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.
Does Maraviroc MERIT a Role in the Initial Treatment of HIV?
Reviewed by Christian B. Ramers, MD
In October 2009, the Food and Drug Administration (FDA) approved the use of maraviroc, a novel CCR5 inhibitor, for treatment-naïve patients with R5-tropic virus, following the agency’s 2007 approval for treatment-experienced patients. A study in the March 15 issue of the Journal of Infectious Diseases details the 48-week analysis of the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study, the pivotal trial that led to the latest approval.
A key issue in the study and use of maraviroc is the need to determine viral tropism using a Trofile assay, which characterizes an individual’s virus as R5-tropic, X4-tropic, or dual/mixed-tropic. Maraviroc appears to have significant virologic activity only against R5-tropic HIV-1.
In the original MERIT study, 721 treatment-naïve patients were randomized to receive maraviroc 300 mg BID or efavirenz 600 mg QD, both with zidovudine-lamivudine BID. Pre-defined coprimary endpoints were the proportion of patients at week 48 achieving virologic suppression to two thresholds, < 400 and < 50 copies/mL. Although maraviroc was non-inferior to efavirenz using the 400 c/mL viral load cutoff (70.6 vs. 73.1 percent), non-inferiority criteria were not reached for the 50 c/mL cutoff (65.3 vs. 69.3 percent). However, patients were screened using an older version of the Trofile assay, causing many to be misclassified as having purely R5-tropic virus. Applying an enhanced Trofile assay blindly to frozen serum samples excluded 107 patients (15 percent) who carried X4-tropic virus at screening.
In the re-analysis, maraviroc resulted in statistically similar virologic suppression rates to efavirenz, at both cutoffs (73.3 vs. 72.3 percent, and 68.5 vs. 68.3 percent, respectively), and thus appears to be non-inferior to efavirenz for treatment-naïve patients. One other observation was a greater CD4+ increase in the maraviroc arm compared to efavirenz (170 cells/mL vs. 140 cells/mL p = 0.008), although the clinical significance of this is uncertain.
Despite FDA’s latest approval of maraviroc for treatment-naïve patients, the December 2009 Department of Health and Human Services guidelines did not recommend it as a preferred first-line agent. Given the cost and complexity of Trofile testing, and the variable prevalence of R5-tropism, its role in treatment-naïve patients remains uncertain.
(Cooper et al. J Infect Dis 2010;201:803-813.)
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Low Recurrence of Hepatotoxicity When Tuberculosis Treatment Is Reinitiated Using Any of Three Strategies
Reviewed by Christopher J. Graber, MD, MPH
Three different strategies for restarting tuberculosis (TB) treatment were associated with low reoccurrence of hepatotoxicity in patients who had had this problem initially with anti-TB therapy in a randomized trial published in the March 15 issue of Clinical Infectious Diseases.
The trial included 175 HIV-uninfected patients in India without chronic liver disease, viral hepatitis, or concomitant hepatotoxic medication use who had experienced hepatotoxicity with standard four-drug therapy (isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol). The patients were restarted on H, R, and Z using one of three strategies following stabilization of liver function tests:
- immediate restart of H, R, and Z at full dose
- weekly incremental introduction of full-dose medication (R, then H, then Z)
- weekly incremental introduction of low-dose medication increased to full-dose over four days (H, then R, then Z)
Initial and recurrent hepatotoxicity were defined as:
- an increase in aminotransferases ≥5x upper limit of normal on one occasion or ≥3x on three consecutive occasions
- an increase in total bilirubin > 1.5 mg/dL, or
- any elevation in aminotransferase with anorexia, nausea, vomiting, and jaundice in combination with absence of evidence of viral hepatitis and resolution upon stopping H, R, or Z.
Nineteen (10.9 percent) of 175 patients had recurrence of hepatotoxicity, with no clear difference between the three strategies (8/58 in the first arm, 6/59 in the second, and 5/58 in the third). Because of the lower-than-anticipated overall rate of recurrent hepatotoxicity (possibly due to the relatively low-risk population enrolled and the somewhat less stringent entry criterion (c) above), the study was underpowered to detect differences in the three arms. However, the overall finding of a low rate of hepatotoxicity recurrence no matter which strategy was used is reassuring to clinicians who frequently encounter this scenario.
(Sharma et al. Clin Infect Dis 2010;50:833-9.)
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The 7-Valent Pneumococcal Conjugate Vaccine: Not Just for Kids Anymore?
Reviewed by Ed Dominguez, MD
Streptococcus pneumoniae is a significant cause of pneumonia, sinusitis, otitis media, and meningitis throughout the world. For HIV-infected individuals, the risk of invasive disease is up to 100 times higher. Although the 7-valent pneumococcal vaccine is effective in preventing invasive disease in children with HIV, the efficacy in infected adults is unknown.
A report in the March 4 issue of the New England Journal of Medicine describes a randomized, double-blind, placebo-controlled trial of secondary prophylaxis involving 496 adults in Malawi, 88 percent of whom were infected with HIV. Patients, all of whom had recovered from invasive pneumococcal illness, were vaccinated with either two doses of Prevnar heptavalent vaccine or matching placebo given four weeks apart. The primary endpoint was invasive disease, defined as a positive culture for a vaccine-specific serotype S. pneumonia during a four-year period.
There were 67 episodes of invasive disease in 52 patients, all with HIV-infection. Of these, 24 (35.8 percent) were caused by a vaccine serotype or serotype 6A; five occurred in vaccine recipients and the remaining 19 in placebo recipients. The vaccine efficacy, therefore, was 74 percent.
There were 73 deaths from any cause in the vaccine group, and 63 in the placebo group, leading to a hazards ratio in the vaccine group of 1.18, which is not statistically significant. While minor adverse events were more common in the vaccine group (41 vs. 13), serious adverse events (death or hospitalization) were less common in the vaccine group (3 vs. 17). Nine deaths were reported in the trial, two in the vaccine group and seven in the placebo group.
The efficacy of the heptavalent vaccine for secondary prophylaxis in adults was high, especially in the first 12 months after vaccination. It was also high for HIV-infected patients with CD4+ counts below 200. Although this was not evaluated, the investigators extrapolate that the vaccine may also be effective as primary prophylaxis for HIV-infected adults. They suggest that the immunogenicity of this adjuvant vaccine merits further investigation as to its possible use with other vaccines in HIV patients.
(French at al. NEJM 2010;362:812-822.)
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Timing of HIV Treatment in TB/HIV Coinfection: Concurrent Treatment Better Than Sequential Therapy
Reviewed by Rachel Simmons, MD
Initiating HIV therapy during treatment for tuberculosis (TB) was associated with a 56 percent reduction in mortality compared to sequential therapy. Investigators reported the findings of the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial in the Feb. 25 issue of the New England Journal of Medicine.
In the open-label trial, 642 people with HIV infection, a CD4+ cell count less than 500, and TB infection were randomized into three groups:
- Early integrated: Antiretrovirals (didanosine, lamivudine, efavirenz) initiated within four weeks of starting tuberculosis therapy.
- Late integrated: Antiretrovirals started within four weeks of completing the intensive phase of TB treatment.
- Sequential: Antiretrovirals started within four weeks after the completion of TB therapy.
Based on a planned interim analysis, the study’s data and safety monitoring committee recommended that all patients in the sequential group start on antiretrovirals. The integrated groups were pooled and compared to the sequential therapy group. The median CD4 T cell count was 150 in the integrated therapy group and 140 in the sequential therapy group.
The death rate in the combined integrated group was 5.4 deaths per 100 person-years (25 deaths among 429 patients), compared to 12.1 deaths per 100 person years in the sequential group (27 deaths among 213 patients). The hazard ratio in the integrated group was 0.44 (95 percent CI 0.25 to 0.79, p = 0.003). There was an increased rate of immune reconstitution inflammatory syndrome (IRIS) in the combined integrated group (12.4 percent) compared to the sequential therapy group (3.8 percent). Five of the 53 people in the combined group that developed IRIS required treatment with glucocorticoids. No deaths were attributed to IRIS, and the rates of serious adverse events were similar in both groups.
This study does not fully address when during TB therapy to start antiretrovirals, but the findings show it is detrimental to wait until the completion of TB treatment.
(Karim et el. NEJM 2010;362:697-706.)
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