ID: 22893583]. https://doi.org/10.1093/cid/cis694.
-
35.
Cacoub P, Dabis F, Costagliola D, Almeida K, Lert F, Piroth L, et al. Burden of HIV and hepatitis C co-infection: the changing epidemiology of hepatitis C in HIV-infected patients in France. Liver Int. 2015;35(1):65-70. [PubMed ID: 25040895]. https://doi.org/10.1111/liv.12639.
-
36.
Guriev V, Spinu C, Sajen O, Spinu I, Popovici S. Viral hepatitis B, C and HIV coinfection: Evaluation of some immunological and epidemiological aspects. HIV & AIDS Review. 2014;13(2):46-9. https://doi.org/10.1016/j.hivar.2014.01.002.
-
37.
Berenguer J, Alejos B, Hernando V, Viciana P, Salavert M, Santos I, et al. Trends in mortality according to hepatitis C virus serostatus in the era of combination antiretroviral therapy. AIDS. 2012;26(17):2241-6. [PubMed ID: 22781223]. https://doi.org/10.1097/QAD.0b013e3283574e94.
-
38.
Hernando V, Alejos B, Monge S, Berenguer J, Anta L, Vinuesa D, et al. All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997-2010. BMC Infect Dis. 2013;13:382. [PubMed ID: 23961924]. https://doi.org/10.1186/1471-2334-13-382.