2009 H1N1 Influenza: What Next for People with HIV?

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As a new flu season gets underway, a series of recent reports have looked at aspects of the 2009 H1N1 influenza strain responsible for last year's "swine flu" epidemic. Spanish researchers reported the promising finding that people with well-controlled HIV disease on antiretroviral therapy (ART) had H1N1 flu outcomes similar to those of HIV negative individuals. But another pair of studies found that HIV positive people -- especially those with low CD4 cell counts -- did not respond as well as HIV negative people to the H1N1 vaccine or an older flu vaccine. Finally, scientists with the National Institute of Allergy and Infectious Diseases (NIAID) recently projected what might happen with H1N1 this year and into the future.

The 2009 H1N1 influenza A strain was identified in Mexico in April 2009 and soon reached pandemic levels. While the World Health Organization (WHO) declared an official end to the swine flu this past August. That does not mean this flu strain has gone away. Experts expect that it will continue to circulate as a seasonal flu variant, though by now a majority of people are thought to have some degree of immunity.

H1N1 Outcomes in People with HIV

In the October 23, 2010 issue of AIDS, Melchor Riera from Hospital Son Dureta in Mallorca, Spain, and colleagues described the clinical presentation and prognosis of HIV positive patients admitted to hospitals with pandemic H1N1 influenza, as compared with the general population.
The analysis included 585 adult admitted to 13 hospitals in Spain with confirmed 2009 H1N1 influenza A between June and November 2009. Participants were prospectively followed until 1 month after discharge.

Within this population, 26 were HIV positive. The HIV patients had long-term well-controlled infection. About 90% were on combination ART (aka HAART), more than 80% had undetectable HIV RNA, and the median CD4 count was about 500 cells/mm3.

The average age of HIV positive and HIV negative people was similar (about 40 years), but those in the HIV group were more likely to be men (69% vs 50%) and less likely to be pregnant (12% vs 53%). HIV positive people were more often smokers and were much more likely to have received the H1N1 flu vaccine (56% vs 11%) and pneumococcal pneumonia vaccine (50% vs 3%). People with HIV were also more likely to have chronic liver disease and chronic obstructive pulmonary disease.

The researchers saw no significant differences between HIV positive and HIV negative people with regard to reported flu symptoms and physical findings upon hospital admission. About half of patients in both groups showed abnormal radiological (x-ray) findings, 30% had respiratory failure, and about 10% developed secondary pneumonia.

People in both groups started to improve after about 2.5 days on average and spent a similar amount of time in the hospital (6-7 days). Almost all patients in both groups received influenza antiviral therapy and most also received antibiotics. Similar percentages required intensive care (12%) and mechanical ventilation (8%-9%). There were no observed differences in clinical outcomes, and most people recovered; no HIV positive patients and only 3 HIV negative patients died.

"In HIV patients, well controlled on HAART, the pandemic influenza virus A H1N1 had a similar clinical outcome and prognosis to that of non-HIV patients," the study authors concluded.

H1N1 Vaccine

A pair of studies in the September 10, 2010 issue of AIDS looked at flu vaccine outcomes in people with HIV.

In the first study, Pablo Tebas and colleagues evaluated the safety and immunogenicity (immune protection) of the 2009 H1N1 vaccine in 120 HIV positive adults seen at a University of Pennsylvania hospital in Philadelphia. About 70% were men, a similar percentage were black, and the median age was 46 years. In this study, all participants except 1 were on ART and more than 90% had undetectable viral load. The median current CD4 cell count was 502 cells/mm3 and the median nadir (lowest-ever) count was 132 cells/mm3.

All participants received a single 15 mcg intramuscular dose of a monovalent, unadjuvanted (that is, not containing extra ingredients to boost immune response), inactivated H1N1 vaccine. At baseline, 25% had antibody evidence of previous H1N1 exposure. Among HIV positive people those without prior exposure, 61% develop protective antibody titers by week 3 after vaccination, compared with typical rates of around 90% for HIV negative people. Non-responders had lower current and nadir CD4 cell counts and less time with suppressed viral load. Among the 9 patients with detectable viral load, only 4 -- less than half -- developed protective immunity.

Given this suboptimal response, the researchers recommended, "Alternative vaccines, dosing, adjuvants, or schedule strategies are needed to achieve effective immunization of this vulnerable population."

In a second study in the same issue, Stefanie Fritz from Basel University in Switzerland and colleagues conducted a prospective study of a different flu shot -- the 2007-2008 seasonal flu vaccine -- in 31 HIV positive and 24 HIV negative people. All HIV positive participants had been on ART for at least 3 months and had HIV RNA < 200 copies/mL.

In this analysis, HIV positive people with CD4 cell counts below 350 cells/mm3 were significantly less likely to develop protective H1N1-specific T-cell responses than those with higher counts, who in turn were less likely than HIV negative individuals (22%, 64%, and 92%, respectively). In the low CD4 group, H1N1-specific immunoglobulin M (IgM) antibody responses were absent, and expansion of interferon-gamma-secreting CD4 T-cells was impaired. However, immunoglobulin G (IgG) responses from memory cells were seen in all 3 groups.

These findings led the investigators to suggest that, "establishing broad influenza-specific (immunoglobulin G) B-cell memory prior to severe immunodeficiency is important," and they recommend that HIV positive people should receive flu vaccines regardless of CD4 count.

A related Canadian study presented at the 48th Annual Meeting of the Infectious Diseases Society of America in October found that children with HIV have suboptimal response even to an adjuvanted H1N1 vaccine, with only about 30% achieving adequate protection.

Fate of H1N1

In the September 28, 2010 issue of the open-access online journal mBio, Anthony Fauci and colleagues from the National Institute of Allergy and Infectious Diseases speculated on the future of H1N1 swine flu, based on the fate of previous pandemic influenza viruses.

Below is the text of a NIAID press release describing their analysis.

What Next for the 2009 H1N1 Influenza Pandemic?

Washington, DC -- September 28, 2010 -- Now that the H1N1 influenza pandemic is officially over, what will happen to the virus? In a perspective article published today in the online open-access journal mBio, scientists from the National Institutes of Health delve into history and explore the fates of other pandemic influenza viruses in order to speculate on the future of the most recent pandemic virus.

"While human influenza viruses have often surprised us, available evidence leads to the hope that the current pandemic virus will continue to cause low or moderate mortality rates if it does not become extinct," write Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) and his NIAID coauthors, Jeffery Taubenberger and David Morens.

The impact of the virus in the upcoming influenza season will depend directly on the degree of existing immunity in the population, provided the virus does not undergo any changes. The authors currently estimate that approximately 59% of the United States population has some level of immunity due to either exposure to the pandemic H1N1 (pH1N1) virus, vaccination or exposure to a closely related influenza virus. That number will continue to increase through immunization with the 2010-2011 seasonal influenza vaccines, which will contain the pH1N1 strain.

In order to continue to survive in a population with such a high immunity, the pH1N1 virus must undergo either an abrupt or a gradual change. In the article, the authors look at the last six influenza pandemics, going back over 163 years, and examine how those viruses adapted. While some died out for reasons not entirely understood, others, like the 1889 and 1918 pandemics, experienced an explosive recurrence. Explosive recurrence of pH1N1 is not very likely because of the already high and increasing population immunity.

"Past history and current understanding suggest cautious optimism that pH1N1 will eventually adapt to stable circulation via genetic changes resulting in continuing moderate or low mortality rates or possibly even disappear entirely," the NIAID scientists write .

Despite their cautious optimism, the authors warn against complacency. Other post-pandemic viruses have continued to cause various rates of excess mortality among younger persons for years after the pandemic appearance and the bulk of the still susceptible population spans the under-50 age group. For that reason they recommend infants older than six months, children, teens and young adults be aggressively targeted for seasonal influenza vaccination for not only their own protection, but to increase the overall population immunity.

Investigator affiliations:

Riera study: Palma De Mallorca, Hospital Son Dureta, Mallorca, Spain.
Tebas study: University of Pennsylvania School of Medicine, Philadelphia, PA.
Fritz study: Department of Biomedicine, Basel University, Basel, Switzerland.
Brophy study: Departments of Pediatrics and Infectious Diseases, Children's Hospital of Eastern Ontario, Ottawa, Canada; Infectious Diseases, McGill University, Montreal, Quebec, Canada; Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

References

M Riera, A Payeras, MA Marcos, and others. Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter study. AIDS 24(16): 2461-2467 (Abstract). October 23, 2010.

P Tebas, I Frank, M Lewis, and others. Poor immunogenicity of the H1N1 2009 vaccine in well controlled HIV-infected individuals. AIDS 24(14): 2187-2192 (Abstract). September 10, 2010.

S Fritz, E Mossdorf, B Durovic, and others. Virosomal influenza-vaccine induced immunity in HIV-infected individuals with high versus low CD4+ T-cell counts: clues towards a rational vaccination strategy. AIDS 24(14): 2287-2289 (Abstract). September 10, 2010.

G Reyes-Teran and ST Butera. Preventing influenza coinfection among HIV-infected persons: a complex picture coming into focus (Editorial Comment). AIDS 24(14): 2283-2285.

JC Brophy, B Ward, LM Samson, and others. Immunogenicity of AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine in HIV-Infected Children. 48th Annual Meeting of the Infectious Diseases Society of America. Vancouver, October 21-24, 2010. (Abstract 1509).

DM Morens, JK Taubenberger, AS Fauci. and others. The 2009 H1N1 pandemic influenza virus: What next? mBio 1(4): e00211-10 (free full text). September 28, 2010.