Landrum, Michael L. MD; Dolan, Matthew J. MD
As patients live longer with HIV infection due to highly active antiretroviral therapy (HAART), the health problems encountered during the course of disease are changing from predominantly treatment and prevention of opportunistic diseases to prevention and treatment of long-term comorbidities, such as viral hepatitis and drug-induced dyslipidemia. These changes in the chronic care of patients living with HIV were addressed by recent guidelines from the Infectious Diseases Society of America, one aspect of which was providing routine vaccination for commonly encountered diseases.1
Unfortunately, despite widespread agreement on the potential benefits of vaccination, evidence suggests that vaccination coverage is typically poor. For example, the coverage rates for hepatitis B vaccine and pneumococcal vaccine have been reported to be 32% and 38%, respectively.2,3 The reasons for this are not entirely known but likely involve concerns regarding cost, lack of need, reduced efficacy, or fear of causing harm.2 This review will discuss for clinicians the currently recommended routine vaccines for HIV-infected patients, as well as summarize the evidence supporting those recommendations focusing primarily on the 2 most commonly indicated vaccines, hepatitis B and pneumococcal vaccines.
Although typical vaccine related adverse events do not appear to occur more commonly in HIV-infected adults compared with the general population,4-10 several studies have investigated the effects of vaccination with pneumococcal,11-14 hepatitis B,15 influenza,16-27 and tetanus toxoid28 vaccines upon HIV disease progression, specifically viral replication and CD4 count. The majority of these involved influenza vaccine, with some reporting increased levels of viral replication after vaccination16,17,21,24,26,27 and others reporting no effect.18-20,22,23,25 Most authors agree that if elevations are seen, they occur early after vaccination, are transient, and unlikely to affect disease progression. Possible explanations for the different outcomes include timing of sample collection after vaccination, utilization of different HIV RNA testing methods, and differences in study design and patient populations. However, increases in viral load after vaccination with influenza and other vaccines before the advent of HAART caused some to debate the risks and benefits of widespread vaccination.29 One large observational study including patients from 1990 to 1998 did not find an association between influenza vaccination and progression to AIDS.30 Unfortunately, data regarding viremia after pneumococcal vaccine12-14 or influenza vaccine17,18,22,24 in subjects receiving HAART are somewhat limited. In these studies, no increase in viremia after pneumococcal vaccine was detected, but small, transient elevations were seen after influenza vaccination in 2 uncontrolled studies.17,24 In one of these, Kolber et al24 investigated the occurrence of novel drug resistance mutations among 34 patients on stable HAART regimens with undetectable viral loads at the time of influenza vaccination. One patient developed previously unidentified zidovudine mutations despite excellent medication compliance, and another patient failed therapy after vaccination, but without comparison to controls, conclusions from this study remain limited. Although more data are needed to definitively address the impact of vaccines upon HIV disease course, current data suggest that if risk exists, it is small and likely outweighed by the benefits of providing these vaccines to this patient population.
In addition to the concerns of immune stimulation and disease progression, the safety of administering live vaccines to HIV-infected patients remains incompletely understood. Several anecdotal reports of vaccine-related disease after immunization have been reported in HIV patients with profound immunosuppression. Fatal vaccine-associated pneumonitis was reported in a 21-year-old male patient with AIDS and an undetectable CD4 count after measles-mumps-rubella (MMR) vaccination,31 and at least 9 cases of disseminated BCG, 7 of which were fatal, have also been reported after vaccination in children and adults with AIDS.32,33 In addition, 1 case of disseminated vaccine strain varicella in a 16-month-old boy34 and 1 case of disseminated vaccinia in a military recruit have been reported.35 In both cases, undiagnosed HIV infection was responsible for advanced immunosuppression at the time of immunization.
Although these anecdotal reports are troubling, other investigators have safely given live attenuated viral vaccines to HIV-infected adults. Published reports include the administration of cold-adapted influenza vaccine to HIV-infected adults with CD4 count >200 cells/μL,9 yellow fever vaccine to HIV-infected travelers with CD4 >200 cells/μL,36,37 and MMR to a total of 45 HIV-infected adults with CD4 counts ranging from 140 to 600 cells/μL.38,39 One study also reported no serious adverse events after the inadvertent administration of smallpox vaccine to 10 HIV-infected patients with CD4 counts ranging from 286 to 751 cells/μL.40 However, many of these live vaccine recipients were seropositive for the respective vaccine agent at baseline.9,39,40 No study of varicella vaccination in adults has been published to date, but studies in children have found the vaccine to be well tolerated.41-43 Although the published data are somewhat limited, they suggest that live vaccines may be safely administered to a select portion of patients with HIV, those with CD4 counts >200 cells/μL. However, given the small numbers of reported live vaccine recipients, the potential for harm, and lack of demonstrated efficacy, the only live vaccine recommended for HIV-infected adults is MMR, which should not be administered to patients with advanced immunosuppression.44 Lastly, although smallpox vaccine is not currently indicated, administration could potentially be recommended in certain situations such as a bioterrorism attack. The reader is referred to guidelines for specific recommendations but will need to weigh the relatively well-characterized potential for vaccine risk against the scenario-specific risk for infection and death given the characteristics of an attack (ie, whether the patient was primarily exposed, the scope of the attack, and the success of initial containment effort).45,46
HEPATITIS B VACCINE
Due to shared modes of transmission, the burden of hepatitis B virus (HBV) infection among patients with HIV is large, with up to 50% of adult HIV patients with positive serologic markers for hepatitis B and an estimated 7% with chronic hepatitis B.47-50 Although the impact of HBV infection upon the course of HIV disease and response to HAART is debated,51,52 several studies have shown persistence of HBsAg, increased levels of HBV DNA, prevalence of cirrhosis, prevalence of chronic hepatitis, and liver-related mortality among HBV/HIV coinfected patients compared with patients infected with HBV alone.53-57 In addition, risk of antiretroviral-associated hepatic toxicity seems to be increased compared with HIV-positive, HBV-negative patients.58-63 Because of these reasons, hepatitis B vaccine has been recommended for all HIV-infected patients without prior evidence of HBV infection (Table 1).44,64-66
Several studies have investigated the serologic response to hepatitis B vaccine in HIV-infected patients, all finding low rates of response. One of the first studies compared antibody response to 3 standard doses (20 μg each) of vaccine among men who have sex with men with and without HIV infection and found that nonresponse occurred in 7 of 16 HIV-seropositive patients, compared with only 6 of 68 HIV-seronegative patients.67 Since that time, other investigations have described initial response rates varying from 17% to 55% with 3 standard doses of vaccine administered over 6 months.2,6,68-74 Risk factors for nonresponse have not always been consistent among studies but have included detectable HIV RNA load at the time of vaccination68 and nadir CD4 count before vaccination.2,74 Although retrospective analyses have not found an association between CD4 count at the time of vaccination and nonresponse,2,68,74 one recent prospective study of 192 patients did find higher response rates in patients with CD4 cell counts ≥350 cells/μL (adjusted odds ratio: 2.86, 95% confidence interval (CI): 1.42-5.75, P = 0.002).6 The impact of concurrent administration of HAART upon vaccine response rates has not been thoroughly investigated, but one study found that among vaccinees receiving HAART, the median duration of treatment for responders was 13.5 months, compared with 3.7 months for nonresponders, P = 0.005.68 Lastly, genetic determinants including human leukocyte antigen and cytokine gene polymorphisms have been associated with response to vaccination among HIV patients.75
In addition to poor initial seroresponse rates, protection may be further reduced by waning antibody levels. One study of 78 hemophiliac patients, 11 of which were also HIV-positive, followed subjects for 4 years after initial vaccination. Anti-HBs levels remained protective after 4 years for all HIV-negative patients, whereas levels waned below protection in 5 of 11 HIV-positive patients.76 More recently, Cooper et al5 found that the percentage of patients with protective anti-HBs decreased from 90% immediately after vaccination to 63% after 12 months despite all patients being on HAART and having suppressed HIV RNA.
Several methods at improving seroresponse rates in HIV-infected patients have been attempted. One method, recommended by the Advisory Committee on Immunization Practices for HIV patients, is administering a double dose of the vaccine (Table 1).65,66 Studied previously in dialysis patients,65 one study of HIV patients recently described a nonstatistically significant increase in overall response rate using 40 μg doses of vaccine compared with 20 μg doses (47% vs 34%, P = 0.07).6 However, among patients with CD4 ≥350 cells/μL, response rates were 64% and 39% for double dose and standard dose, respectively (P = 0.008). Likewise, significantly increased response rates were found among patients with HIV RNA loads <10,000 copies/mL (58% vs 37%, P = 0.01).
One additional promising method studied recently in HIV-infected patients but not currently available clinically is the addition of an adjuvant consisting of cytosine and guanine nucleotides linked by phosphate bonds (CpG) to HBV vaccine.5,77 CpG oligodeoxynucleotides are short motifs of bacterial DNA that interact with Toll-like receptor 9 resulting in activation of a broad array of innate immune responses.78 Through modifications to their end components, the type of immune response elicited can be modified. Addition of one such motif, CpG 7909, to hepatitis B vaccine was studied in HIV-positive patients with viral suppression on HAART and resulted in significantly increased levels of anti-HBs for up to 1 year after vaccination, without reducing safety.5 In this study, seroprotective titers at 1 year were found in 100% of subjects that had received CpG in addition to HBV vaccine compared with 63% of subjects that had received vaccine alone, P = 0.008.
Unfortunately, there are only limited data in HIV-infected patients establishing an anti-HBs level ≥10 IU/L as a correlate of protection and regarding clinical efficacy. Hadler et al79 reported long-term immunogenicity and efficacy of plasma-derived HBV vaccine among men who have sex with men and subsequently characterized clinical outcomes for the 340 subjects who developed breakthrough HBV infection.80,81 Of those participants, 64 were determined to be HIV-infected before HBV infection using banked specimens. Interestingly, although all patients developed breakthrough infection, the only group of HIV-infected patients protected from developing chronic hepatitis was the group that had an initial anti-HBs ≥10 IU/L after 3 doses of vaccine. Those receiving an incomplete vaccination series or with nonresponse had equal or higher rates of chronic HBV infection compared with placebo. The study also described worse clinical outcomes in vaccinated HIV-positive individuals with breakthrough HBV infection, as 33% developed chronic infection compared with only 5.9% of HIV-negative vaccine failures (P < 0.001). More recently, a large cohort study of more than 16,000 HIV patients reported that receipt of one or more doses of HBV vaccine was independently associated with reduced incidence of acute HBV infection (odds ratio: 0.6, 95% CI: 0.4-0.9), but no data on seroresponse were reported.47 Lastly, we recently described in our cohort that anti-HBs ≥10 IU/L measured 6 months after the last vaccine dose was significantly associated with prevention of hepatitis B infection over a median of 8 years of follow-up.82 During this time, not one case of chronic hepatitis B occurred among vaccine recipients with anti-HBs ≥10 IU/L after immunization.
Although encouraging, the above data taken collectively suggest that although vaccination seems beneficial for some, a large portion of HIV patients remain unprotected due to either failure to administer the vaccine or a lack of a response. All HIV-infected adults without evidence of hepatitis B infection should be vaccinated, and efforts are needed to improve physician and patient education regarding the need for and benefits of HBV vaccine. The currently recommended dose and schedule are 40 μg at 0, 1, and 6 months.66 Anti-HBs should be measured after completion of the series, and up to 3 additional doses of vaccine should be given to those with anti-HBs <10 IU/L.66 The need for routinely obtaining anti-HBs titers and providing booster doses of vaccine is not clear. Some authorities recommend this approach,56 but to our knowledge, not one case of chronic hepatitis B has been reported in patients achieving anti-HBs ≥10 IU/L after vaccination. Therefore, we do not routinely follow anti-HBs titers or provide booster doses to those with anti-HBs ≥10 IU/L after vaccination. Further studies are needed to clarify many issues including barriers to vaccine administration, methods to improve immunogenicity and maintain long-term protection, vaccine efficacy, determination of clinical correlates of protection, and the need for booster doses of vaccine.
Similar to HBV coinfection, the burden of pneumococcal disease in HIV-infected patients is substantial, despite the advent of HAART.83,84 Although some studies have found a reduction in the incidence of invasive disease since the introduction of HAART,83-85 one recent study did not.86 The estimated incidence in HIV-infected adults remains approximately 500 cases/100,000 person-years (PY), approximately 30-fold higher than in non-HIV-infected adults.83,84,86-88 Streptococcus pneumoniae isolates covered by the currently available 23-valent polysaccharide vaccine (PPV) account for approximately 80% to 94% of cases in adults, whereas only 40% to 56% of isolates would be covered by the currently licensed 7-valent conjugate vaccine (PCV).87-90 In addition, the mortality rate of invasive disease may be increasing from 8% in the pre-HAART era to 21% to 26% in the era of HAART.84,89,91 For these reasons, vaccination with PPV is recommended for all HIV-infected adults after diagnosis, and revaccination should be considered when it has been >5 years since previous immunization or after immune reconstitution if the CD4 count was <200 cells/μL at the time of the initial vaccination.44,64,92 Unfortunately, as for hepatitis B vaccine, the data supporting these recommendations are limited.
Several studies have investigated serologic responses to PPV, describing low response rates in patients infected with HIV.8,12-14,93-101 Factors predictive of a good or poor response remain largely unknown. In general, responses seem best when the vaccine is administered early in the course of disease,13,97 and whereas some prospective studies have shown higher CD4 counts at the time of vaccination to be associated with improved responses,97-99 others have not.12,93,96 In addition, one early investigation found that zidovudine monotherapy improved responses,94 but more recent studies have found no improvement in vaccine response in patients receiving monotherapy96 or HAART,93,97 supporting the assumption that pneumococcal polysaccharides are T-cell-independent antigens. Similar to hepatitis B vaccine, the duration of response is reduced in HIV-infected patients compared with otherwise healthy controls.96,99 Limited data also show that a second sequential dose of PPV does not improve antibody levels in those without an initial response.102 Lastly, whereas revaccination is recommended,64 antibody responses to revaccination ≥5 years after initial immunization are significantly lower in frequency and magnitude compared with responses seen in newly HIV-infected subjects.13
Studies evaluating antibody responses to PCV in HIV-infected patients have also been disappointing. Ahmed et al8 compared polysaccharide and conjugate vaccine responses in HIV-infected patients and healthy controls. Pneumococcal conjugate vaccine was found to elicit significantly higher IgG antibody titers than PPV in healthy subjects, but responses to the 2 vaccines were similar in HIV-infected patients.8 Two studies have investigated antibody responses after giving sequential combinations of PPV and PCV in the following sequences: PCV-PCV, PCV-PPV, and PCV-PCV-PPV.7,14 Unfortunately, despite the various vaccination strategies attempted with PCV, none conclusively demonstrated improved immunogenicity compared with PPV alone. The T-cell-dependent manner in which PCV elicits an improved vaccine response in healthy individuals may contribute to the failure of PCV to consistently provoke a more robust response than PPV in HIV-infected patients. Although responses to PCV do correlate with CD4 count,7,8 aberrant T-cell function even in those with CD4 count >500 cells/μL seems to be sufficient to impair immunogenicity. The effect of HAART upon antibody responses after PCV remains to be determined.
Data regarding clinical efficacy are somewhat limited with only one prospective trial, and results have been mixed.3,86,91,103-105 In case-control studies, Gebo et al104 found that the use of PPV in patients with CD4 count >200 cells/μL was associated with a reduced risk of pneumococcal disease (adjusted odds ratio: 0.22, 95% CI: 0.05-0.98), and Breiman et al103 found an overall vaccine efficacy of 49% (95% CI: 12-70, P = 0.02). Of note in this latter study, the only subgroup with a statistically significant level of protection was white patients, and there was no difference in efficacy when stratified by CD4 count. The strongest evidence supporting the use of PPV was a large cohort investigation of more than 39,000 patients with nearly 71,000 PY of observation, which showed that vaccination was independently associated with a reduction in the incidence of pneumococcal disease from 9.3/1000 PY to 2.6/1000 PY (relative risk: 0.5, 95% CI: 0.3-0.9, P = 0.02) only for patients with CD4 count ≥500 cells/μL at the time of vaccination.3 However, more recent observational investigations have found no protective effect from PPV administration.86,106
Even more troubling are data from the only randomized, double-blinded, placebo-controlled trial regarding PPV in HIV-infected patients, done in Uganda. Including nearly 1400 randomized patients, over half of which were WHO stage 3, the study found a trend toward increased rates of invasive disease among vaccinees and an increased risk of all-cause pneumonia within the first 6 months in those receiving PPV (hazard ratio: 2.82, 95% CI: 1.19-6.66).105 Although generalizations to other populations are difficult and limited by many factors including the advanced stage of disease of patients and the lack of ART use, the results are still concerning. The authors hypothesized that the vaccine had resulted in some deleterious effect upon antipneumococcal immunity. However, in a follow-up study comparing 31 case patients with 124 controls, this was not the case, and the investigators found significant relationships between lower antipneumococcal polysaccharide IgG concentrations, lower opsonophagocytic killing, and case status.107
Considering the data together, it is clear that many questions regarding pneumococcal vaccination in HIV patients remain, including clinical efficacy. Because of the perceived risk-benefit ratio and low cost, vaccination remains recommended despite the lack of clear evidence supporting its use. By our estimation, a prospective randomized trial in the United States would require approximately 20,000 PY of follow-up to show that the vaccine was 60% efficacious in preventing invasive disease with 80% power. Without such data, decisions regarding the use of PPV will continue to be based on surrogate end points. More research is needed concerning improving immunogenicity and clinical efficacy, as well as clinical correlates of protection, such as opsonophagocytic activity107,108 and other qualitative differences in antibody function.109
Although data regarding the natural history and severity of influenza in HIV-infected patients remain limited,110,111 annual influenza vaccination with inactivated vaccine is recommended.44,64,112 Similar to other vaccines, serologic responses to inactivated influenza vaccine are lower compared to healthy controls.10,22,23 Higher CD4 cell count and lower HIV RNA level at the time of vaccination have both been independently correlated with improved antibody response to vaccine.10,16,20,23 In addition, one study described a direct correlation with increased viral load after vaccination and antibody response.27 However, unlike healthy controls, successive annual vaccination was not found to improve postvaccination antibody titers in HIV patients not receiving HAART.10
Studies investigating the efficacy of inactivated influenza vaccine in HIV-infected adults have been conducted and were the subject of a recent meta-analysis.111 Fine et al111 described an influenza outbreak in a metropolitan AIDS residential facility and found a statistically insignificant reduction of 27% of influenza-like illness (ILI) among AIDS patients. However, vaccination was associated with a significant reduction of ILI among AIDS patients with either CD4 cell count >100 cells/μL or HIV RNA load <30,000 copies/mL. A more recent, prospective nonrandomized investigation of 626 patients reported a vaccine efficacy of 71% in preventing laboratory-confirmed ILI. Efficacy was no different regardless of HAART use, but too few patients with CD4 counts <200 cells/μL were included in the study to evaluate efficacy in those with advanced immunosuppression.114 One small prospective randomized, double-blind trial of 102 patients before the advent of HAART found a vaccine efficacy of 93% in preventing culture or serologically confirmed ILI.115 However, mean CD4 count for all participants was approximately 400 cells/μL, making generalizations to patients with more advanced disease difficult. Nonetheless, the current data suggest that influenza vaccine seems to be as effective in HIV-infected adults as it is in otherwise, healthy adults.
Other recommended vaccines include tetanus/diphtheria/pertussis (Td/Tdap), hepatitis A, MMR, and meningococcal vaccine.44 Both hepatitis A and meningococcal vaccines are recommended only if an additional medical, occupational, or lifestyle risk factor is present. There are no data regarding clinical efficacy of any of these vaccines specifically in patients with HIV. Serologic responses to tetanus and diphtheria toxoid were 83% to 100% and 61% to 73%, respectively, with response rates to both antigens directly related to CD4 counts.116 Hepatitis A vaccine has been found to induce seroresponse rates in 48% to 94% of recipients without inducing changes in HIV RNA load or CD4 count.4,117-119 Improved responses are seen in those with higher CD4 count, and at least one study described waning antibody responses at 1 year for patients with CD4 counts <300 cells/μL at the time of vaccination.120 No data regarding combination hepatitis A/hepatitis B vaccine (Twinrix) have been reported. Lastly, of the 9 measles seronegative HIV-infected adults reported to have received measles vaccine, only 2 had a positive serologic response after vaccination.38,39
Finally, although not currently recommended for patients with HIV infection, a quadrivalent human papillomavirus (HPV) vaccine (HPV types 6, 11, 16, 18) was recently approved for use by the Food and Drug Administration and recommended for use in adolescent females.121-123 The vaccine has yet to be studied in HIV-infected patients. Estimates of HPV prevalence in HIV-infected individuals range from 63% to 93% with vaccine-specific HPV types accounting for a significant proportion of infection.124-128 With such high prevalence rates, it is unclear how many HIV-infected patients would be candidates for the vaccine, especially when considering that the vaccine did not demonstrate efficacy in those with evidence of infection with vaccine HPV types at baseline.121 In addition to this concern, another study found that immunogenicity was reduced in young women aged 16 to 23 years compared with adolescent males and females aged 10 to 15 years.129 Human papillomavirus vaccine is a recombinant peptide similar to hepatitis B vaccine, so similar seroresponse rates and risk factors for poor response might be anticipated. However, given the concerns listed above, it is not clear whether the vaccine will significantly impact HPV-associated disease in the HIV-infected population outside the benefit achieved through universal adolescent immunization.
Despite recommendations for use of many routine vaccinations in HIV-infected adults, data suggest that the use of vaccines is poor. Although response to these immunizations may in some cases be less than that seen in otherwise healthy adults, large subsets of HIV-infected adults who would benefit from vaccination remain at risk. Therefore, the use of these vaccines, particularly HBV vaccine, represents an excellent target for the improvement of care. Research goals for the long-term include improving immunogenicity for the currently available vaccines, clarifying the role of HAART in improving vaccine response, and the study of newly available vaccines, such as HPV vaccine.
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