Influenza
HIV-infected adults have an elevated risk of severe infections and complications from influenza and hence are considered a key target population for vaccination [
15‐
21]. Further, HIV-infected pregnant women are at particular risk for severe disease and represent an important group for targeted vaccination. Although ART is associated with a reduction in hospitalizations due to influenza, HIV-infected adults remain at higher risk than the general population; hence, vaccination is advocated to reduce influenza infections and related complications [
17]. All major advisory groups recommend HIV-infected adults receive annual influenza vaccination regardless of CD4 count [
8‐
14] (Table
1).
There are two overall types of influenza vaccines, a live attenuated influenza vaccine (LAIV) and an inactivated influenza vaccine (IIV). The LAIV is administered as a nasal spray, but is generally avoided among HIV-infected adults because of the theoretical risk of prolonged viral shedding and/or disease acquisition in the setting of underlying immunosuppression; however, this concern has not been clearly demonstrated [
22‐
24]. Hence, guidelines recommend using the inactivated vaccine (IIV), which is typically administered by intramuscular injection. There are two main types of inactivated vaccines, which can be categorized into trivalent (containing two A viruses and one B virus) and quadrivalent (containing an additional B virus) forms.
The WHO recommends influenza vaccination to be determined by national capacity and resources, with pregnant women having the highest priority followed by additional risk groups including those with specific chronic medical conditions such as HIV [
7].
The BHIVA recommends using IIV and suggests using the quadrivalent form if available to provide the maximal anti-influenza virus coverage [
8]. The EACS simply recommends an annual influenza vaccine and cites the BHIVA for further guidance [
12]. The French guidelines recommend IIV, but also note that LAIV may be considered if the CD4 count is >200 cells/mm
3 [
14].
In the US, the IIV is recommended for annual administration. LAIV is contraindicated since it is a live vaccine, and there is an inactivated vaccine (i.e., IIV) available. Further, the lack of efficacy of LAIV among the US general population during recent seasons has resulted in this vaccine not currently being recommended for any population group [
9]. US guidelines do not indicate a preference for the specific type of IIV among HIV-infected persons [
9].
In addition to the standard-dose inactivated vaccine, a high-dose vaccine (containing four times the hemagglutinin antigenic content, Fluzone
® high-dose) is available in the US (where it is approved for persons ≥65 years of age) and other geographic locations including Canada. This vaccine elicits improved antibody responses and greater effectiveness at protecting against influenza in select groups, and it has been shown to be cost-effective and prevent more deaths compared with the standard-dosed vaccine among the elderly [
25‐
27]. Currently, the vaccine does not have a specific indication for younger HIV-infected adults in any of the guidelines.
The efficacy of influenza vaccination among HIV-infected persons is reduced compared with HIV-uninfected persons [
28‐
32]. Poorer responses among HIV-infected persons may partly be attributed to reduced CD4 counts and HIV viremia [
29]. However, studies among patients with well-controlled HIV have demonstrated poorer post-vaccination responses versus HIV-uninfected persons [
28] suggesting that additional HIV-related factors, including heightened immune activation and inhibition of B cell and cytotoxic T-cell immune responses, may be responsible [
29,
33,
34]. Additionally, HIV appears to worsen age-associated deficits of immune responses post-influenza vaccination [
33]. A recent meta-analysis incorporating findings from several studies (i.e., three randomized-controlled trials and three cohort studies,
n = 1562) confirmed that vaccination among HIV-infected adults reduces laboratory-confirmed influenza with a pooled efficacy of 85% (95% CI 22–97%); however, there were wide variations between the study results, and vaccination did not show a benefit for secondary outcomes [e.g., influenza-like illness (ILI)] [
35]. A randomized trial among HIV-infected pregnant women noted a vaccine efficacy of 58% [
36].
Given these data [
28,
29,
37], improving the immune responses generated after influenza vaccination is of clinical interest. In one study, the administration of a second dose of influenza vaccine (this study utilized the H1N1 influenza vaccine) significantly increased seroprotective responses (from 68% to 92% after the second dose); however, the study utilized an adjuvant plus vaccine [
38]. Current guidelines do not recommend additional doses of influenza vaccination during the same season. Another potential strategy is the utilization of vaccines with higher antigen content. The use of a high-dose vaccine (Fluzone
®, which contains 60 mcg of antigen per strain vs. 15 mcg) was evaluated among 190 HIV-infected adults. In this study, seroprotection rates were greater in the high-dose group for H1N1 (96% vs. 87%,
p = 0.03) and influenza B (91% vs. 80%,
p = 0.03) and similar for H3N2 (96% vs. 92%,
p = 0.30) strains [
39]. However, a more recent, smaller study of HIV-infected children and young adults did not show improved antibody responses with high-dose vaccination [
40]. Intradermal vaccines have been studied, and although they allow for the use of smaller antigenic doses, they do not appear to elicit greater immune responses and may be associated with more local and systemic side effects [
41,
42]. Finally, the use of adjuvanted vaccines (e.g., with AS03
® or MF59
® adjuvants) have generally produced greater immune responses post-vaccination [
38,
43‐
45]. An adjuvanted vaccine is now available in the US (Fluad™) and is targeted for persons ≥65 years, but has not been studied or approved specifically for HIV-infected adults. Although the aforementioned studies suggest the potential for improvement in antibody responses using these alternate vaccine approaches, studies have been limited and have not evaluated effectiveness in preventing clinical influenza; hence, none of these strategies are currently recommended by guidelines [
7‐
12].
Some health care providers have wondered if HIV-infected persons should be preferentially vaccinated later in influenza season because of concerns regarding possible reduced durability of protection. Vaccination generally elicits immune protection 2 weeks after vaccination, but the duration of protection has been questioned. A recent study among the general population found waning of effectiveness over time with ~7% loss of efficacy per month, although most recipients remained protected during the influenza season (October–April in the Northern hemisphere) post-vaccination [
46]. Among immunocompromised hosts, however, durability may be shortened given lower post-vaccination antibody responses [
47]. A retrospective study among HIV-infected persons in the US showed that those who received influenza vaccine early in the season were more likely to develop influenza or an ILI than those vaccinated later in the season (i.e., after 15 November) [
48]. Additional data from Canada also suggest that waiting later (mid-November to early December) [
49] is preferred. As such, the BHIVA recommends vaccine administration between September and early November [
8], while US guidelines do not advocate for a specific timeframe for influenza vaccination among HIV-infected adults [
9,
10,
13]. Vaccination can continue until March [
8] and until community influenza activity has ended. Of note, defining narrow windows for vaccination must be weighed against the possibility of influenza occurring early in the season and missed vaccination opportunities.
Despite challenges in the efficacy and durability of influenza vaccination, guidelines recommend the use of the influenza vaccine since it provides some level of protection and reduces severe complications [
17]. Despite these recommendations, vaccine coverage remains suboptimal among HIV-infected adults in many locations including the US (average 38% coverage, range 26–50%) [
50]; therefore, targeted efforts for optimizing vaccine rates are advocated.
Influenza vaccination has been shown to be safe overall with local reactions being the most common reaction. Pregnant women can receive the inactivated vaccines with studies demonstrating safety in this group [
36]. No long-term negative effects on CD4 counts, HIV RNA levels, or progression to AIDS or death have been noted [
51]. Persons with mild egg allergies (only hives without other allergic symptoms) may receive the inactivated vaccine per the US CDC guidelines [
9]. A recombinant vaccine (not made using eggs or egg proteins, FluBlok
®) is also available in some countries (e.g., US, Mexico) for those with more severe forms of egg allergy [
9]. For those with an allergy to the vaccine itself or with a history of severe reactions (e.g., Guillain-Barré syndrome), vaccination should be avoided unless deemed safe by an expert in this field (e.g., allergy/immunology specialist). For those not able to receive vaccination, anti-viral prophylaxis may be warranted, especially among those at high risk of exposure and severe disease. Additionally, those exposed and not vaccinated or those who may not have generated an adequate post-vaccination response (e.g., CD4 count <200 cells/mm
3) should be considered for antiviral prophylaxis (e.g., with oseltamivir). Finally, vaccinating close contacts to reduce the possibility of influenza exposure is recommended.
Pneumococcal
HIV-infected persons have been recognized to be at risk for pneumococcal disease since the beginning of the epidemic [
52] and continue to have an elevated risk (20- to 40-fold higher) despite the use of ART [
1,
53‐
55]. The elevated risk is due to immunodeficiency as well as the concurrent high rate of adverse health behaviors (smoking, drug use) in this population. Infections caused by
Streptococcus pneumoniae include invasive disease (e.g., meningitis, bacteremia) and pneumonia. There are currently two main types of pneumococcal vaccination—the polysaccharide pneumococcal vaccine (PPV), which contains 23 serotypes (covering ~85% to 90% of the strains leading to invasive disease), and the conjugate pneumococcal vaccine (PCV) containing up to 13 serotypes depending on the valency (the same serotypes are also included in PPV except 6A).
The current WHO guidelines (published in 2012) do not recommend PPV for HIV-infected adults residing in resource-limited settings given competing health priorities and a low level of evidence to support its use in this setting (Table
1) [
7]. The conjugate vaccine, PCV, is not discussed in the WHO guidelines for HIV-infected adults [
7]; however, recommendations were published prior to the availability of several studies regarding this vaccine in adults.
British and US guidelines [
8‐
11,
13] recommend pneumococcal vaccination among HIV-infected adults, although the type and number of vaccinations differ by guideline (Table
1). The BHIVA guidelines recommend that HIV-infected adults receive 1 dose of PCV given its proven immunogenicity and efficacy in HIV-infected persons [
8]. This recommendation is largely based on a randomized, double-blind, placebo-controlled trial (using PCV-7) among HIV-infected adults in Malawi, which showed a 74% efficacy against vaccine-type invasive pneumococcal disease, with good efficacy even at CD4 counts <200 cells/mm
3 [
56]. Hence, BHIVA guidelines recommend a single dose of PCV among HIV-infected adults irrespective of CD4 count, HIV viral load, or ART use. The BHIVA currently recommends PPV only among HIV-infected persons who are >65 years or among younger adults with a concurrent comorbidity (e.g., asplenia) requiring vaccination based on the national program recommendations. This represents a change from the prior BHIVA guideline in 2008 that had recommended PPV for all HIV-infected adults. When both PPV and PCV vaccines are administered, BHIVA guidelines recommend that doses be separated by at least 3 months. Repeat doses of either vaccine (PCV or PPV) are not currently recommended [
8]. Similar to the BHIVA guidelines, the EACS guidelines also recommend a dose of PCV-13 instead of PPV and state no recommendations for booster doses [
12]. The French guidelines differ by advising both vaccines with an initial dose of PCV followed by PPV at least 2 months later; among those already having received PPV, at least 3 years should elapse, and then administering PCV followed by PPV 2 months later is recommended [
14].
US recommendations advise the administration of both PPV and PCV among HIV-infected adults regardless of concurrent comorbidities. PCV (i.e., Prevnar-13
®) is recommended at HIV diagnoses regardless of CD4 count [
9‐
11,
13]. The use of PCV as the initial vaccination is based on its excellent priming ability and efficacy [
56]. The continued recommendation for PPV among HIV-infected adults is based on the additive risk that HIV conveys for the development of invasive pneumococcal disease, studies that show PPV reduces pneumococcal bacteremia and death [
55,
57,
58], and the additional serotypes covered compared with PCV-13. This recommendation is also supported by studies showing that a PCV prime followed by a PPV boost strategy may enhance both the breadth and magnitude of antibody responses among HIV-infected adults [
59,
60], although the clinical impact of this strategy remains unclear [
61,
62]. Overall, US guidelines recommend PCV followed by PPV administered ≥8 weeks later in pneumococcal vaccine-naïve persons. The delay in the timing between the vaccinations is to reduce hyporesponsiveness [
30,
59,
61]. Since HIV-infected persons with CD4 counts <200 cells/mm
3 may have poorer vaccine responses to PPV, vaccination can be deferred until the CD4 count is ≥200 cells/mm
3 if ART will be initiated soon [
10]; alternatively, if administered before immune reconstitution, revaccination may be offered after a CD4 count >200 cells/mm
3 has been achieved [
13]. Revaccination with PPV is also recommended at 5 years after the initial PPV dose and then again at age ≥65 years (≥5 years should separate each PPV dose). If a newly diagnosed HIV-infected adult has already received PPV, a single dose of PCV is administered ≥1 year after the last PPV dose and then another PPV dose ≥5 years after the initial PPV vaccination [
9,
63]. Although US guidelines recommend repeated PPV doses, it only recommends a single dose of PCV.
The divergent guidance regarding pneumococcal vaccination by various advisory groups is likely reflective of the timing of the publication of each guideline, the pros and cons of each type of vaccine (e.g., PCV has improved immunogenicity, but covers fewer serotypes), the paucity of large, randomized clinical efficacy studies on pneumococcal vaccinations among HIV-infected adults, and divergent results from studies conducted in the developed vs. developing world. For example, PPV efficacy is mainly based on observational data that have shown divergent results [
55,
57,
64‐
66], and a randomized, double-blind, placebo-controlled trial in Uganda found a higher risk of pneumonia following PPV administration in HIV-infected adults not receiving ART [
67] (although additional follow-up noted a decrease in all-cause mortality post-vaccination) [
58]. Further, there are no current head-to-head trials comparing PPV with PCV among HIV-infected adults. A recent systematic review of the existing data (including 1 randomized trial and 15 observational studies) in HIV-infected adults concluded there was moderate evidence to support PPV use [
68]. In summary, the US and French guidelines currently recommend both PPV and PCV in distinction to the WHO, BHIVA, and EACS guidelines. Even though the former approach may provide the most anti-pneumococcal protection to HIV-infected persons if doses are appropriately sequenced, the overall cost-effectiveness and efficacy compared with simpler strategies (i.e., a single PCV dose) remain unclear.
Updates to current pneumococcal vaccine guidelines are anticipated as further data on vaccine efficacy become available as well as the patterns of disease and causative serotypes change over time. For example, since the introduction of PCV among infants is associated with herd protection, a shift of invasive infections due to replacement strains (not contained in PCV) is emerging [
69]. As such, surveillance data on the serotypes causing disease among HIV-infected adults in diverse geographic locations are needed to inform future vaccine guidelines. Further, a conjugate vaccine containing additional serotypes (beyond those in PCV-13) is desirable, but not yet available.
Regarding PPV23 immunogenicity, data have shown reduced immune responses to PPV among HIV-infected persons compared with HIV-uninfected persons, with some studies demonstrating poorer responses at lower CD4 counts [
70,
71]. Regarding efficacy, observational studies have shown varying results with a 20–79% effectiveness of PPV for preventing invasive disease and 20–35% for pneumonia [
8], although some studies have shown no benefit. As noted above, a review found moderate evidence for a reduced risk of invasive disease after PPV administration among HIV-infected adults [
68], although further data on clinical efficacy are needed.
Due to concerns regarding the limited durability of immune responses after PPV among immunosuppressed persons [
72], revaccination with a second dose of PPV at 5 years has demonstrated increased antibody responses, although the magnitude and breath of responses were reduced compared with those originally observed after the first dose [
73]. Although immunogenicity studies have been performed, we are unaware of any clinical efficacy data to support the use of repeated PPV doses among HIV-infected adults. Hence, whether repeated PPV vaccinations are clinically beneficial and the ideal timing for revaccination remain unknown. At this time, US guidelines recommend PPV vaccination with a booster at 5 years and again at age 65 years (assuming 5 years has elapsed from the prior dose) for a total of three doses over time, but BHIVA and EACS guidelines do not recommend doses (either initial or booster) of PPV for HIV-infected adults without additional indications (beyond HIV infection alone).
Regarding PCV immunogenicity, HIV-infected persons generate reduced antibody levels compared with HIV-uninfected persons after vaccination [
74,
75], similar to those noted for PPV. Regarding efficacy, as noted above, a randomized trial demonstrated a 74% efficacy at reducing invasive disease [
56]. Although this trial utilized two doses of PCV, the additional dose may provide little, if any, additional benefit [
76,
77]. BHIVA, EACS, French, and US guidelines [
8‐
10,
12] recommend a single dose of PCV among HIV-infected adults; no additional PCV doses are recommended by any guideline.
Both PPV and PCV have shown no serious safety concerns, with the most common reported adverse event of local reactions, with fevers or myalgias reported in <1%. Some data suggest more local pain at the injection site after PCV vaccination than after PPV, perhaps given the greater immunogenicity of the former vaccine [
61,
78].
Hepatitis B Virus
HBV is important among HIV-infected persons given the viruses’ shared routes of transmission. Additionally, HIV-infected persons have both a higher risk of HBV infection after exposure and an increased risk for progression to cirrhosis and HBV-related complications after infection [
3,
79]. Further, chronic HBV infection is associated with poorer HIV outcomes, with a nearly two-fold higher risk of AIDS and/or death [
80,
81].
All guidelines included in this review recommend that non-immune HIV-infected persons be vaccinated against HBV (Table
2). This is because vaccination has been shown to reduce the risk of both newly acquired HBV infections and the development of chronic infections among those newly infected [
82].
Testing for HBV infection and immunity is recommended among HIV-infected adults. In resource-limited settings, testing prior to vaccination can be deferred if not available [
7]. Although the exact tests to evaluate for HBV immunity vary by guideline, obtaining hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B surface antigen (anti-HBs) provides the most complete picture of HBV status [
10]. The presence of anti-HBs at levels of ≥10 mIU/ml is consistent with seroprotection, and vaccination is not required. Some people have an isolated positive anti-HBc (HBsAg negative and anti-HBs negative). This pattern represents: (1) a false positive test, (2) a resolved infection with waning anti-HBs over time, or (3) a chronic HBV infection with an undetectable HBsAg. The latter group may have chronic inactive infection (HBV DNA is undetectable) or ‘occult’ infection (HBV DNA is detectable). Among those with an isolated anti-HBc, testing for HBV DNA is recommended by the US guidelines and, if negative, then the HBV vaccine series administered [
13]. The BHIVA guidelines suggest administration of a single dose of vaccine rather than DNA testing to evaluate for an anamnestic response, and if a response is detected (anti-HBs ≥10 mIU/ml), no further vaccination is needed; if the anti-HBs are <10 mIU/ml, then completion of a series is advised [
8]. Of note, studies among HIV-infected persons with an isolated anti-HBc have generally shown a low rate of anamnestic responses, suggesting that a full vaccine series is often needed [
83,
84]. The French guidelines are similar to the BHIVA guidelines [
14]. Contrary to the US and BHIVA guidelines, the EACS guidelines currently state that given the lack of data on the impact of immunization in isolated anti-HBc positive persons, vaccination is not presently recommended for this group [
12].
Among HIV-infected adults requiring vaccination, the WHO guidelines recommend the use of standard dosing (20 mcg) with either a schedule of 0, 1, and 6 months or 0, 1, 2, and 12 months for those with a CD4 count >500 cells/mm
3 [
6]. Those with lower CD4 counts (200–500 cells/mm
3) are advised to receive the latter more intensive schedule. The WHO recommends deferring vaccination among those with a CD4 count <200 cells/mm
3 until ART has been started, and the CD4 count has risen to >200 cells/mm
3. These recommendations are based on studies showing a strong association between pre-vaccination CD4 counts and ART use on post-vaccine immune responses [
85,
86]. If a person does not respond to vaccination (anti-HBs <10 mIU/ml measured ≥4–8 weeks after the series), then booster doses or initiation of a new vaccination series using higher doses (40 mcg) in a four-dose series is advised; of note, varying strategies have been cited in different WHO protocols [
6,
7,
87].
The BHIVA recommends that non-immune persons receive a non-adjuvanted vaccine (e.g., Engerix B
® or HBvaxPRO
®) at a dose of 40 mcg or an adjuvanted vaccine (i.e., Fendrix
®) at a 20 mcg dose [
8]. Each are recommended as a four-dose series (0, 1, 2, and 6 months). An ultra-rapid course [using 3 standard doses (not higher doses given lack of data) over 3 weeks] can be considered if there is an urgency to ensure rapid completion of the series, but is not recommended among those with CD4 counts <500 cells/mm
3. For those not responding to the initial series, three more doses are recommended (Engerix B
®, HBvaxPRO
®, or Fendrix
® with a slight preference for Fendrix
®) [
88] with doses given at monthly intervals. Among non-responders to the initial series with low CD4 counts, delaying the revaccination series until a CD4 count of >350 cells/mm
3 and viral load suppression on ART have been achieved can be considered. Finally, those with a low protective level after the initial series (defined as ≥10, but <100 mIU/ml) are to be offered a single dose booster based on data showing that this group will have a titer <10 mIU/ml in the near future [
89]. Similarly, the EACS and French guidelines recommend vaccination among those without anti-HBs [
12,
14]. The EACS suggests that among initial non-responders, re-vaccination should be considered using the double-dose vaccine (40 mcg) at 3–4 time points (months 0, 1, 6, and 12) to help to improve response rates [
12]. The French guidelines recommend initial HBV vaccination using 40 mcg at four time points (0, 1, 2, and 6 months) and recommend that initial non-responders receive high-dose (40 mcg) vaccination every 1–2 months until a protective titer has been achieved, but without exceeding six injections in total [
14]. Further guidance is based on national guidelines [
12].
In the US, Engerix-B
® (20 mcg/ml) or Recombivax HB
® (10 mcg/ml) as a three-dose series (0, 1, and 6 months) or Engerix-B
® (40 mcg/ml) or Recombivax HB
® (20 mcg/ml) as a four-dose (0, 1, 2, and 6 months) series is recommended. Guidelines have increasingly recommended higher doses of HBV vaccine among immunosuppressed persons including those with HIV [
10,
13]. Similar to other guidelines, seroprotection should be measured 4 weeks after the initial vaccine series, and those with anti-HBs <10 mIU/ml should be revaccinated with a second series with advisement for the higher dose series (e.g., 40 mcg/ml Engerix-B
® at 0, 1, 2, and 6 months). In addition, consideration for delaying the revaccination series until CD4 count improvement and ART receipt is suggested, but must be balanced with data suggesting that a longer time to revaccination may predict non-response to the second series [
90] and that they may be at risk for newly acquired HBV infection.
Regarding HBV vaccine interruption, a real-life situation given the need for multiple vaccine doses over a 6-month period, the vaccine series can simply be resumed. The use of tracking and electronic (including text) reminders may be useful for ensuring series completion [
91].
Regarding vaccine immunogenicity, seroprotective HBV vaccine responses are lower among HIV-infected compared with HIV-uninfected persons, with rates of 18–71% and 60–95%, respectively [
11,
92‐
96]. Patients vaccinated prior to HIV infection have seroprotective responses similar to HIV-uninfected persons [
97], suggesting that completion of the vaccine series prior to HIV infection is optimal. Among those already HIV-infected, receiving at least three doses, not using the accelerated schedule, higher CD4 counts, lower HIV viral loads, and receipt of ART have been associated with improved post-vaccination responses [
85,
98,
99].
Given the lower seroconversion rates among HIV-infected persons, higher doses of HBV vaccine (40 vs. 20 mcg/ml) for the initial vaccine series have been advocated. For example, HIV-infected persons randomized to a standard dose (20 mcg/ml) vs. double dose (40 mcg/ml) of recombinant hepatitis B vaccine found seroconversion rates of 34% vs. 47%, respectively (
p = 0.07) [
100]. Interestingly, higher seroconversion rates were noted among those with CD4 counts ≥350 cells/mm
3, but not with lower CD4 counts. In another study, the percentage of responders was 82% in the group receiving 40 mcg/ml (using a 4-dose vaccine series) and 65% in the 20 mcg/ml group (using a 3-dose vaccine series) (
p < 0.001) [
101]. Finally, a meta-analysis including five clinical studies (
n = 883 HIV-infected persons, most of whom were vaccine naïve) found a significant increase in response rates using the higher dose vaccine (OR 1.96, 95% CI 1.47–2.61) [
102].
Response rates to a second vaccine series vary, but have been reported as 36–85% [
98,
103,
104]. Since vaccine response rates are correlated with the immunocompetence of the host, some experts suggest delaying the second vaccine series until receipt of ART and achievement of a higher CD4 count. Some, but not all, studies have found superior response rates for high-dose versus standard-dose revaccination series [
105‐
107]. Importantly, persons who were non-responders to primary vaccination series but who responded to revaccination lost protective anti-HB concentrations faster than those who responded after the first vaccination cycle; hence, this group may benefit from closer follow-up evaluations of protective anti-HB levels [
103,
108]. Overall, the varying guidelines’ recommendations exemplify the less than ideal vaccine responses and somewhat conflicting data for the best approaches for HBV vaccination among HIV-infected persons; however, all guidelines recommend vaccination in an effort to protect non-immune persons.
Among those who receive a second vaccine series, a post-vaccination level should again be measured 4–8 weeks after the series per all the guidelines; among those who still do not have an anti-HBs >10 mIU/ml, the benefit of additional doses is unclear, and they are generally not recommended. These persons should be advised of their risk for HBV infection and counseled on appropriate precautions. In addition, those who do not respond to the revaccination series should be tested for HBsAg to exclude chronic infection. Some guidelines (e.g., BHIVA, WHO) also recommend annual HbsAg testing [
8], or HbsAg and anti-HBc testing [
6,
87], among non-responders to evaluate for potential newly acquired HBV infections over time. Of note, HIV-infected persons receiving antiretroviral therapy with tenofovir (either TDF or TAF), emtricitabine, or lamivudine may have additional protection against HBV infection given the anti-HBV activity of these agents [
82,
109,
110].
The durability of the immune responses after HBV vaccination and the significance of seroreversion remain important questions. In the general population, initial vaccine responses appear to predict life-long HBV immunity, and retesting is generally not recommended [
111]. Although few data exist among HIV-infected persons, the anti-HBs level measured 4 weeks after vaccine series completion appears to predict the durability of seroprotection [
89,
112]. For example, those with a level 10–100 mIU/ml, 100–1000 mIU/ml, and >1000 mIU/ml had a mean time to loss of a seroprotective anti-HBs level of 2, 3.7, and 4.4 years, respectively, in one study [
112]. While US guidelines do not specifically recommend follow-up testing among vaccinees with an initial titer antiHBs >10 mIU/ml [
10,
13], the WHO, BHIVA, and French guidelines recommend regular testing of anti-HBs levels (e.g., every 1–4 years depending on the specific guideline and based on both the initial antibody level and HIV control over time) [
6,
8,
14,
87]; of note, studies have found a relationship between suppressed HIV viral loads and improved anti-HB levels over time [
89,
113]. Those whose anti-HBs level becomes <10 mIU/ml are recommended to receive a booster dose [
6,
8,
14].
HBV vaccines are considered safe with the most common side effect being local site reactions. Studies have found significantly higher rates of local adverse reactions [
107] and pain at the injection site with high dose (40 mcg) compared to standard dose (20 mcg) [
114].
Tetanus, Diphtheria, and Pertussis
Since these diseases do not have elevated incidence rates and are not known to be associated with poorer outcomes among HIV-infected adults, vaccination recommendations mirror those for the general population. All major guidelines advise receipt of these vaccinations among HIV-infected adults stating that the primary doses are generally given during infancy, with boosters administered periodically to adults over time (Table
1). Specific guidance regarding those with an unknown or incomplete receipt of the primary series is addressed in each guideline [
6‐
9].
For those having received the primary vaccination series, WHO recommends tetanus toxoid (TT) and/or tetanus-diphtheria (Td) vaccines given to HIV-infected adults using the same schedule and doses as for HIV-uninfected persons [
6]. The guidelines stress the importance of vaccination especially among illicit drug users to prevent tetanus, especially in areas without needle exchange programs. Tdap vaccination is not specifically mentioned in the context of HIV-infected adults, but is recommended among pregnant women (during the 2nd or 3rd trimesters) and for healthcare workers caring for those at risk for disease (e.g., infants).
The BHIVA guidelines recommend giving a Td booster every 10 years, especially among those at risk for exposure (e.g., travel to an area where post-exposure prophylaxis would be difficult to receive after a tetanus-prone injury), among those who received the full primary vaccination series (5 doses) [
8]. Among those >50 years, shortening the interval for booster doses to every 5 years is suggested. Regarding pertussis, BHIVA recommends following the national guidelines, which currently recommend pertussis vaccination (e.g., Boostrix
®) among pregnant women (28–32 weeks) and during an outbreak. Vaccination among those meeting indications is advised regardless of the CD4 count, HIV viral load, or ART use [
8]. There are no specific EACS guidelines as HIV-infected persons should follow country guidance [
12]. Similarly, French guidelines recommend following national vaccination recommendations including the administration of dTP boosters every 10 years without altered schedules among HIV-infected persons [
14].
The US guidelines similarly recommend that previously vaccinated HIV-infected adults receive booster doses of Td every 10 years [
9]. A single dose of Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Boostrix
® or Adacel
®) is advised to replace a dose of Td if the person has not previously received Tdap. Additionally, HIV-infected adults who become pregnant should receive Tdap during each pregnancy (at 27–36 weeks). Also, HIV-infected adults caring for infants aged less than 12 months (at work or home) should also be considered for Tdap vaccination [
9].
Compared with HIV-uninfected adults, studies have shown lower antibody responses after tetanus and diphtheria vaccination among HIV-infected persons [
30,
115,
116]. For example, one study showed protective antibodies among 83–100% and 61–73% for tetanus and diphtheria, respectively, with variation by CD4 counts [
115]. Durability is poorly studied, but a study among HIV-infected children found that response rates after tetanus vaccination waned quickly [
117], raising the question whether Td boosters every 10 years are adequate. Further, seroprotective responses among older adults may be suboptimal [
118]; hence, the BHIVA guidelines recommend considering more frequent booster dosing among those >50 years [
8]. There are no current data regarding responses to the pertussis vaccination among HIV-infected adults, but antibody titers are lower than expected among HIV-infected children [
119].
Vaccination is overall safe with no increased adverse events noted among HIV-infected adults.