Immune Exhaustion and Immune Senescence: Two Distinct Pathways for HBV Vaccine Failure During HCV and/or HIV Infection

Given the shared risk factors for transmission, co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) is quite common, and may lead to increases in morbidity and mortality. As such, HBV vaccine is recommended as the primary means to prevent HBV super-infection in HCV- and/or HIV-infected individuals. However, vaccine response (sero-conversion with a hepatitis B surface antibody titer >10 IU/L) in this setting is often blunted, with poor response rates to standard HBV vaccinations in virally infected individuals when compared with the healthy subjects. This phenomenon also occurs to other vaccines in adults, such as pneumococcal and influenza vaccines, in other immunocompromised hosts who are really at risk for opportunistic infections, such as individuals with hemodialysis, transplant, and malignancy. In this review, we summarize the underlying mechanisms involving vaccine failure in these conditions, focusing on immune exhaustion and immune senescence—two distinct signaling pathways regulating cell function and fate. We raise the possibility that blocking these negative signaling pathways might improve success rates of immunizations in the setting of chronic viral infection.     

Inadequate hepatitis B vaccination of adolescents and adults at an urban community health center.

Hepatitis B remains a major public health problem in the United States, but public vaccination policy has targeted infants rather than the high-risk adults who constitute the vast majority of patients at imminent risk of infection. The effects of this policy were studied at a community health center in Boston. Adolescents and adults who attended a community health center between January 1, 1992 and May 31, 1993 and had human immunodeficiency virus (HIV) or another sexually transmitted disease (STD)--indications for vaccination according to the Centers for Disease Control and Prevention--were identified through chart review. The vaccination rate and missed opportunities were determined. In addition, directors of Boston health centers were surveyed on hepatitis B vaccine at their clinics. Of 178 individuals with HIV or another STD and without serologic evidence of prior exposure to hepatitis B, two (1.1%) received the vaccine. There were 342 missed opportunities. Only two of 14 medical directors said their clinics routinely offered vaccine to individuals with STDs. The medical directors rated financial barriers as more important obstacles to hepatitis B vaccination than nonfinancial barriers. These results indicate that many high-risk adolescents and adults do not receive a preventive intervention that is federally recommended, potentially life saving, and cost effective. Inadequate public funding for vaccine may be a key barrier for this population.     

Response to hepatitis B vaccination in patients with liver cirrhosis

Hepatitis B vaccination is strongly recommended for all infants and children but also for adults who are at risk of HBV infection. Attempts to immunize patients with liver cirrhosis have been proven relatively ineffective, and several strategies have already been used to improve the immune response in this group. The primary aim of this review is to examine, discuss, and summarize the immunogenicity of hepatitis B vaccination in patients with liver cirrhosis. MEDLINE search identified 11 studies (n = 961). The dose of the vaccine and the schedule of the vaccination varied. The response rates to the HBV vaccination ranged from 16% to 87% among patients with cirrhosis regardless of the number and vaccine dose. In particular, patients who received the standard dose of vaccination achieved seroprotection rates ranged from 16% to 79% (mean response rate 38%) and those who received a double dose achieved relatively better seroprotection rates (range: 26%‐87%; mean response rate 53%). The overall mean response rate to the HBV vaccination was 47%. In conclusion, cirrhotic patients achieve lower seroprotection rates after the completion of HBV vaccination series. Several strategies have tried to improve the immunogenicity; however, there is a great need for additional studies to further explore (1) the immune response in relation to poor vaccination responsiveness confounding factors, (2) novel strategies to improve immunogenicity, and (3) the immune mechanism underlying the differences in response rates to HBV vaccination.     

Management of hepatitis B and C in HIV co-infected patients

Morbidity and mortality from co-morbid hepatitis B (HBV) and hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of HIV and HBV or HCV co-infected individuals is now one of the most challenging clinical management issues. Less than 10% of all HIV-infected patients show markers of chronic HBV infection. Hepatitis B in HIV co-infected patients is characterized by high levels of HBV replication and a high risk for cirrhosis. Treatment of HBV with lamivudine (3TC) remains the best treatment option at this time. Initial results of studies of adefovir or tenofovir, however, demonstrate good antiretroviral efficacy, even in patients with 3TC-resistant HBV. In Europe, it is estimated that approximately 30% of HIV-infected individuals are co-infected with HCV. HIV accelerates HCV liver disease especially when HIV-associated immune deficiency progresses. Within 10-15 years of initial HCV infection, 15-25% of patients who are co-infected with HIV develop cirrhosis compared with 2-6% of patients without HIV infection. With the introduction of pegylated interferon in combination with ribavirin, promising treatment options have become available for HIV/HCV co-infected patients leading to early virological response rates of approximately 50%. The high number of HIV/HCV and HIV/HBV co-infections, as well as the much more unfavorable course of HBV and HCV in these patients, underlines the need to establish treatment strategies for HBV and HCV in HIV co-infected individuals.     

Long-term immunogenicity after one and two doses of a monovalent MF59-adjuvanted A/H1N1 Influenza virus vaccine coadministered with the seasonal 2009-2010 nonadjuvanted Influenza virus vaccine in HIV-infected children, adolescents, and young adults in a randomized controlled trial

Few data are available on the safety and long-term immunogenicity of A/H1N1 pandemic influenza vaccines for HIV-infected pediatric patients. We performed a randomized controlled trial to evaluate the safety and long-term immunogenicity of 1 versus 2 doses of the 2009 monovalent pandemic influenza A/H1N1 MF59-adjuvanted vaccine (PV) coadministered with the seasonal 2009-2010 trivalent nonadjuvanted influenza vaccine (SV) to HIV-infected children, adolescents, and young adults. A total of 66 HIV-infected patients aged 9 to 26 years were randomized to receive one (group 1) or two (group 2) doses of PV coadministered with 1 dose of SV. The main outcome was the seroconversion rate for PV at 1 month. Secondary outcomes were the geometric mean titer ratios and the seroprotection rates at 1 month for all vaccines, seroconversion rates at 1 month for SV, and longitudinal changes of antibody titers (ABTs) at 1, 2, 6, and 12 months for all vaccines. Groups 1 and 2 had similar CD4 counts and HIV RNA levels during the study. The seroconversion rate for PV was 100% at 1 month in both groups. ABTs for PV were high during the first 6 months and declined below seroprotection levels thereafter. Longitudinal changes in ABTs were similar in groups 1 and 2 for both PV and SV. The side effects of vaccination were mild and mostly local. In HIV-infected children, adolescents, and young adults, the immune response triggered by a single dose of PV was similar to that obtained with a double dose and was associated with long-term antibody response.     

Changing hepatitis A epidemiology and the need for vaccination in Korea

Hepatitis A is a vaccine-preventable disease with 1.5 million people infected world-wide annually. Improvement in the socio-economic status and general public health measures of Asian countries over the last 20 years has led to a shift in the seroprevalence of hepatitis A in many of these countries. In Korea, like in many other developed countries, this lowered endemicity has caused an upward shift in the average age of infection, resulting in larger numbers of individuals at risk of clinically significant hepatitis A infection. Sporadic outbreaks increase the public health burden of the disease. Inactivated hepatitis A vaccines are an effective prevention measure and have been shown to be safe, efficacious and well-tolerated in Korean children. Given this changing epidemiology of the disease and the associated increase in morbidity, vaccination of young children who are not immune, as well as other high risk groups, should be recommended.     

Protective efficacy of hepatitis B vaccines in neonates

A literature search was carried out to investigate the factors that influence the protective efficacy (PE) of hepatitis B vaccines when given to neonates of hepatitis B surface antigen and e antigen positive mothers. Hepatitis B vaccines with either high or low antigen doses are very effective in preventing chronic hepatitis B infection in neonates at risk, but there is evidence that with lower dosages simultaneous use of hepatitis B immune globulin (HBIG) administration is more important than with higher dosages to elicit good protection (PE ≧ 90%). There is also a tendency for lower dosages to confer high PE less consistently, with noticeably greater numbers of chronic surface antigen carriers in neonates who received a complete vaccination course. Furthermore vaccination courses with higher vaccine dosages give high PEs, without concomitant HBIG administration at birth, provided that the first vaccine dose is given at birth and that the second dose follows within 2 months. © 1994 Wiley-Liss, Inc.     

Hepatitis B vaccination in patients with chronic hepatitis C.

The aim of the study was to evaluate the safety, immunogenicity, and possible therapeutic effect of hepatitis B vaccine in patients with chronic hepatitis C. The subjects studied included three groups: group I, 26 patients with chronic hepatitis C who were susceptible to hepatitis B virus infection; group II, 35 healthy subjects who were susceptible to both hepatitis B and hepatitis C virus infection; and group III, 30 patients with chronic hepatitis C receiving no hepatitis B vaccination as controls. Three 20 microg/dose of recombinant hepatitis B vaccines were given to subjects of groups I and II in months 0, 1, and 6. Blood samples from the subjects were collected before and 1 month after each dose of vaccination for serological testing. The subjects of groups I and II had similar antibody to hepatitis B surface antigen (anti-HBs) response rates after the first (30.8% vs. 17.1%), second (61.5% vs. 60.0%), and third (88.5% vs. 91.4%) doses of vaccination. Also, their geometric mean titers of anti-HBs did not differ much when vaccination completed in 7 months (360 vs. 581 mIU/ml). During vaccination period, patients with chronic hepatitis C demonstrated no significant change of serum cytokines and HCV RNA levels, but significantly lowered ALT levels after three doses of vaccination. Hepatitis B vaccination is safe and immunogenic in patients with chronic hepatitis C. It did not significantly affect their levels of HCV RNA, but tended to lower ALT levels.     

Immunizations in HIV-infected adults

The incidence or severity of certain vaccine-preventable diseases is higher in HIV-infected individuals. However, immune responses to vaccination may be diminished, particularly in those with severe immunosuppression. Higher doses of vaccine, more frequent boosters, or revaccination after antiretroviral therapy-induced immune reconstitution are strategies to be considered for patients in certain circumstances. In addition, some vaccines may be harmful when given to severely immunocompromised patients. The challenge for healthcare providers is assessing the safety and effectiveness of vaccines for HIV-infected patients, especially when information on vaccines has not been fully characterized in the HIV-setting. This review presents state-of-the-art knowledge about immunizations for HIV-adults. The efficacy and safety of current vaccines, their current indications in HIV-infected adults, and the strategies aimed to enhance their results are discussed.     

Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men

To study the duration of antibody persistence and protection provided by the hepatitis B vaccine, we followed 773 homosexual men for five years after completion of vaccination. Among the 635 participants in whom antibody levels above 9.9 sample ratio units (SRU) developed after vaccination, 15 percent lost antibody altogether, and in another 27 percent, antibody levels declined below 10 SRU within five years. The extent of the maximal antibody response strongly predicted the persistence of protective antibody. Hepatitis B infection occurred in 55 men; 8 of these infections were clinically important (characterized by the presence of the hepatitis B surface antigen and elevation of liver-enzyme levels), and two of the patients became hepatitis B virus carriers. The long-term risk of hepatitis B infection was inversely related to the maximal antibody response to vaccine. Most severe infections occurred among those who responded poorly or had no response to the vaccination. The risk of late infection with hepatitis B in those with an initially adequate vaccine response increased markedly when antibody levels decreased below 10 SRU, but only 1 of 34 late infections resulted in viremia and liver inflammation. A second series of vaccinations induced a moderate antibody response in 50 percent of the subjects who initially had no response or a poor response; however, the persistence of antibody was poor. Both antibody loss and the risk of severe disease should be considered when booster-dose strategies for the hepatitis B vaccine are being designed.     

Hepatitis B infection is highly endemic in Uganda: findings from a national serosurvey

Background

Infant immunization against hepatitis B began in Uganda in 2002.

Objective

To determine the baseline prevalence of hepatitis B virus (HBV) infection and explore risk factors.

Methods

A hepatitis B prevalence study was nested in the 2005 national HIV/AIDS serobehavioural survey. Demographic characteristics and risk factors were explored by questionnaire. One third of blood specimens (n=5875) from adults aged 15 to 59 years were tested for hepatitis B core antibodies (HBcAb); positive specimens were tested for hepatitis B surface antigen (HBsAg).

Results

HBcAb was present in 52.3% (95% CI: 51.0–53.6) of adults, and HBsAg in 10.3% (9.5–11.1). By 15–19 years of age, 40.0% had been infected with HBV. Prevalence of both markers was significantly higher across northern Uganda, in rural areas, among the poor and least educated, and in uncircumcised men. Other independent predictors of infection were age, ethnic group, occupation, number of sex partners, and HIV and HSV-2 status.

Conclusion

Hepatitis B virus infection is highly endemic in Uganda, with transmission occurring in childhood and adulthood. More than 1.4 million adults are chronically infected and some communities disproportionately affected. The hepatitis B infant immunization programme should be sustained and catch-up vaccination considered for older children.     

HIV and co-infections

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti-retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.     

Human Papillomavirus Vaccines: Where Do They Fit in HIV-Infected Individuals?

Human papillomavirus (HPV) is the etiological agent for cervical cancer and a large majority of anal cancers worldwide. In 2006 two preventive vaccines against the HPV were approved by the US Food and Drug Administration and have since been approved in over 100 countries. HIV-infected populations are at an increased risk for HPV-related cancers. None of the efficacy trials for these vaccines included HIV-infected populations. However, studies in HIV-infected children and adult men show that the vaccine is safe and highly immunogenic. Studies evaluating the vaccine in HIV-infected women are in progress. Based on these studies, the American Council on Immunization Practices recommends HPV vaccination for all HIV-infected children and young adults up to age 26?years. HPV vaccine policies in resource-limited countries, many of which have a high prevalence of HIV infection, are still being developed. Future studies should examine the role of HPV vaccination for older HIV-infected adults who likely have ongoing HPV infection.     

Pattern of T cell activation in absence of protective immunity against hepatitis B virus. Review

Hepatitis B is an important cause of morbidity and mortality around the world. One-third of the world's population has been estimated to be infected with hepatitis B virus (HBV). A significant amount of evidence suggests that both humoral and cellular immune responses are important to eliminate the virus and that, cellular immunity is involved in the pathogenesis of the disease. Vaccination with HBsAg is considered as the main strategy for effective control of the infection and viral transmission. However, approximately 5-10% of immunized individuals fail to elicit detectable specific antibodies and remain at risk for hepatitis B infection. In this work we have reviewed the current status in the pathogenesis of the disease and the mechanisms described to explain nonresponsiveness to the vaccine as well. Since nonresponders to the vaccine are at risk for the infection, a common mechanism to explain the absence or inappropriate immune response to virus components is proposed. Within the suggested model an impaired activation of T lymphocytes against viral antigens, both in nonresponders to vaccination and chronically infected patients, is described. These observations could be consistent with potential differences in the MHC/Ag presentation; therefore contributing to our understanding of the altered T helper response as an underlying mechanism for the lack of protective immunity against VHB.     

Prevalence of hepatitis B virus and hepatitis C virus in patients with human immunodeficiency virus infection in central China

Co-infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) with human immunodeficiency virus (HIV) has an adverse effect on liver disease progression. This study investigated the prevalence of HBV and/or HCV co-infection in HIV-infected patients in Central China. A total of 978 HIV-infected patients from Hunan Province were enrolled. HBV serum markers, anti-hepatitis-C-virus antibody (anti-HCV), HBV DNA, and HBV genotypes were analyzed. The prevalence of hepatitis B surface antigen (HBsAg) and anti-HCV in HIV-infected patients was 19.4 % and 62.4 %, respectively. The prevalence of anti-HCV in HIV-positive intravenous drug users was 93.6 %. Among HBsAg-positive patients, 88.1 % were found to have at least one HBV serum marker. The rates of HIV mono-infection, HBV/HIV dual infection, HCV/HIV dual infection, and HBV/HCV/HIV triple infection were 30.4 %, 7.2 %, 50.2 %, and 12.2 %, respectively. Antibody to HBsAg (Anti-HBs) was more common in anti-HCV-positive than anti-HCV-negative patients (53.3 % vs 40.2 %, P = 0.000), but isolated hepatitis B core antibody (anti-HBc) was more common in anti-HCV-negative than anti-HCV-positive patients (24.2 % vs 12.3 %, P = 0.000). Hepatitis B e antigen (HBeAg) and sexual transmission were independent risk factors for active HBV replication. Intravenous drug use and male sex were independent risk factors, but old age and presence of HBeAg were independent protective factors for anti-HCV. Co-infection of HBV and/or HCV with HIV infection is common in central China. HCV status is associated with anti-HBs and isolated anti-HBc in co-infected patients.     

Vaccination against drug resistance in HIV infection

HIV-1 resistance to currently employed antiretroviral drugs and drug-associated adverse reactions and toxicity point to a need for additional measures to control HIV-1 replication in HIV-infected patients. The immune system of HIV-infected individuals mount an immune response against the regions harboring drug-resistance mutations, sometimes stronger than that against the parental wild-type sequences. A potent cross-reactive immune response against drug-resistant pol proteins can suppress the replication of drug-escaping HIV. This suggests the possibility for a vaccination against existing and anticipated drug-resistant HIV variants. If successful, therapeutic vaccines against drug resistance would ease the therapeutic modalities and limit the spread of drug-resistant HIV. A better understanding of the complex interactions between patterns of drug-resistance mutations, immune responses against these mutations and their antigen presentation by particular human lymphocyte antigen alleles could help to tailor these vaccines after new drugs/new mutations. In this review, we describe the developments in the field of immunization against mutations conferring drug resistance and evaluate their prospects for human vaccination.     

Recombinant Glycoprotein Vaccines for Human Immunodeficiency Virus-Infected Children and Their Effects on Viral Quasispecies

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccine-associated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.     

Recombinant glycoprotein vaccines for human immunodeficiency virus-infected children and their effects on viral quasispecies.

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccine-associated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.     

Antiretroviral therapy in chronic liver disease: focus on HIV/HCV coinfection--statements of the First Italian Consensus Workshop

Hepatitis C virus common transmission routes and HCV coinfection is frequent in persons living with HIV. Liver enzyme elevation following the initiation of antiretroviral therapy is frequently seen in HIV-infected patients with chronic liver disease, particularly those with chronic hepatitis C. This complication may lead to treatment discontinuation, complicating HIV therapeutic management. Multiple factors influence the risk of liver toxicity under antiretroviral therapy, including the specific drug in use (e.g. use of full doses of ritonavir), and environmental factors (e.g. alcohol abuse). However a beneficial effect of antiretroviral therapy on liver disease has been supported by some studies. Despite increasing knowledge of HCV/HIV coinfection, there is no clear consensus on how to treat HIV in HCV-coinfected patients An Italian group of experts were invited to discuss in detail the current risks and implications of antiretroviral treatment in HIV-infected persons with chronic hepatitis C, and their main conclusions are summarized in this consensus document.