Influenza Transmission Dynamics in HIV

An overview of results

This study set out to identify the effectiveness of influenza vaccine in HIV positive patients and found that influenza vaccine is indeed effective in such patients. A recent study conducted by Cohen et al (2018) looking at household transmission of seasonal influenza from HIV- infected and uninfected individuals in South Africa between the years 2013-2014 revealed influenza burden may be affected by differential transmission from HIV-infected in comparison to HIV-uninfected individuals. The researchers estimated the household secondary infection risk (SIR) and serial interval (SI) for influenza transmission from HIV-infected and HIV-uninfected index cases and identified associated factors. The study enrolled 28 HIV infected cases and 57 HIV-uninfected index cases (those that display symptoms first in a household) and found that HIV-infected index cases were less likely to transmit influenza to household contacts. Factors associated with increased SIR included index age group 1-4 years and 25-44 and contact age group 1-4 years compared to 5-14 years. HIV-infection of an index case was not associated with SI. The study concluded that increased infectiousness of HIV-infected individuals is likely not an important driver of community influenza transmission. (best placed in intro?)

It is well established that patients with the HIV virus are more susceptible to contracting flu because of the HIV-driven immune response and potential for immune compromise, if untreated. This systematic literature review is of particular importance because it gives a deeper insight into the effectiveness of the flu vaccine as a medical intervention to protect HIV-positive individuals from the virus. There are a number of vaccines given to HIV positive patients, but this study chose the flu vaccine as an object of interest because the existing evidence base reveals that flu is amongst the most common cause of respiratory illness among HIV positive patients (Carevolo et al, 2013). Secondly, flu was of specific interest to the study because research by Glinka et al indicates that it leads to an exacerbation of respiratory diseases, which are common among HIV patients. Last but not least, the flu vaccine was of particular interest to this study as according to Glinka and colleagues, HIV positive patients who are not on antiretroviral therapy are more likely to experience higher flu-related complications, increased severity and longer duration of such illnesses. This realization has a major implication on the health and well-being of this group of patients especially due to the fact that a proportion of those infected by HIV-positive patients have not been diagnosed yet they remain susceptible to HIV-related immune compromise and infections with flu and other infectious diseases.

Conclusions made by this study on the effectiveness of the flu vaccine are limited because the study only involved 5 research studies that were eligible for inclusion into the study and the variability of the results of each included study. However, there is evidence to suggest that there is flu vaccine effectiveness and efficacy in HIV positive patients. This statement can be supported as all the vaccines used in 3 (i.e. Ellis et al, Garg et al, and Mark et al) out of 5 studies proved to be either safe or effective. For instance, Ellis et al confirmed that the trivalent inactivated flu vaccine is effective in preventing the flu among HIV positive individuals. Besides, Garg et al concluded that both standard-dose intramuscular flu vaccine and the intradermal trivalent inactivated flu dose had no adverse events HIV positive patients. Mark et al also found that doses of unadjuvanted inactivated P1H1N1 vaccine were effective in HIV positive pregnant women. However, due to the limited number of sample participants in 4 out of the 5 studies, this efficacy and effectiveness might have been underestimated.

Studies by Sybil et al found that the flu vaccine was highly effective in HIV positive patients. Their statistical analysis revealed a confidence interval (CI) of between 75% - 100% for symptomatic influenza with a p-value of 0.001%, and a protective efficacy of 100%, confidently revealing that the flu vaccine offers protection to HIV positive patients. Their conclusion was also supported by the fact that they did not find any substantial changes in the participants’ CD4 count and viral load. In regard to the knowledge of how effective the influenza vaccine is, Ellis et al found that a considerable number of their participants (35%) had knowledge that the flu vaccine was effective in preventing them from contracting the flu. However, Ellis et al failed to indicate whether these remarks were out of the participants’ experience or not.

An overview of methodological processes

Due to all the studies in this review having different objectives, they all adopted different methodological processes thereby making it difficult to combine the results of the five studies in a meta-analysis. However, 2 of the studies were randomised controlled trials and therefore as will be illustrated herein, their results were easily comparable. First, the study by Glinka et al was not comparable to any of the four other studies because it was of a unique methodology i.e. a retrospective cohort study. There are several methodological shortcomings of this study. For instance, the researchers retrospectively analysed the computerised patient records but failed to have any control over the group’s outcome assessments or exposures. The retrospective nature of the study exposed the study results to miss-classification bias or selection bias, and the researchers could not establish any temporal relationships. Lastly, the study needed a large sample, yet at some point, the outcomes could have been rare. An advantage of the study is that by choosing the retrospective study methodology, the researchers were able to achieve their research objectives within a short time because they relied on already existing data. The study would have also been manageable because of its small-scale nature. More importantly, the retrospective nature of the study enabled the researchers to analyse the results of multiple outcomes, i.e. the outcomes of those considered to have had an early vaccination as well as those considered to have had a late vaccination.

Secondly, results by Ellis et al were not comparable to any of the study results because no other study took the cross-sectional methodological approach. The study’s outcome measures were so different from those of other studies; hence it could not be combined with other studies in a meta-analysis. It is also important to note that the study had several limitations that might have affected the validity and reliability of its outcomes. For example, the researchers were not generally able to discern the temporal relationship between the exposure and outcomes, hence, the researchers could not establish the cause-effect relationship, it is a possibility as to why they did not indicate the reason why some respondents stated that the flu vaccine was effective, as well as why some claimed that the flu vaccine would make them feel ill and terrible. This limitation, therefore, made it difficult to draw any predictive outcome from the study results and conclusion.

Mark et al intended to measure the safety and immunogenicity of the flu vaccine in HIV infected pregnant women. Their longitudinal cohort study had different measurements of safety and immunogenicity of flu vaccine compared to the other four studies. However, Mark et al made a follow-up within 2, 10 and 21 days after the administration of each vaccine (there was no indication of the mean time difference). However, it is not possible to compare and determine the appropriateness of these follow-up durations due to of a lack of another cohort study included in this systematic literature review. There are several limitations inherent in longitudinal cohort studies that may be of importance to note. Firstly, even though the researchers collected data at different points of the study (i.e. at baseline, 2, 10 and 21 days after vaccination), they could not take any account of these observational periods irrespective of any happenings at each point of observation. More worryingly, the respondents might have altered their qualitative responses to suit what they think the researcher was trying to observe. Nonetheless, it is important to appreciate that the study did not experience any case of panel attrition as all the participants were available for all the follow-ups.

Both Sybil et al and Garg et al were randomised controlled trials. The two studies also had different outcome measurements making it impossible to compare their results. For instance, Sybil et al measured the effectiveness of the flu vaccine in HIV infected persons by measuring their antibody titers, HIV RNA level, and CD4 counts. On the other hand, Garg et al compared the immunogenicity of ID and IM flu vaccines by testing serum specimens of the participants to determine the seroconversion and seroprotection levels of the specimens. This comparison reveals totally different outcome measurements that could not allow for the inclusion of the two studies in a meta-analysis. However, it is important to note that one trial revealed that the flu vaccine was effective and had some level of efficacy in HIV positive patients, while the other trial revealed that both ID and IM were safe and associated with no adverse events. This is demonstrated in Sybil et al who found that the flu vaccine had a 100% protective efficacy (or vaccine effectiveness), with a confidence interval of 75% to 100%. On the other hand, Garg et al found that both ID and IM were equally safe and had an equal level of immunogenicity with a p-value of .8 and .7 respectively.

Strengths and limitations of the structured literature review

The researcher believed that the systematic literature review methodology was the best approach for evaluating the effectiveness of the flu vaccine in HIV-positive individuals. It is important to be cognisant of the fact that the study process was characterised by several practical challenges, strengths and limitations. In regard to practical challenges, there was a time constraint placed on the duration of the study which led to only 5 articles being reviewed in a limited time as well as only one researcher conducting the review. This would not make it feasible to review many studies which would have been advantageous in the study results; however, due to the purpose of this review being an academic form of assessment this is acceptable.

However, there emerged several advantages of this systematic literature review in comparison with traditional literature review. For instance, this study helped in reducing the implicit researcher bias in comparison to traditional literature reviews. Due to there being several traditional literature reviews on the same topic area, these materials become too restricted to already popular authors, and they are not conducted based on deep and detailed research. This implies that most traditional literature reviews are inherently characterised by persistent bias. The current systematic literature review eliminates this bias by relying on detailed and systematic research, thereby developing evidence from unique and quality research articles.

As opposed to traditional literature reviews that do not focus on study designs, analytical methods and data used, this systematic review had an in-depth focus on the causality, validity, impact and evidence. Highlighting the design (e.g. data collection techniques or sampling methods) of the studies included in the systematic literature review was able to measure the robustness of the evaluated research evidence. This study also classified the characteristics and quality of the studies through a standardised criterion, thereby developing a cross-study comparison that yielded verified evidence. Last but not least, the use of systematic literature review methodology enabled the researcher to have a step by step guidance throughout the study while maintaining the methodological transparency of the study for purposes of enabling any future replication.

Comparison of the study findings with the current available evidence base

Safety of the flu vaccine

The findings of this study resonate and corroborate with various pieces of literature highlighting the current knowledge base of the flu vaccine and HIV-positive patients. Firstly, there are many studies that have confirmed the tolerability of the flu vaccine in HIV-positive patients. Existing studies have confirmed good tolerability of the flu vaccine in HIV-positive patients, and that the vaccine contributes to a disappearance of flu symptoms without short term sequelae (Glenn et al 2009). However, Glenn et al acknowledge that there is a paucity of evidence over the concern of adverse events in the long-term.

All the 4 studies in the present systematic literature review did not report any serious adverse events related to post flu vaccine. Adverse events here denote any occurrence that leads to death that requires hospitalisation, that leads to disability or that leads to any form of congenital anomaly (Amendola et al, 2001). This corroborates with several other studies conducted globally, which revealed no adverse events on patients after receiving the flu vaccination. Nonetheless, there are other studies that have attempted to look into the side effects of some influenza vaccines and made important observations that are worth mentioning here. For instance, a recent systematic review study by Sarkanen et al (2018) attempted to evaluate the incidence of narcolepsy among recipients of H1N1 influenza vaccination, especially during the mass vaccination campaign in 2009-2010. The study was informed by the revelation that earlier observational studies were marred with several cases of bias such as selection biases and recall biases. The systematic review found that the risk of narcolepsy was associated with with one particular vaccine i.e. Pandemrix®.

One of the most common flu vaccines used in HIV-positive patients is the Trivalent Influenza Vaccine (TIV). However, existing literature by O’Brien et al (2005) revealed that TIV vaccine has a good safety profile and is associated with no serious adverse events. Likewise, a study conducted by Durado et al (2008) indicated an absence of any serious adverse events after comparing two flu vaccines i.e. one with MF59 adjuvant and one without the adjuvant. However, it is important to note that some male participants in Durado et al experienced cases of transitory ischemic attack, even though the incidences had no correlation with the flu vaccine itself. Another study undertaken by Cooper et al (2009) revealed no adverse events following vaccine. Specifically, Cooper et al used a trivalent non-adjuvant influenza vaccine in HIV- positive adult patients and results showed no adverse events. The vaccine was tolerated with no increase in reactogenicity even after a higher boosting or antigen dose. It is also important to note that Cooper et al divided their study sample population into three major categories. One category received a 0.5 mL hemagglutinin as well as a booster dose 28-day after the vaccine. The second category received 30μg hemagglutinin with a booster dose 28 days post-vaccination, while the third category of participants received only one dose of the hemagglutinin vaccine.

One study in this systematic literature review (Mark et al) used the pH1N1 vaccine on HIV-positive pregnant women and did not report any serious adverse events. This corroborates with the findings of other studies that have found no adverse events with the pH1N1 influenza vaccine. For instance, Crum-Cianflone et al (2011) evaluated the effectiveness of the pH1N1 vaccine in HIV-positive patients and compared it with its effectiveness in HIV-negative patients. In this study, only one participant experienced an adverse event characterised by angioedema, which resolved after 7 days after undergoing antihistamine therapy. Ceravolo et al (2013) also report a study where 111 adults and 892 children were exposed to attenuated flu vaccine and did not experience any case of adverse event related to the vaccine. The vaccine was said to be safe and effective. The findings on the safety and effectiveness of influenza vaccine are extended by Weinberg et al (2010) who assert that live attenuated flu vaccines should not be used in patients with immunodeficiency issues and that the vaccine should be evaluated for use in HIV-positive patients. Nonetheless, Gabutti et al (2005) report that the virosomal influenza vaccine is not associated with any adverse events following no experience of such reports among his study participants who comprised of HIV-positive children and adults.

Furthermore, Launay et al (2011) reported only three cases of adverse events among the study participants, 42 days after vaccination with monovalent adjuvant flu vaccine with ASO3. These cases consisted of hospitalisation after the administration of the second dose. Likewise, Palmar et al, while evaluating the safety and immunogenicity of immunovalent adjuvant flu vaccine among HIV-positive patients, reported no serious adverse events or death upon conducting a study follow-up. Palmar and colleagues also found no correlation between any severe adverse event and the flu vaccine. On the same not, many studies such as (Calmy et al 2012, Launay et al 2011, and Crum-Cianflone et al 2011) have reported that influenza vaccine regardless of being adjuvant or not, are safe, effective and well tolerated by HIV positive patients.

One study included in this systematic review (Garg et al) evaluated the effectiveness of the flu vaccine in HIV-positive patients by measuring any systemic reactions post-vaccination. The study did not find any higher systemic reactions among the participants except for a few cases that displayed malaise, headache, and myalgia. These results corroborate with the findings of several other studies that have evaluated the aspect of systemic reaction post-influenza vaccination in HIV-positive patients. Systemic reactions are those that are experienced a few hours after vaccination and most of them may only last for one to one-and-a-half days (Ceravolo et al, 2013). According to Ceravolo et al (2013), these reactions may be as a result of immune system reactivity, vaccine adjuvant toxicity, or endotoxins activity. More importantly, these reactions are normally mild but may sometimes be severe and may require treatment.

In the study by Durado et al which compared the safety and effectiveness of two subunit influenza vaccine with adjuvant in HIV-positive patients, there were reports of fever and headache in both groups at 25.9% and 28.4% respectively. In another study, Evison et al compared adverse systemic effects in subunit influenza vaccine vs. virosomal influenza vaccine among HIV-positive patients. The study reported fatigue, malaise, and headache as the most common systemic reactions in both groups. To this end, it is important to note that systemic reactions are the most frequent in patients receiving adjuvant vaccines (Ceravolo et al, 2013).

Flu vaccine: CD4 cell count and HIV-RNA

One study (Sybil et al) included in the current systematic literature review measured the efficacy and effectiveness of the flu vaccine by assessing the effects of the vaccine on the participants’ CD4 cell count, HIV-RNA, and changes in the participants’ viral load post-vaccination. The results of Sybil et al contributed to the conclusion made by this literature review that the flu vaccine works effectively in HIV-positive patients. Indeed, this conclusion corroborates with other existing studies that have attempted to make an inquiry into the effectiveness of the flu vaccine. A deeper evaluation of existing evidence (especially studies produced between 1995 and 2012) reveals conflicting data regarding viral load increase and CD4 count decrease after flu immunisation in HIV-positive patients. However, Ceravolo et al (2013) and Crum-Cianflone et al (2011) point out that the conflicting nature of reports could be a result of many factors such as a difference in sample sizes, a difference in vaccines used, demographic characteristics of the population sample or the timing of sampling assays. Studies by Zanetti et al (2002) and O’Brien et al (1995) report an increase in viral load among participants after receiving the flu vaccine. To expand further, Calmy et al (2012) strongly believe that an increase in viral load is usually attributable to activation of quiescent HIV infected CD4 cells. Gunthard et al (2000) also indicates that when there is an up-regulation of HIV cells, the patient is likely to experience an increase in their viral load.

The conflicting evidence on the effects of the flu vaccination in HIV-positive adults is also exemplified in the studies by Machado et al (2011) and Kosalaraska et al (2011). For instance, the latter found that there was an increase in HIV-RNA levels in children from the age 6 months and below 18 years even though they insisted that the increase in HIV-RNA was as a result of transient factors that were of little clinical significance. On the contrary, Machado et al found no increase in CD4 counts or viral load among children of 12 years average age. Nonetheless, studies by Taker et al found an increased replication of HIV and a decrease in the percentage of CD4 cells when they evaluated HIV-positive patients who had received a flu vaccine. To explain their results, the authors highlighted that the effect could have been as a result of failure to treat the participants with ART. However, it is important to note that recent studies (e.g. Fuller et al 1999 and Calmy et al 2012) with better research designs do not reveal any evidence regarding HIV replication or immune stimulation as a result of flu vaccination, nor have they revealed any significant change in CD4 cell counts or plasma virus. These studies indicate the transient nature and the rarity of increased T-cell response or an increased HIV-RNA level after flu vaccination.

Implications for Policy and Practice

One of the studies in this literature review, Glinka et al, has concluded that vaccinating HIV patients early in the flu season yields more effective results than vaccinating them late in the season. This conclusion is based on the premise that HIV infected patients have a low immune response to the flu vaccine and that any immune response quickly wanes. When the immunity wanes, it puts the patients at high risk of flu later in the flu season. A possible implication of this is that physicians should consider giving high-dose or re-vaccination as a possible remedy for reducing HIV patients from high risk of contracting the flu virus. Besides, having confirmed the effectiveness of flu vaccines in HIV-positive patients, physicians can consider using other types of flu vaccines such as VANTAFLU® and FLAUD®, both of which have been confirmed by latest research evidence (i.e. Yoo et al 2018) to be effective especially in adults of age 65 or above. Another influenza vaccine supported by latest evidence-based research, which can be used in the MF59-adjuvanted (MF59-TIV) influenza vaccine which was found by Domnich et al (2016) to be effective in reducing influenza outcomes especially among the elderly. Another alternative could be giving the flu vaccine at the optimal timing enhance its effectiveness. For purposes of high-dose or re-vaccination, the immunisation authorities must allocate more funds in the case of HIV-positive population groups compared to the HIV- negative population. It may also be important to compare, which among MF59-adjuvant the high-dose vaccines are most effective. Nevertheless, the findings of this study are that the flu vaccine is more effective in HIV-positive patients when delivered early in the flu season than later in the season and implies that practitioners can delay booster flu vaccination for HIV-positive recipients so as to eliminate the likeliness of contracting flu later in the season.

It is well established that the flu vaccine is beneficial to healthier adults. When there is a decrease in illness, adults are able to dedicate their time to work and earn an income. The effectiveness and efficacy of the flu vaccine documented in this study call on policymakers and clinicians to provide for and embrace routine flu vaccination for HIV-positive adults. This study supports the safety and effectiveness of both ID and IM flu vaccine in women. A possible implication for policy-makers is that there is a need for continued efforts in regulating, monitoring and ascertaining the production of ID and IM flu vaccines not only for healthy patients but also for HIV-positive patients so as to protect and reduce the likelihood of contracting the flu virus.

This study has also evaluated the awareness of the effectiveness of the vaccine in HIV-positive adults. Whilst there is a considerable level of HIV awareness among HIV-positive patients regarding the flu vaccine, achieving a wide-spread and high-level awareness requires that health authorities should invest more resources and labour in awareness programs that improve flu vaccine uptake among HIV-positive patients. Clinicians who interact with HIV patients more frequently should take the initiative to educate and assist HIV-patients to understand the importance and need for flu vaccine immunisation.