Infectious Disease – Page 2

Week 22 – Effect of Early vs. Deferred Therapy for HIV (NA-ACCORD)

“Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival”

N Engl J Med. 2009 Apr 30;360(18):1815-26 [free full text]
—

The optimal timing of initiation of antiretroviral therapy (ART) in asymptomatic patients with HIV has been a subject of investigation since the advent of antiretrovirals. Guidelines in 1996 recommended starting ART for all HIV-infected patients with CD4 count < 500, but over time provider concerns regarding resistance, medication nonadherence, and adverse effects of medications led to more restrictive prescribing. In the mid-2000s, guidelines recommended ART initiation in asymptomatic HIV patients with CD4 < 350. However, contemporary subgroup analysis of RCT data and other limited observational data suggested that deferring initiation of ART increased rates of progression to AIDS and mortality. Thus the NA-ACCORD authors sought to retrospectively analyze their large dataset to investigate the mortality effect of early vs. deferred ART initiation.

Population:

Treatment-naïve patients with HIV and no hx of AIDS-defining illness, treated 1996-2005

Two subpopulations analyzed retrospectively:
1. CD4 count 351-500
2. CD4 count 500+

Intervention: none

Outcome: within each CD4 sub-population, mortality in patients treated with ART within 6 months after the first CD4 count within the range of interest vs. mortality in patients for whom ART was deferred until the CD4 count fell below the range of interest

Results:
8362 eligible patients had a CD4 count of 351-500, and of these, 2084 (25%) initiated ART within 6 months, whereas 6278 (75%) patients deferred therapy until CD4 < 351.

9155 eligible patients had a CD4 count of 500+, and of these, 2220 (24%) initiated ART within 6 months, whereas 6935 (76%) patients deferred therapy until CD4 < 500.

In both CD4 subpopulations, patients in the early-ART group were older, more likely to be white, more likely to be male, less likely to have HCV, and less likely to have a history of injection drug use. Cause of death information was obtained in only 16% of all deceased patients. The majority of these deaths in the both early- and deferred-therapy groups were from non-AIDS-defining conditions.

In the CD4 351-500 subpopulation, there were 137 deaths in the early-therapy group vs. 238 deaths in the deferred-therapy group. Relative risk of death for deferred therapy was 1.69 (95% CI 1.26-2.226, p < 0.001) per Cox regression stratified by year. After adjustment for history of injection drug use, RR = 1.28 (95% CI 0.85-1.93, p = 0.23). In an unadjusted analysis, HCV infection was a risk factor for mortality (RR 1.85, p= 0.03). After exclusion of patients with HCV infection, RR for deferred therapy = 1.52 (95% CI 1.01-2.28, p = 0.04).

In the CD4 500+ subpopulation, there were 113 deaths in the early-therapy group vs. 198 in the deferred-therapy group. Relative risk of death for deferred therapy was 1.94 (95% CI 1.37-2.79, p < 0.001). After adjustment for history of injection drug use, RR = 1.73 (95% CI 1.08-2.78, p = 0.02). Again, HCV infection was a risk factor for mortality (RR = 2.03, p < 0.001). After exclusion of patients with HCV infection, RR for deferred therapy = 1.90 (95% CI 1.14-3.18, p = 0.01).

Implication/Discussion:
In a large retrospective study, deferred initiation of antiretrovirals in asymptomatic HIV infection was associated with higher mortality.

This was the first retrospective study of early initiation of ART in HIV that was large enough to power mortality as an endpoint while controlling for covariates. However, it is limited significantly by its observational, non-randomized design that introduced substantial unmeasured confounders. A notable example is the absence of socioeconomic confounders (e.g. insurance status). Perhaps early-initiation patients were more well-off, and their economic advantage was what drove the mortality benefit rather than the early initiation of ART. This study also made no mention of the tolerability of ART or adverse reactions to it.

In the years that followed this trial, NIH and WHO consensus guidelines shifted the trend toward earlier treatment of HIV. In 2015, the INSIGHT START trial (the first large RCT of immediate vs. deferred ART) showed a definitive mortality benefit of immediate initiation of ART in CD4 500+ patients. Since that time, the standard of care has been to treat “essentially all” HIV-infected patients with ART [UpToDate].

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. INSIGHT START (2015), Pubmed, NEJM PDF
4. UpToDate, “When to initiate antiretroviral therapy in HIV-infected patients”

Summary by Duncan F. Moore, MD

Week 13 – CURB-65

“Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study”

Thorax. 2003 May;58(5):377-82. [free full text]
—

Community-acquired pneumonia (CAP) is frequently encountered by the admitting medicine team. Ideally, the patient’s severity at presentation and risk for further decompensation should determine the appropriate setting for further care, whether as an outpatient, on an inpatient ward, or in the ICU. At the time of this 2003 study, the predominant decision aid was the 20-variable Pneumonia Severity Index. The authors of this study sought to develop a simpler decision aid for determining the appropriate level of care at presentation.

Population: adults admitted for CAP via the ED at three non-US academic medical centers

Intervention/Comparison: none

Outcome: 30-day mortality

Additional details about methodology: This study analyzed the aggregate data from three previous CAP cohort studies. 80% of the dataset was analyzed as a derivation cohort – meaning it was used to identify statistically significant, clinically relevant prognostic factors that allowed for mortality risk stratification. The resulting model was applied to the remaining 20% of the dataset (the validation cohort) in order to assess the accuracy of its predictive ability.

The following variables were integrated into the final model (CURB-65):

Confusion
Urea > 19mg/dL (7 mmol/L)
Respiratory rate ≥ 30 breaths/min
low Blood pressure (systolic BP < 90 mmHg or diastolic BP < 60 mmHg)
age ≥ 65

Results:
1068 patients were analyzed. 821 (77%) were in the derivation cohort. 86% of patients received IV antibiotics, 5% were admitted to the ICU, and 4% were intubated. 30-day mortality was 9%. 9 of 11 clinical features examined in univariate analysis were statistically significant (see Table 2).

Ultimately, using the above-described CURB-65 model, in which 1 point is assigned for each clinical characteristic, patients with a CURB-65 score of 0 or 1 had 1.5% mortality, patients with a score of 2 had 9.2% mortality, and patients with a score of 3 or more had 22% mortality. Similar values were demonstrated in the validation cohort. Table 5 summarizes the sensitivity, specificity, PPVs, and NPVs of each CURB-65 score for 30-day mortality in both cohorts. As we would expect from a good predictive model, the sensitivity starts out very high and decreases with increasing score, while the specificity starts out very low and increases with increasing score. For the clinical application of their model, the authors selected the cut points of 1, 2, and 3 (see Figure 2).

Implication/Discussion:
CURB-65 is a simple 5-variable decision aid that is helpful in the initial stratification of mortality risk in patients with CAP.

The wide range of specificities and sensitivities at different values of the CURB-65 score makes it a robust tool for risk stratification. The authors felt that patients with a score of 0-1 were “likely suitable for home treatment,” patients with a score of 2 should have “hospital-supervised treatment,” and patients with score of ≥ 3 had “severe pneumonia” and should be admitted (with consideration of ICU admission if score of 4 or 5).

Following the publication of the CURB-65 Score, the author of the Pneumonia Severity Index (PSI) published a prospective cohort study of CAP that examined the discriminatory power (area under the receiver operating characteristic curve) of the PSI vs. CURB-65. His study found that the PSI “has a higher discriminatory power for short-term mortality, defines a greater proportion of patients at low risk, and is slightly more accurate in identifying patients at low risk” than the CURB-65 score.

Expert opinion at UpToDate prefers the PSI over the CURB-65 score based on its more robust base of confirmatory evidence. Of note, the author of the PSI is one of the authors of the relevant UpToDate article. In an important contrast from the CURB-65 authors, these experts suggest that patients with a CURB-65 score of 0 be managed as outpatients, while patients with a score of 1 and above “should generally be admitted.”

Further Reading/References:
1. Original publication of the PSI, NEJM (1997)
2. PSI vs. CURB-65 (2005)
3. Wiki Journal Club
4. 2 Minute Medicine
5. UpToDate, “CAP in adults: assessing severity and determining the appropriate level of care”

Summary by Duncan F. Moore, MD

Week 5 – Albumin in SBP

“Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis”

N Engl J Med. 1999 Aug 5;341(6):403-9. [free full text]

—

Renal failure commonly develops in the setting of SBP, and its development is a sensitive predictor of in-hospital mortality. The renal impairment is thought to stem from decreased effective arterial blood volume secondary to the systemic inflammatory response to the infection. In our current practice, there are certain circumstances in which we administer albumin early in the SBP disease course in order to reduce the risk of renal failure and mortality. Ultimately, our current protocol originated from the 1999 study of albumin in SBP by Sort et al.

Population: adults with SBP (see paper for extensive list of exclusion criteria)
Intervention: cefotaxime and albumin infusion 1.5gm/kg within 6hrs of enrollment, followed by 1gm/kg on day 3
Comparison: cefotaxime alone
Outcome:
1º: development of “renal impairment” (a “nonreversible” increase in BUN or Cr by more than 50% to a value greater than 30 mg/dL or 1.5 mg/dL, respectively) during hospitalization
2º: mortality during hospitalization

Results:
126 patients were randomized. Both groups had similar baseline characteristics, and both had similar rates of resolution of infection. Renal impairment occurred in 10% of the albumin group and 33% of the cefotaxime-alone group (p=0.02). In-hospital mortality was 10% in the albumin group and 29% in the cefotaxime-alone group (p=0.01). 78% of patients that developed renal impairment died in-hospital, while only 3% of patients who did not develop renal impairment died. Plasma renin activity was significantly higher on days 3, 6, and 9 in the cefotaxime-alone group than in the albumin group, while there were no significant differences in MAP among the two groups at those time intervals. Multivariate analysis of all trial participants revealed that baseline serum bilirubin and creatinine were independent predictors of the development of renal impairment.

Implication/Discussion:
Albumin administration reduces renal impairment and improves mortality in patients with SBP.

The findings of this landmark trial were refined by a brief 2007 report by Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis.” “High-risk” patients, identified by baseline serum bilirubin of ≥ 4.0 mg/dL or Cr ≥ 1.0 mg/dL were given the intervention of albumin 1.5gm/kg on day 1 and 1gm/kg on day 3, and low-risk patients were not given albumin. None of the 15 low-risk patients developed renal impairment or died, whereas 12 of 21 (57%) of the high-risk group developed renal impairment, and 5 of the 21 (24%) died. The authors concluded that patients with bilirubin < 4.0 and Cr < 1.0 do not need scheduled albumin in the treatment of SBP.

The current (2012) American Association for the Study of Liver Diseases guidelines for the management of adult patients with ascites due to cirrhosis do not definitively recommend criteria for albumin administration in SBP – they instead summarize the above two studies.

A 2013 meta-analysis of four reports/trials (including the two above) concluded that albumin infusion reduced renal impairment and improved mortality with pooled odds ratios approximately commensurate with those of the 1999 study by Sort et al.

Ultimately, the current recommended practice per expert opinion is to perform albumin administration per the protocol outlined by Sigal et al. (2007).

Further Reading:
1. AASLD Guidelines for Management of Adult Patients with Ascites Due to Cirrhosis (skip to page 77)
2. Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis”
3. Meta-analysis: “Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials”
4. Wiki Journal Club
5. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 3 – Dexamethasone in Bacterial Meningitis

“Dexamethasone in Adults With Bacterial Meningitis”

N Engl J Med 2002; 347:1549-1556 [NEJM free full text]

—

The current standard of care in the treatment of suspected bacterial meningitis in the developed world includes the administration of dexamethasone prior to or at the time of antibiotic initiation. The initial evaluation of this practice in part stemmed from animal studies which demonstrated that dexamethasone reduces CSF concentrations of inflammatory markers as well as neurologic sequelae after meningitis. RCTs in the pediatric literature also demonstrated clinical benefit. The best prospective trial in adults was this 2002 study by de Gans et al.

Population: adults with suspected meningitis

Intervention: dexamethasone 10mg IV q6hrs x4 days started 15-20 minutes before first IV abx

Comparison: placebo IV with same administration as above

Outcome:
primary = Glasgow Outcome Scale at 8 weeks (1 = death, 2 = vegetative state, 3 = unable to live independently, 4 = unable to return to school/work, 5 = able to return to school/work)
secondary = death, focal neurologic abnormalities, and others
subgroup analyses performed by organism

Results/Conclusion:
301 patients were randomized. At 8 weeks, 15% of dexamethasone patients had an unfavorable outcome (Glasgow Outcome Scale score of 1-4), vs. 25% of placebo patients (RR 0.59, 95% CI 0.37 – 0.94, p= 0.03). Among patients with pneumococcal meningitis, 26% of dexamethasone patients had an unfavorable outcome, vs. 52% of placebo patients. There was no significant difference among treatment arms within the subgroup of patients infected with meningococcal meningitis. Overall, death occurred in 7% of dexamethasone patients and 15% of placebo patients (RR 0.48, 95% CI 0.24 – 0.96, p = 0.04). In pneumococcal meningitis, 14% of dexamethasone patients died, vs. 34% of placebo patients. There was no difference in rates of focal neurologic abnormalities or hearing loss in either treatment arm (including within any subgroup).

Implication/Discussion:
Early adjunctive dexamethasone improves mortality in bacterial meningitis.

As noted in the above subgroup analysis, this benefit appears to be driven by the efficacy within the pneumococcal meningitis subgroup. Of note, the standard initial treatment regimen in this study was amoxicillin 2gm q4hrs for 7-10 days, not our standard ceftriaxone + vancomycin +/- ampicillin. Largely on the basis of this study alone, the IDSA guidelines for the treatment of bacterial meningitis (2004) recommend dexamethasone 0.15 mg/kg q6hrs for 2-4 days with first dose administered 10-20 min before or concomitant with initiation of antibiotics. Dexamethasone should be continued only if CSF Gram stain, CSF culture, or blood cultures are consistent with pneumococcus.

Further Reading:
1. IDSA guidelines for management of bacterial meningitis (2004)
2. Wiki Journal Club
3. 2 Minute Medicine

Summary by Duncan F. Moore, MD