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Nov./Dec. 2009
Vol. 19 No. 11
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IDSA Journal Club
November/December 2009

In this feature, a panel of IDSA members identifies and critiques important new infectious diseases studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

Good News and Not So Good News: Hepatitis B Vaccine Associated with Long-Term Immunogenicity, But Prophylactic Paracetamol Following Childhood Vaccinations May Diminish Immunogenicity
Reviewed by Khalil Ghanem, MD, PhD

Booster doses following hepatitis B vaccination are not needed even more than two decades after primary immunization. The encouraging results come from a study published in the Nov. 1 issue of The Journal of Infectious Diseases.

Among 493 Alaska Native adults and children who received the primary doses of hepatitis B vaccine in 1981, 60 percent still had antibody levels ≥10 mIU/mL (protective level) 22 years later. Among those who had lower or undetectable levels of antibody, 81 percent responded to a booster dose, suggesting that immunological memory was preserved. In addition, none of the vaccinated patients, even those with undetectable antibodies, were found to be infected with hepatitis B.  These data highlight two important points:  Immunity to hepatitis B vaccine is long-lived, and antibody concentrations may not be the best indicator of long-term protection, as other immune mechanisms, such as cellular immunity, may be important in mediating continued protection.

In another vaccination related study, prophylactic paracetamol, also known as acetaminophen, given to children for 24 hours after immunizations decreased post-vaccination febrile episodes but also significantly decreased antibody titers to the vaccine. The findings were published in the Oct. 17 issue of The Lancet.

Four hundred and fifty nine infants (mean age 12 weeks) were randomized to receive either placebo or three doses of prophylactic paracetamol following primary and booster immunizations (a 10-valent pneumococcal non-typeable H. influenzae conjugate vaccine, DTPa-HBV-IPV/Hib and rotavirus vaccines) in this open label study. Although severe febrile reactions were uncommon in both groups, children receiving paracetamol were approximately 50 percent less likely to experience fevers greater or equal to 38 ̊C.  However, there was a significant reduction in mean antibody titers in infants receiving paracetamol in response to several of the vaccines, including pneumococcal conjugate, Hib, diphtheria, and tetanus.

The big question is whether this study should change clinical practice. Although paracetamol use decreased febrile reactions and pain, serious reactions were exceedingly rare in both groups, suggesting that, short of minimizing mild discomfort, paracetamol use was of limited clinical benefit. However, the long-term implications of reduced antibody titers are not clear.  The authors’ conclusion appears reasonable: Prophylactic paracetamol administration in infants should not be routinely recommended without careful weighing of the potential risks and benefits.  Whether these findings are applicable to older children and adults is unknown.

(McMahon et al. J Infect Dis 2009;200:1390–1396 and Prymula et al. Lancet 2009;374:1339-1350)

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Treating Hyperlipidemia in Patients on Protease Inhibitors (PIs): Rosuvastatin Versus Pravastatin
Reviewed by Kathryn E. Stephenson, MD, MPH

A recent study from the journal AIDS sheds some light on a common clinical question: What is the best way to lower cholesterol in HIV patients taking antiretroviral regimens that include boosted protease inhibitors (PIs)?  Statins are the most effective drugs to treat hyperlipidemia, but many are metabolized by the CYP3AF enzyme, which is inhibited by PIs, particularly ritonavir.  Pravastatin does not use CYP3AF and is thus widely used for these patients.  However, it is not the most effective statin, especially when compared with rosuvastatin, which also does not use CYP3AF. 

In this French study, published online ahead of print, patients with HIV-1 and dyslipidemia (LDL > 158 mg/dL) were randomized to receive either pravastatin or rosuvastatin in a multicenter, open-label trial.  All patients were required to be on a stable antiretroviral regimen containing a boosted PI.  Over a two-year period, 88 patients were enrolled at 21 centers.  Both groups were balanced in terms of type of PI therapy and baseline lipid levels.

After 45 days of statin therapy, pravastatin lowered LDL levels by a median of 19 percent compared with 37 percent in the rosuvastatin group (P<0.001).  Pravastatin also lowered triglyceride levels by a median of 7 percent compared with 19 percent in the rosuvastatin group (P=0.035).  Trough plasma concentrations of both statins were within expected ranges, and there were no significant differences in lab parameters or adverse events in the two groups. 

These results indicate that rosuvastatin is more effective than pravastatin, and just as safe, in reducing LDL and triglyceride levels in patients with HIV on antiretroviral regimens containing a boosted PI.  The primary weakness of this study is that the data is not tied to clinical endpoints, such as cardiovascular events or mortality.

(Aslangul et al. AIDS 2009:23: (ahead of print))

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The Thai HIV Vaccine Trial: A Possible Milestone, but More Research Is Needed
Reviewed by Jonathan Li, MD

For the first time, a group of researchers has found a significant, though modest, protective effect afforded by an HIV vaccine. The findings of their study, published online in the New England Journal of Medicine on Oct. 20, also suggest there is more work to be done before an effective vaccine can be developed for widespread use.

Investigators enrolled 16,402 healthy Thai adults between the ages of 18 and 30 years old in a multicenter randomized controlled trial.  Patients in the experimental arm first received four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV) followed by two booster does of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The study was designed to evaluate two co-primary endpoints: the prevention of HIV infection and the effect of the vaccine on post-infection viral load. 

In the modified intention-to-treat analysis (the primary analysis criteria), the vaccine had a significant 31.2 percent efficacy in preventing new HIV infections.  In the vaccine arm, 51 of 8,197 individuals became infected as compared to 74 of 8,198 individuals who received placebo (P=0.04).  Analysis of the data by the intention-to-treat and per protocol analysis found vaccine efficacy rates of 26.4 percent and 26.2 percent, respectively.  However, these effects were not statistically significant.  Individuals were enrolled in this study regardless of their risk of acquiring HIV, and the majority were low risk (47.5 percent) or moderate risk (28.4 percent).  Surprisingly, the vaccine efficacy was found predominantly in those at low or medium risk of infection.  There was no significant effect of the vaccine on post-infection viral load. 

While there has been some controversy about the most appropriate methodology to analyze the data, this trial does seem to show a likely modest benefit from the vaccine.  However, there is still a long way to go before such a vaccine is ready for routine use to prevent infection.  As the accompanying editorial notes, the most important contribution of this trial may lie in the opportunity to further our understanding of the immune response necessary to prevent HIV infection.  The lessons learned from this trial will be crucial in the development of the next generation of HIV vaccines.

(Rerks-Ngarm et al. N Engl J Med 2009;Oct. 20 and Dolin R. N Engl J Med 2009;Oct 20)

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Preventing Neonatal Sepsis With Lactoferrin Supplementation
Reviewed by Jason Weinberg, MD

Supplementing infant feedings with bovine lactoferrin (BLF), a component of milk that has antimicrobial and immunomodulatory capabilities, reduces the incidence of late-onset sepsis in very low birth weight premature infants, according to a study in the Oct. 7 issue of the Journal of the American Medical Association.

Infants were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial in which feedings were supplemented with BLF alone or in combination with the probiotic Lactobacillus rhamnosus GG (LGG).  The incidence of late-onset sepsis was reduced from 17.3 percent in the placebo group to 5.9 percent in infants receiving BLF and to 4.6 percent in infants receiving BLF and LGG.  The milk component alone provided protection against gram-positive but not gram-negative bacteria.  The use of BLF had no effect on fungal colonization but did provide protection against invasive fungal infection.

Subgroup analyses showed that the overall protective effect of supplementation was significant for the smallest (less than 1,000 g) and most premature (less than 27 weeks gestation) infants, possibly because these infants received proportionately more BLF for longer periods of time.  Infection-related mortality was decreased in both treatment groups, while necrotizing enterocolitis occurred less frequently and only in infants receiving both BLF and LGG.

Sepsis remains a substantial cause of morbidity and mortality in premature infants.  The promising and robust results of this study should encourage further research on the use of BLF in these premature infants at risk for infection, exploring mechanisms underlying the milk component’s effects and other issues, such as optimal dose and duration of treatment.

(Manzoni et al.  JAMA 2009; 302(13):1421-1428)

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A Human Gammaretrovirus and the Pathogenesis of Chronic Fatigue Syndrome (CFS)
Reviewed by George R. Thompson III, MD

Researchers identified xenotropic murine leukemia virus-related virus (XMRV), a human gammaretrovirus, in two-thirds of patients in a chronic fatigue syndrome (CFS) cohort, although it remains unclear what causal role, if any, the virus may play. The findings and an accompanying editorial were published in the Oct. 23 issue of Science.

XMRV had previously been detected in nearly a quarter of all prostate cancer biopsies, and prior reports of alterations in RNase L, an antiviral enzyme, in both prostate cancer and CFS led the authors to speculate that XMRV may be a contributing factor in the pathogenesis of CFS.

Using a national tissue repository, which contains samples from well-characterized cohorts of CFS patients, the investigators assayed samples for the presence of XMRV.  The virus was detected in 68 of 101 CFS patients (67 percent), compared with only 8 of 218 healthy controls (3.7 percent).  Further laboratory investigation revealed latent infection in B and T lymphocytes, and preparations from these cells were infectious and could be transmitted to other cell lines.  CFS patients also exhibited an antibody response to XMRV more frequently than healthy controls.  Immune dysfunction is a known feature of CFS, and the authors suggest that infectious XMRV in lymphocytes may be responsible.

It remains to be seen if XMRV infection is causal in the pathogenesis of CFS or merely a “passenger virus” in CFS patients who have dysregulated immunity from other causes.  XMRV may be more frequent in the same geographic region as the studied CFS cohort, and viral transmission, prevalence, and distribution remain largely unknown.  The frequency of infection in healthy controls is relatively high, suggesting many people worldwide are potentially infected with a virus whose pathogenic potential is largely unknown.  Clearly, more research is needed to study XMRV and to potentially develop effective diagnostic and treatment strategies. 

(Lombardi et al. Science 2009;326:585-589 and Coffin et al. Science 2009;326:530-531)

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