Avian Flu Diary: CIDRAP On Two NEJM Pandemic H1N1 Studies

# 4637

Last night Robert Roos of CIDRAP reviewed two studies that appeared yesterday in the New England Journal of Medicine (NEJM).

One on the use of Oseltamivir (Tamiflu) as a prophylactic measure among military units in Singapore, and a second on the transmission of novel H1N1 among family members in Hong Kong.

First the CIDRAP article (follow the link to read in its entirety), then a little discussion.

Studies examine H1N1 spread in military units, households

Robert Roos News Editor

Jun 9, 2010 (CIDRAP News) – When the H1N1 pandemic influenza began hitting Singapore's military forces last summer, health officials largely arrested its spread by giving oseltamivir to everyone in the affected units, in combination with other preventive steps, according to a report released today.

Among 1,175 soldiers in four settings, 75 were infected before the preventive steps were taken, and only seven became infected afterward, according to the report in the New England Journal of Medicine (NEJM). The findings suggest that antiviral "ring prophylaxis," along with quick identification and isolation of infected people, can be effective in halting outbreaks in "semiclosed" settings, the researchers said.

In a second study, also released today by NEJM, Hong Kong researchers looked at flu in a modest-sized sample of households and found that pandemic H1N1 and seasonal flu viruses spread at about the same rate and caused illnesses of similar severity.

(Continue . . . )

Lee VJ, Yap J, Cook AR, et al. Oseltamivir ring prophylaxis for containment of 2009 H1N1 influenza outbreaks. N Engl J Med 2010 Jun 10;362(23):2166-74 [Full text]
Cowling BJ, Chan KH, Fang VJ, et al. Comparative epidemiology of pandemic and seasonal influenza A in households. N Engl J Med 2010 Jun 10;362(23):2175-84 [Full text]
Uyeki TM. 2009 H1N1 virus transmission and outbreaks. (Editorial) N Engl J Med 2010 Jun 10;362(23):2221-23 [Full text]

I’m going to wander a bit away from these two articles with some background, but I will come back.

There are basically three uses for antivirals:

Treatment of those infected
Outbreak Prophylaxis for people who are likely to be exposed
PEP (Post Exposure Prophylaxis) - giving antivirals to those exposed, but not yet symptomatic to prevent infection.

Treatment is pretty much self explanatory. Patients exhibiting flu-like symptoms (or who have tested positive for influenza) may be given antivirals for 5+ days to inhibit viral replication and mitigate the severity of the infection.

Outbreak Prophylaxis would be used to protect those at high risk of infection, such as ICU and ER doctors and nurses during a pandemic wave. This would require a daily dose of the drug for weeks or even months.

PEP (Post Exposure Prophylaxis) is the U.S. equivalent of the ring chemoprophylaxis described in the Singapore study.

While the idea of Household PEP was floated by the HHS working group on antivirals back in June of 2008 in their Proposed Guidance on Antiviral Drug Use during an Influenza Pandemic, it was not officially endorsed.

In the two or three years before novel H1N1 erupted - as we watched and waited for a more severe H5N1 pandemic - the HHS built up the U.S. stockpile of oseltamivir (Tamiflu) to nearly 80 million courses (10 pills/course), and promoted the idea that hospitals and other large employers in the private sector stockpile antivirals for their staff.

In June of 2008, the HHS went so far as to hold a teleconference with officials from Roche Laboratories, to announce an antiviral reservation plan called RAPP, or the Roche Antiviral Protection Program (see Roche Offers Companies Option To Reserve Tamiflu).

The US Strategic stockpile of antivirals, at 80 million courses, was hoped to be enough to provide treatment during a severe pandemic, but would fall far short of what was needed if Outbreak Prophylaxis or PEP was to be implemented.

Without adding PEP, the HHS working group determined that the number of courses of antivirals the United States needs on hand for a severe pandemic would be at least 195 million

Roughly 2.4 times more than the government had stockpiled.

In Proposed Guidance on Antiviral Drug Use during an Influenza Pandemic the HHS working group urged that the private sector, mostly businesses - but `families and individuals as appropriate' - stockpile the rest.

This would provide:

6M doses for deployment overseas to try to stop an outbreak
79M treatment courses for the infected here in the United States
103M courses to provide prophylaxis for healthcare and emergency service workers
5M courses for outbreak control in Nursing homes, prisons, and other closed settings
2M courses for people who are severely immuno-compromised

The authors of this HHS document point out that more than 150,000 American lives could be saved in a severe pandemic if households had antivirals available for PEP, or Post Exposure Prophylaxis.

To implement household PEP, however, would require another 106 million courses of antivirals, bringing the total needed to just over 300 million courses.

While some companies did procure antivirals for their employees, most declined. The costs, logistics of storage and dispensing, legal barriers for dispensing prescription medications – plus the potential liability – dissuaded many employers from participating.

Fortunately, the pandemic of 2009 wasn’t severe enough to require the kind of antiviral intervention envisioned by the HHS working group back in 2008. The next time, we may not be so lucky.

H5N1 is still out there, and still has pandemic potential. As are a number of other novel influenza strains.

The Singapore study is valuable because it proves that ring prophylaxis (or PEP) apparently can work to slow down or contain an influenza outbreak in a closed or semi-closed setting.

It also bodes well for the effectiveness of Outbreak Prophylaxis among medical personnel, although there remain open questions on the wisdom of taking antivirals for weeks or perhaps months at a time.

And there remain legitimate concerns that the large scale use of PEP and Outbreak Prophylaxis strategies might contribute to the creation and spread of antiviral resistant strains of influenza.

And to add another complication, the second NEJM study out of Hong Kong also suggested that patients infected with novel H1N1 who were treated with Tamiflu produced lower levels of antibodies than those who went untreated, opening the possibility that they might be at risk for re-infection.

Even if antiviral resistance and side effects from long-term use of these medications were not concerns, the quantity of antivirals required for large scale chemoprophylaxis, and the need to deploy and dispense them rapidly in an outbreak, remain daunting challenges.

Frankly, I’ve serious doubts that in this economy, and after the relatively `mild’ pandemic experience of 2009, that the private sector can ever be induced to pick up the 100 million to 200 million course `shortfall’ in this country’s antiviral stockpile.

So the point, at least here in the US, may be moot.

Besides, even if they did make the investment in antivirals– given the concerns over potentially generating resistant flu strains - getting the government’s green light to dispense them might prove difficult.