Adult Immunizations: 2007–2008

Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, October 2007–September 2008. Ann Intern Med 2007;147:725–9.

Poland GA, Schaffner W. Adult immunization guidelines: a patient safety and quality-of-care issue. Ann Intern Med 2007;147:735–7.

The latest update of recommendations for adult immunizations include the addition of several new vaccines; these include the varicella zoster vaccine designed to prevent herpes zoster, which is now recommended for individuals aged ⩽60 years, and the quadrivalent human papillomavirus vaccine, which is recommended for all girls and women aged 11–26 years. Administration of an acellular pertussis vaccine (with diphtheria and tetanus toxoid) is routinely indicated in a single, 1-time dose to all adults aged ⩾64 years whose last tetanus-diphtheria booster was received ⩽10 years previously; intervals as short as 2 years are acceptable for postpartum women, close contacts of infants aged <12 months, and all health care workers with patient contact.

In addition, new recommendations have been made regarding the use of older vaccines. Renewed emphasis was placed on the importance of immunizing all health care workers against influenza. The live, attenuated influenza virus vaccine may be given to health care workers. The resurgence of mumps in college-aged individuals has led to recommendations for a second dose of mumps vaccine (usually as a component of the measles, mumps, and rubella vaccine) to individuals in specified age groups with risk factors and to adults working in health care facilities. Hepatitis B vaccination is now recommended for all sexually active adults who are not in a long-term, mutually monogamous relationship, as well as for some other groups. Additional changes include the recommendation of varicella vaccination for adults of all ages who do not have evidence of immunity to this virus. Varicella vaccine, which consists of live, attenuated virus, may be administered to HIV-infected individuals with CD4 T lymphocyte counts ⩽200 cells/μL.

Telbivudine versus Adefovir for Chronic Hepatitis B Virus (HBV) Infection

Chan HLY, Heathcote J, Marcellin P, et al. Treatment of hepatitis B e antigen-positive chronic hepatitis with telbivudine or adefovir. Ann Intern Med 2007; 147:745–54.

In an open-label trial, 135 treatment- naive, hepatitis B e antigen (HBeAg)-positive adults (<90% of whom were Asian) were randomized to receive (1) treatment with either telbivudine or adefovir for 52 weeks or (2) 24 weeks of adefovir followed by telbivudine for an additional 28 weeks. The reduction in the plasma HBV DNA level at 24 weeks (the primary end point of the study) was superior for patients who were initially given telbivudine, as was the proportion of patients with undetectable virus (39% vs. 12%). Telbivudine recipients also had better virologic outcomes at 52 weeks, regardless of whether they received telbivudine ab initio or switched from adefovir to telbivudine at 24 weeks, although an unadjusted analysis revealed no significant difference. In this analysis, rates of normalization of the alanine aminotransferase level and loss of HBeAg were also similar. Virologic “breakthrough,” defined as a 11-log increase in the HBV DNA level relative to the nadir value, occurred in 4 adefovir recipients and 3 telbivudine recipients after 24 weeks of therapy (none were observed in the patients who “switched” regimens). Although no signature resistance mutations were detected in those who broke through while receiving adefovir, the signature M204I mutation was detected at week 52 in 3 of the 4 telbivudine recipients who experienced failures.

Overall, these data suggest that telbivudine is superior to adefovir for the treatment of HBeAg-positive Asian persons after 24 weeks and, depending on the analysis, after 52 weeks, but there is a not insignificant risk of emergence of virologic resistance. The authors summarize available information on the emergence of resistance in patients receiving various small-molecule therapies for chronic HBV infection: with lamivudine, the rate of resistance approaches 70% after 4 years; with adefovir, the rate is 29% after 5 years (for HBeAg-negative patients); for entecavir, the rate is 0.8% at 4 years (although the rate is higher for patients with previous exposure to lamivudine); and for telbivudine, the rate approaches 20% at 2 years. Thus, although telbivudine appears to be a useful agent, the high frequency of selection of resistance mutants appears to place it in a risk category for this event closer to that of lamivudine than to that of entecavir, with adefovir being associated with intermediate risk.

Telbivudine versus Lamivudine for Chronic HBV Infection

Hsu CW, Thongsawat S, Wang Y, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576–88.

Hsu and colleagues randomized 1370 patients with chronic HBV infection (both HBeAg-positive patients and HBeAg-negative patients) to receive treatment with either telbivudine (600 mg once per day) or lamivudine (100 mg once per day) for 52 weeks. A therapeutic response (defined as a decrease in the serum HBV DNA level to <5 log₁₀ copies/mL together with normalization of the alanine aminotransferase level or loss of detectable serum HBeAg) was achieved in 75.3% and 67.0% of telbivudine and lamivudine recipients, respectively ( P = .005). Telbivudine therapy was superior in both HBeAg-positive and HBeAg-negative patients. A significant improvement in liver histologic findings was also noted for patients who were treated with telbivudine. Drug resistance occurred in 5.0% of HBeAg-positive patients and 2.3% of HBeAg-negative patients who were treated with telbivudine, compared with 11.0% and 10.7% of lamivudine recipients, respectively. Elevations in the creatine kinase level occurred in 7.5% of telbivudine recipients and in only 3.1% of those given lamivudine; elevations in the aspartate aminotransferase level occurred more frequently in the latter group. Thus, telbivudine therapy was associated with higher response rates and less-emergent antiviral resistance, compared with lamivudine treatment.

The Circle Continues Unbroken: Now Corticosteroids Are Not Effective for Septic Shock

Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111–24.

The administration of corticosteroids to patients with sepsis of varying severity has become common. The recently updated guidelines of the Surviving Sepsis Campaign state, however, that “stress-dose steroid therapy be given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy” [1, p. 296]. Sprung and colleagues have reexamined the issue by randomizing 499 adults with septic shock to receive adjunctive therapy with 50 mg of either hydrocortisone or placebo every 6 h for 5 days, followed by a tapering dose given for an additional 6 days. Patients were required to have evidence of a systemic inflammatory response to infection, an onset of shock (defined as systolic blood pressure <90 mm Hg, despite receipt of adequate fluid replacement, and a need for vasopressor support for at least 1 h) within the previous 72 h, together with evidence of hypoperfusion or organ dysfunction attributable to sepsis.

No significant difference between treatment with hydrocortisone and placebo was identified with regard to the primary end point of the study (28-day mortality) for the patients who did not respond to a cortisone stimulation test (who constituted 46.7% of the total population). Thus, the 28-day mortality rate for this group was 39.2% for hydrocortisone recipients and 36.1% for placebo recipients (P=.69); the 28-day mortality rates for patients who responded appropriately in the hydrocortisone stimulation tests were 28.8% and 28.7%, respectively. Shock reversed more rapidly in hydrocortisone recipients among patients for whom this result was achieved. Any benefit, however, was offset by a greater risk of superinfection, sepsis, and septic shock in persons who received this corticosteroid.

No microbiologic information was provided by the study investigators, and importantly, neither was any assessment of the adequacy of the prescribed antibiotic therapy. Although there are a number of differences between this study and others that have reported improved outcomes for patients experiencing septic shock who receive hydrocortisone, and although the power of this study was somewhat limited by the sample size (which was lower than planned), this study provides no significant inkling of benefit for widespread adjunctive hydrocortisone treatment for patients with septic shock. The investigators do, however, acknowledge that there is a possible benefit for some patients, such as those who are treated very early after the onset of shock or who lack responsiveness to vasopressor therapy.

Intensive Attempts to Maintain Euglycemia Are Harmful to Patients with Severe Sepsis

Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–39.

Van den Berghe and colleagues previously reported the results of a randomized clinical trial from 2001 that found that maintenance of the blood glucose level at 80–110 mg/dL in critically ill patients who underwent surgery reduced the rate of subsequent mortality—in particular, the rate of mortality due to multiple-organ system failure with a septic focus [1]. Much of the apparent benefit of tight control of the glucose level was observed in patients who underwent cardiac surgery and who had received a large postoperative glucose load. Despite these limitations— especially the fact that patients in the study were not known to be infected at the time of study entry—these data have been widely extrapolated for use in patients with sepsis.

Brunkhorst and colleagues randomized patients with severe sepsis to receive either intensive insulin therapy or conventional insulin therapy. A second randomization examined the relative benefits of fluid resuscitation with either 10% pentastarch or Ringer's lactate. The authors found that pentastarch resuscitation was associated with an increased risk of acute renal failure and need for renal replacement therapy.

Among evaluable patients, intensive insulin therapy was associated with lower mean blood glucose levels (112 mg/dL vs. 151 mg/dL). There was no difference in the mortality rate or organ failure score at 28 days. However, the trial was aborted early because of an increased risk of hypoglycemic events in the intensive insulin therapy group. The blood glucose level decreased to ⩽40 mg/dL in 17% of participants in the intensive therapy group and in 4.1% of those who received conventional therapy. Serious adverse events in general were also more common in the intensive insulin therapy group. Thus, there was no evidence of a benefit for intensive insulin therapy in patients with severe sepsis; on the contrary, such therapy was associated with harm. The most recent guidelines of the Surviving Sepsis Campaign recommend targeting (after initial stabilization) a blood glucose level of <150 mg/dL [2], which was the mean level achieved in this study in the conventional therapy group.