The impact of seasonal influenza in patients with HIV infection has been debated in the medical literature and systematic clinical guidance on treatment and benefits of vaccination has yet to clearly emerge, in part owing to limited data. A significant excess mortality due to pneumonia or influenza has been found in this population , but a typical clinical presentation and a rate of secondary complications similar to those of non-HIV infected individuals have also been reported . Without question, HAART has improved the clinical course of HIV-infected individuals and significantly decreased mortality , and hospitalization rates owing to cardiopulmonary disease . Similar therapeutic benefit may be deduced from initial reports focused on HIV-infected persons with the pandemic influenza virus A (H1N1) during 2009. One such study involved 20 HIV patients on HAART (median CD4 cell count of 494 cells/μl; viral load of <400 copies/ml), the clinical presentation of influenza disease was not distinctive from that reported in HIV-negative individuals, and a favorable outcome was observed in the majority of individuals . Another study included 56 individuals with controlled HIV infection (median CD4 cell count of 583 cells/μl; 95% had <50 copies/ml); HIV infection did not make influenza A (H1N1) more clinically severe and influenza A (H1N1) did not have a major effect on clinical measures of HIV infection . In contrast, among patients with advanced HIV disease, H1N1 infection appeared more severe with clinical and radiographic symptoms masked by active opportunistic infections, thus delaying H1N1 antiviral treatment . These initial studies clearly suggest that stage of HIV disease and accessibility of HAART must be considered when estimating the impact of influenza.
Influenza vaccination is recommended for persons with HIV infection [Centers for Disease Control and Prevention. Updated interim recommendations: HIV-infected adults and adolescents – considerations for clinicians regarding 2009 H1N1 influenza (http://www.cdc.gov/h1n1flu/guidance_HIV.htm)]; however, a diminished immunogenicity and efficacy of the influenza vaccine has been described in this population, especially, among those with lower CD4 cell counts. Immune responsiveness to vaccination is expected to be less effective in those individuals with advanced HIV disease . However, data on clinical vaccine effectiveness among persons at different stages of HIV disease progression are quite limited. One small retrospective study did find that among persons with CD4 cell counts of more than 100 cells/μl or HIV loads of less than 30 000 copies/ml, the inactivated influenza vaccine likely reduced illness severity among HIV-infected persons . In this issue, Tebas et al.  analyzed the efficacy of a licensed monovalent, unadjuvanted, inactivated, split virus (H1N1) 2009 vaccine in 120 HIV-infected individuals. Even though all study individuals except one were on HAART and well controlled (median CD4 cell count of 502 cells/μl; 92% had <400 copies/ml), only 61% developed what is generally considered a likely protective influenza titers, defined in this study as at least 1: 40. Immunogenicity and clinical effectiveness are separate issues and the true test of vaccine-induced protection ultimately is clinical effectiveness. But, the study does suggest that a significant proportion of HIV-infected individuals will remain vulnerable to influenza after vaccination. The study also suggests that more immunogenic influenza vaccines may be needed for immune compromised persons, including those with advanced HIV disease. In addition, authors include experiences from countries with limited resources, where only a fraction of the vulnerable HIV-infected population have access to or receive antiretroviral therapy (ART). In support of these findings, a low rate of seroconversion after vaccination with another influenza A (H1N1) 2009 licensed vaccine was recently reported in HIV-1-infected patients .
Another study presented in this issue, involves a novel influenza vaccination strategy for HIV-infected individuals. In a prospective trial with a trivalent virosomal influenza vaccine, Fritz, et al.  found that HIV-infected individuals with low CD4 T-cell counts (<350 cells/μl) were unable to develop influenza specific-immunoglobulin M responses and expansion of interferon-γ secreting CD4 T-cell counts; but most importantly, they were able to develop specific immunoglobulin G (IgG) responses to the tested influenza vaccine. Two immediate conclusions are derived from this finding: first, the fact that B cell memory was still functional in these individuals was evidenced by the observed specific IgG response. Therefore, influenza vaccination strategies might remain advantageous owing to this partially preserved B cell memory function even among HIV-infected individuals with low CD4 T-cell counts. This second conclusion has direct clinical relevance in that the study provides an immunological rational supporting the strategy for annual influenza-vaccination of all HIV-infected individuals, regardless of their CD4 T-cell count. The molecular mechanisms mediating virosomal-induced immune responses also deserve to be explored, particularly in the case of influenza vaccines in HIV-infected individuals, as live attenuated influenza vaccines are contraindicated and only inactivated virus vaccines can be used in this population. Centers for Disease Control and Prevention. HIV/AIDS and the flu. (http://www.cdc.gov/flu/protect/hiv-flu.htm).
Because influenza vaccination is the main prophylactic approach aimed at protecting the population against influenza, suboptimal vaccine efficacy in HIV-infected persons represents a critically important matter. Current evidence evaluating influenza vaccination efficacy in HIV population remains insufficient and additional data would further solidify current public health recommendations . As stated earlier, one key issue would be if HIV-infected persons would benefit from more immunogenic or adjuvated influenza vaccines. Randomized studies in HIV populations with representative sample sizes, evaluating clinical outcomes such as incidence, severity and duration of influenza disease are required. The inclusion of patients, grouped according to the stage of HIV disease, with documented CD4 T-cell count reconstitution during HAART would be valuable to describe the effect HIV treatment on influenza vaccine response. Comparability of data across studies would represent an added value by allowing subsequent meta-analyses.
Late presentation for HIV care may also contribute to suboptimal efficacy of influenza vaccination in HIV infection. Data from multiple clinical sites across the United States and Canada indicate that many patients continue to present first for HIV care with a CD4 cell count below 350 cells/μl, the lower level at which initiation of ART is currently recommended by multiple major national guideline committees . However, in countries with limited resources, where the majority of people with HIV infection reside, presentation for HIV care occurs even later. For instance, across Africa, patients first present for HIV care with an estimated average range between 85 and 125 CD4 T cells/μl, depending on the country . Therefore, implementation of effective public health programs for timely detection and care of HIV will also impact influenza morbidity and mortality rates in this population. The use and benefits of approved antiviral treatment for influenza among HIV-infected patients also needs to be more fully explored and clinically defined. All of these various clinical and immunological aspects of HIV infection must come together to bring effective influenza policies into focus.
We thank Claudia Alvarado-de la Barrera for preparation of the manuscript.
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