Response to single dose hepatitis B vaccine in Congolese non-HIV hemodialysis patients: a prospective observational study

Response to single dose hepatitis B vaccine in Congolese non-HIV hemodialysis patients: a prospective observational study

Pitchou Yemasai Kengibe¹, Jean-Robert Risassy Makulo^2,3,&, Yannick Mayamba Nlandu², François Bompeka Lepira², Ernest Kiswaya Sumaili², Justine Busanga Bukabau², Charles Nlombi Mbendi¹, Steve Mundeke Ahuka⁴, Antoine Wola Tshimpi^1,5, Patrick Kisoko Ngoma¹, Nseka Nazaire Mangani², Sebastien Nsukini Mbendi¹

 

¹Division of Hepato-gastroenterology, University of Kinshasa, Kinshasa, Democratic Republic of the Congo, ²Division of Nephrology, University of Kinshasa, Kinshasa, Democratic Republic of the Congo, ³Hemodialysis Unit of Ngaliema Medical Center, Kinshasa, Democratic Republic of the Congo, ⁴Division of Microbiology, University of Kinshasa, Kinshasa, Democratic Republic of the Congo, ⁵Climy Medical Center of Hepato-gastroenterology, Kinshasa, Democratic Republic of the Congo

 

 

^&Corresponding author
Jean-Robert Risassy Makulo, Division of Nephrology, University of Kinshasa, Hemodialysis Unit of Ngaliema Medical Center, Kinshasa, Democratic Republic of the Congo

 

 

 

 

Hepatitis B virus (HBV) is relatively stable in the environment and remains viable for at least one week on environmental surfaces at room temperature; its transmission happens through per cutaneous or mucosal exposition to infected blood or body fluids [1]. It is the most causes of cirrhosis and hepatocellular carcinoma in the world [2]. The prevalence of this infection varies worldwide. Higher prevalence is encountered in low-income countries, including those of sub-Saharan Africa (SSA) where HBV infection is hyperendemic. Indeed, in the general population, more than 8% of people are hepatitis B surface antigen (HBs Ag) chronic carriers [3]. Five HBV genotypes are more frequently detected in Africa, A, B, C, D and E genotypes [4]. Patients on chronic hemodialysis are considered as a high risk group for hepatitis B infection because of many therapeutic procedures routinely used in this group increase probability of HBV infection [5]. In this regard, HBs Ag has been detected in dialysis centers on clamps, scissors, dialysis machine control knobs, and door knobs [6]. Thus, blood-contaminated surfaces that are not routinely cleaned and disinfected represent a reservoir for HBV transmission. In addition, dialysis staff members can transmit HBV to patients from contaminated surfaces by hands, gloves or through use of contaminated equipment and supplies [6]. Thus, controlling the spread of HBV infection in dialysis centers has been one of the major advances in the treatment of patients with end stage renal disease (ESRD). Nowadays, especially in developed countries, the prevalence of HBs Ag carriers on chronic dialysis has decreased significantly through preventive measures, such as routine vaccination of patients and health care workers, regular use of erythropoietin as a substitute for blood transfusions, early serological diagnosis, isolation of infected patients, and cleaning and disinfecting procedures [7]. Many protocols recommend routine HBV vaccination prior to dialysis with four doses of 40 μg each administered intramuscularly in the deltoid muscle within 0, 1, 2, and 6 months of the procedure [7-9]. However several worldwide studies have shown that one-third of chronic hemodialysis patients do not respond adequately to immunization [7, 10, 11]. The decline in immunity observed in chronic hemodialysis patients plays an important role in explaining this non-response [12]. Few studies have examined the efficacy of HBV vaccination in SSA chronic hemodialysis patients [13, 14]. Several specificities can influence the HBV vaccine response in this population. Indeed chronic kidney disease is usually detected very late, at stage requiring dialysis in emergency; in addition, patients generally have many comorbidities and present uremic syndrome that may reduce their immunity [15]. More often, patients who have to support themselves their medical care cannot afford the cost of double dose of HBV vaccine. Therefore, in DR Congo, many centers usually provide a single-dose regimen to HD patients, unless they have HIV to receive the double dose. The present study aimed to evaluate the single-dose vaccination's Protocol and identify determinants of the lack of seroconversion in chronic hemodialysis patients.

 

 

We conducted a prospective study including all consent patients who started chronic hemodialysis treatment in three centers in Kinshasa, DR Congo (Division of Nephrology, University of Kinshasa; Hemodialysis Unit of Ngaliema Medical Center, Kinshasa, and Afia Medical Center of Hemodialysis, Kinshasa) during the period from January 1^st 2014 to December 31^st 2016. Only patients who were serologically negative for HBs Ag, anti-HBs and antibody against hepatitis B core antigen (anti-HBc) were selected. The diagnosis of End stage renal disease (ESRD) and the indication of chronic hemodialysis treatment were made according to the 2012 KDIGO's recommendations [16]. The vaccines Euvax® used were administered intramuscularly to the deltoid muscle in single dose (20 μg each) at days 0, 30, 60 and 180. Patients who received a double dose of vaccine were not included in the present analyzes (HIV-infected patients and some patients infected with the hepatitis C virus). Serum was collected at day 240 to perform quantitative tests, measuring the anti-HBs titer. The endpoint was seroconversion defined as anti-HBs titer ≥ 10 IU/l (10-99 IU/l=low protective vaccine response; ≥ 100 IU/l = highly protective vaccine response) while anti-HBs titer < 10 IU/l defined the lack of seroconversion [7, 17]. Other parameters of interest studied were as follows: etiology of chronic kidney disease (CKD), co-morbidities, residual diuresis (RD), C Reactive protein (CRP), serum albumin, tobacco use, alcohol consumption, number of dialysis sessions per week and KT/V.

 

Statistical analysis: data were analyzed using SPSS software version 21. Tables or graphs were used for the presentation of results. Quantitative variables were presented as mean ± standard deviation (SD) and qualitative variables as a percentage. Comparison of proportions, medians and averages was performed using Chi-square or Fisher exact tests, Mann Whitney Wilcoxon and Student t-tests, respectively. A Logistic regression model was used to identify factors associated with the lack of anti-HBs seroconversion. A value of p <0.05 defined the threshold of statistical significance.

 

Ethical Considerations: this study has been approved by the Ethics Committee of the School of Public Health of the University of Kinshasa, referenced ESP/CE/013/2017. Patients' recruitment was done anonymously and on the basis of free and informed consent in accordance with Helsinki's recommendations.

 

 

General characteristics: all three hemodialysis centers used Fresenius generators and high flux permeability dialyzers. A total of 117 chronic hemodialysis patients were recruited, however 26 did not meet the inclusion criteria. During the study, 13 patients were deceased, 10 lost to follow-up, 8 traveled abroad and 4 patients were non-compliant to the vaccination schedule. Thus, 56 patients were included in the present analysis (73% men). Their mean age was 55.6 ± 15.1 years and 36% of them were diabetic versus 86% hypertensive.

 

The vaccine response: in the whole group, the lack of vaccine response was encountered in 18% versus 82% of patients had seroconvesion (a low protective response and a highly protective in 32% and 50%, respectively). Age, body mass index (BMI), hypertension as well as albuminemia, CRP and KT/V showed a difference between groups according to the vaccine response (Table 1, Table 2).

 

Risk factors of the lack of anti-HbS seroconversion: CRP > 6 mg/L, albuminemia < 30 g/L and KT/V < 1.2 have emerged as the main factors associated with the lack of the anti-HbS seroconversion (Table 3).

 

 

Our finding of a low HBV vaccine response is consistent with previous reports on HBV vaccine among chronic HD patients relative to the general population. Indeed, while HBV vaccination induces seroprotection in 90 to 95% of cases in the general population, immunogenicity is lower in patients with renal failure [7, 10, 11]. This weak induced immunogenicity is thought to rely upon an altered humoral and cellular immunity with subsequent decrease in the activity of immune system cells (B and T lymphocytes, monocytes, macrophages) [12, 13]. This decreased cellular activity results in reduced phagocytosis by polynuclear cells, production of interleukin-1 and interleukin-2 by macrophages and T4 lymphocytes, respectively, and production of antibodies by B lymphocytes [13]. Potential factors explaining this altered immune system activity include, among others, decreased uremic toxin clearance, nutritional deficiency and, also, immunosuppressive drugs used to treat some glomerular diseases [13, 14]. This immune dysfunction is responsible for the decline in the vaccine seroconversion rate as well as a more rapid decrease in antibody levels compared to healthy subjects [7, 10, 11].

 

The anti-HbS seroconversion rate in our series is similar to that reported by Boumansour et al. in Algeria and Feriani et al. in Morocco, who reported a seroconversion rate of 76% and 85%, respectively [18, 19]. Ibrahim et al. in Egypt reported 93% of seroconversion [20]. However Ayub et al. reported 59% of seroconversion in Brazil [21]. Studies in Europe and North America have also shown divergent results [22-24]. It is difficult to compare results of different studies because of differences in criteria of selection and methodology used. Multivariate analysis showed that several factors could influence the vaccine response in hemodialysis patients. The chronic inflammatory state, as expressed by CRP levels, had a negative influence on the vaccine response. Our findings are consistent with those of other authors who noted a decrease in CRP in patients performing dialysis with high-throughput membranes and consequently a better vaccine response compared with patients with a marked inflammatory state using low-flow membrane [25]. Chronic inflammation is associated with an immune deficiency that explains the decline in vaccine response in this population. The mechanisms responsible for this chronic inflammatory state in the dialysis, as reviewed in details by Kaysen [26], are multiple and include those secondary to CKD such as oxidative stress due to the decrease in anti-oxidative defenses and the accumulation of toxic molecules such as advanced glycation end-products [26]. Inflammatory phenomenon induced by hemodialysis treatment may be linked to the interaction between the blood and the hemodialysis membrane or to the quality of the water used for HD [26]. Schiffl et al. have shown that the use of an ultrapure dialysate reduces the average serum levels of CRP in hemodialysis patients [25].

 

Hypoalbuminemia showed a negative impact on the vaccine response to HBV. Malnutrition, with subsequent hypoalbuminemia, has a negative influence on the vaccine response. This condition is common in hemodialysis patients and can be explained by loss of appetite due to uremic waste products and toxins, intermediate metabolic abnormality and increased catabolism due to hyperparathyroidism and acidosis, loss of amino acids and glucose in dialysate and chronic inflammation [27]. KT/V <1.2 was significantly associated with lack of response. Many studies have shown association between vaccine response to HBV and the quality of dialysis expressed by KT/V [28]. In our study, age did not influence seroconversion, perhaps because of the small sample. Previous reports from the literature found a declining vaccine response with increasing age [29]. The mechanisms underlying the bad vaccine response with aging could be immunosenesis, various anatomical and physiological changes related to aging but also malnutrition and comorbidities; these abnormalities limit the capacity of host vaccine response [29]. The small sample size does not give enough power to statistical tests to identify potential associations between variables of interest. However, the present study provides some guidance and arguments for advocacy to modify the hepatitis B vaccination protocol. Inflammation, hypoalbuminemia and sub-dialysis are very common in chronic hemodialysis patients in Kinshasa; on the other hand, as these factors are associated with a poor vaccine response, it seems more logical to generalize the double dose of HVB vaccine to all patients.

 

 

Half of the patients in the study had either a lack or a low protective vaccine response. Patient-related factors and hemodialysis parameters were the main factors associated with the lack of anti-HbS seroconversion. These results highlight the need to maximize doses of vaccine in all patients.

 

 

The authors declare no competing interests.

 

 

Kengibe YP participated in protocol elaboration, data collection and analysis and revised the manuscript. Makulo JR designed the study, participated in data analysis and wrote the first draft of the manuscript. Lepira FB, Ahuka S, Tshimpi AW, Ngoma P, Mokoli VM, Nlandu YM, Bukabau JB, Sumaili EK, Mbendi SS, Nseka NM,and Mbendi CL revised the manuscript and approved the final version.

 

 

The authors thank the nurses Mbo Mpeti, Joelle Zola and Suzette Samba, Doctor Samuel Lelo, laboratory technicians Orlain Mboko and Donatien Bazebi who participated in data collection.

 

 

Table 1: clinical and biological parameters as function of the HBV vaccine response

Table 2: hemodialysis parameters as function of the HBV vaccine response

Table 3: risk factors of the lack of Anti-HbS seroconversion after single vaccine schedule

 

 

1. Lee WM. Medical Progress: Hepatitis B Virus infection: review articles. N Engl J Med. 1997; 337: 1733-1745. Google Scholar


2. Wright TL, Lau JYN. Clinical aspects of hepatitis B virus infection. Lancet. 1993 Nov 27; 342(8883): 1340-4. PubMed | Google Scholar


3. Zampino R, Boemio A, Sagnelli C. hepatitis B virus burden in developing countries. World J Gastroenterol. 2015; 21(42): 11941-11953. PubMed | Google Scholar


4. Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res. 2007; 37(s1): S9-S19. PubMed | Google Scholar


5. Kondili LA, Genovese D, Argentini C, Chionne P, Toscani P, Fabro R, Cocconi R et al. Nosocomial transmission in simultaneous outbreaks of hepatitis C and B virus infections in a haemodialysis center. Eur J Clin Microbiol Infect Dis. 2006; 25(8): 527-531. PubMed | Google Scholar


6. Burdick RA, Bragg-Gresham JL, Woods JD, Hedderwick SA, Kurokawa K, Combe C et al. Patterns of hepatitis B prevalence and Seroconversion in hemodialysis units from three continents: the DOPPS. Kidney Int. 2003; 63(6): 2222-2229. PubMed | Google Scholar


7. Peces R, De La Torre M, Alcazar R, Urra JM. Prospective analysis of the factors influencing the antibody response to hepatitis B vaccine in hemodialysis patients. Am J Kidney Dis. 1997; 29(2): 239-245. PubMed | Google Scholar


8. Grzegorzewska AE. Prophylactic vaccinations in chronic kidney disease: Current status. Hum Vaccine Immunother. 2015; 11(11): 2599-2605. PubMed | Google Scholar


9. Rangel MC, Coronado VG, Euler GL, Strikas RA. Vaccine recommendations for patients on chronic dialysis. Semin Dial. 2000;13(2):101-107. PubMed | Google Scholar


10. Sit D, Esen B, Atay AE, Kayabasi H. Is hemodialysis a reason for unresponsiveness to hepatitis B vaccine? Hepatitis B virus and dialysis therapy. World World J Hepatol. 2015 Apr 18: 7(5): 761-768. PubMed | Google Scholar


11. Tele SA, Martins RM, Lopes CL, dos Santos Carneiro MA, Souza KP et al. Immunogenicity of a recombinant hepatitis B vaccine (Euvax-B) in haemodialysis patients and staff. Eur J Epidemiol. 2001; 17(2): 145-149. PubMed | Google Scholar


12. Kara IH, Yilmaz ME, Suner A, Kadiroglu AK, Isikoglu B. The evaluation of immune responses that occur after HBV infection and HBV vaccination in hemodialysis patients. Vaccine. 2004; 22(29-30): 3963-3967. PubMed | Google Scholar


13. Igetei R, Awobusuyi JO, Wright OK, Olaleye DO. Occult Hepatitis B Virus Infection in Nigerian Patients on Hemodialysis. Trop J Nephrol. 2015; 10(2): 79- 85. Google Scholar


14. Bernieh B. Viral hepatitis in hemodialysis: An update. J Transl Intern Med. 2015; 3(3): 93-105. PubMed | Google Scholar


15. Naicker S. End-stage renal disease in sub-Saharan and South Africa. Kidney Int Suppl. 2003 Feb; 83: S119-22. PubMed | Google Scholar


16. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney IntSuppl. 2013; 3: 1-150. Google Scholar


17. Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis B antibody is protective? J Infect Dis. 1999; 179(2): 489-492. PubMed | Google Scholar


18. Boumansour N, Midoun N. Vaccination préventive contre l'hépatite virale B chez les insuffisants rénaux chroniques à Oran, Algérie. Revue d'épidémiologie et de santé publique. September 2014; 62(5): S231.


19. Feriani H, Chaker H, Habib S, Aguerbi I, Toumi S, Mnif Ket al. Vaccination intradermiquecontrel'hépatite B chez les hémodialyséschroniques. Nephrol Ther. 2015; 11(5): 327. Google Scholar


20. Ibrahim S, El-din S, Bazzal. Antibody level after Hepatitis-B vaccination in Hemodialysis Patients: Impact of Dialysis Adequacy, Chronic Inflammation, Local Endemicity and Nutritional Status. J Natl Med Assoc. 2006; 98(12):1953-7. PubMed | Google Scholar


21. Ayub MA, Bacci MR, Fonseca FLA, Chehter EZ. Hemodialysis and hepatitis B vaccination: a challenge to physicians. Int J Gen Med. 2014; 7: 109-114. PubMed | Google Scholar


22. Schiller A, Timar R, Siriopol D, Timar B, Bob F, Schiller O et al. Hepatitis B and C virus infection in the hemodialysis population from three Romanian regions. Nephron. 2015; 129(3): 202-8. PubMed | Google Scholar


23. Grzegorzewska AE. Hepatitis B Vaccination in Chronic Kidney Disease: Review of Evidence in Non-Dialyzed Patients. Hepat Mon. 2012; 12(11): e7359. PubMed | Google Scholar


24. Crosnier J, Jungers P, Courouce A, Laplanche A, Benhamou E, Degos F et al. Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in french haemodialysis units. Lancet. 1981 Apr 11; 1(8224): 797-800. PubMed | Google Scholar


25. Schiffl H, Lang S, Stratakis D, Fischer R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters. Nephrol Dial Transplant. 2001; 16(9): 1863-1869. PubMed | Google Scholar


26. Kaysen G. The microinflammatory state in uremia: Causes and potential consequences. J Am Soc Nephrol. 2001; 12(7): 1549-1557. PubMed | Google Scholar


27. Fernandez E, Betriu MA, Gomez R, Montoliu J. Response to the hepatitis B virus vaccine in hemodialysis patients: influence of malnutrition and its importance as a risk factor for morbidity and mortality. Nephrol Dial Transplant. 1996; 11(8): 1559-1563. PubMed | Google Scholar


28. Kovacic V, Sain M, Vukman V. Efficient haemodialysis improves the response to hepatitis B virus vaccination. Intervirology. 2002; 45(3):172-176. PubMed | Google Scholar


29. Jadoul M, Goubau P. Is anti-hepatitis B virus (HBV) immunization successful in elderly hemodialysis (HD) patients? Clin Nephrol. 2002; 58(4): 301-304. PubMed | Google Scholar