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.

• Late Presentation for HIV Care Suggests Need for Increased and Earlier Testing
• Very Early Antiretroviral Treatment in Patients with Cryptococcal Meningitis: Not So Fast?
• The Potential for Airborne Dispersal of Clostridium difficile
• Travel-Related Illness in Children: More Common Than Previously Thought?
• Telaprevir Adjunctive Therapy for Chronic HCV Patients with Prior Treatment Failure

For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.

Late Presentation for HIV Care Suggests Need for Increased and Earlier Testing
Reviewed by Rachel Simmons, MD

Despite increases over the past 10 years, more than half of HIV-infected patients have a CD4 count below the current recommended threshold for starting antiretroviral therapy (350 cells/mm³) when they present to care. Published in the June 1 issue of Clinical Infectious Diseases, these findings come from a study by investigators with the North American-AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

The study included 44,491 HIV infected people presenting from 1997 to 2007 to 22 NA-ACCORD sites across the U.S. and Canada. The first CD4 count was used as a proxy for the first presentation to care.

During the study period, the median age at first presentation increased from 40 in 1997 to 43 in 2007 (P<0.01). The proportion of patients reporting injection drug use as a transmission risk decreased from 26 percent to 14 percent (P<0.01); men reporting having sex with men as a risk factor increased from 24 percent to 33 percent (P<0.01), while those reporting heterosexual sex increased from 38 percent to 46 percent (P<0.01). The median CD4 count at initial presentation increased from 256 to 317 cells/mm³ over the study period (P<0.01). Overall, the estimated annual change in CD4 count was 6 cells/mm³. The highest annual increase in CD4 count was among Latinos, and lower annual increases were seen in African Americans and heterosexuals. The percentage of patients presenting with a CD4 count greater than 350 cells/mm³ increased from 38 percent to 46 percent during the study period (P<0.01).

This large study underscores the importance of broad implementation of the Centers for Disease Control and Prevention (CDC)’s recommendation to routinely screen people aged 13 to 64 for HIV infection to link patients to care earlier. Despite public health efforts to diagnose patients earlier, the findings indicate more than half of HIV patients are being diagnosed after antiretroviral treatment should have begun.

(Althoff et al. Clin Infect Dis. 2010;50:1512-1520 and Gay. Clin Infect Dis. 2010;50:1521–1523.)

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Starting antiretroviral therapy (ART) within 72 hours of diagnosing cryptococcal meningitis (CM) was associated with a nearly three-fold higher hazard of death compared to delaying ART for 10 weeks in a randomized clinical trial from Zimbabwe published in the June 1 issue of Clinical Infectious Diseases.

From October 2006 to April 2008, 54 HIV-infected adults not on ART began immediate treatment for CM with fluconazole 800 mg daily and were randomized to start ART (stavudine, lamivudine, and nevirapine) either ≤ 72 hours (n=28, mean CD4 count 27 cells/mm³) or 10 weeks after diagnosis (n=26, mean CD4 count 52 cells/mm³).  Mortality at three years was 73 percent: 88 percent in the early ART arm and 54 percent in the delayed arm (p<0.006), with most deaths occurring within one month.  Early ART was associated with a hazard ratio of death of 2.85 in a multivariate model (95 percent confidence interval 1.1-7.23).  CM was determined to be the sole or contributing cause of death in 19 of the 23 deaths in the early ART arm and in 10 of 12 deaths in the delayed arm.  No attempts at defining immune reconstitution syndrome (IRIS) or fluconazole resistance were made.

While the clinical applicability of this study is limited by suboptimal CM treatment, it does suggest that waiting for some degree of disease stabilization before starting ART in the setting of CM may be prudent.  While other studies have suggested that initiation of ART following opportunistic infection should be on the order of 1-2 weeks rather than 1-2 months, starting ART earlier clearly requires more study, particularly with regard to CM.

(Makadzange et al. Clin Infect Dis. 2010;50:1532-8 and Meintjes et al. Clin Infect Dis. 2010;50:1539–1541.)

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If Clostridium difficile infection (CDI) wasn’t worrisome enough, a recent British study, published in the June 1 issue of Clinical Infectious Diseases, addresses whether C. difficile spores can become airborne.

In the study, the air and solid surfaces surrounding geriatric inpatients—some with symptomatic CDI and some with asymptomatic carriage—were sampled for the presence of viable C. difficile bacteria, and molecular techniques were used to link isolates epidemiologically. Of 50 patients whose surrounding air was sampled for just one hour, 10 percent of those with CDI and 2 percent of those without symptoms were positive. However, when the air surrounding ten patients was sampled for 40 hours, seven had positive cultures—and the same strains were identified on nearby solid surfaces. Intriguingly, airborne spore counts rose significantly during activities such as bed linen changes, presumably because these mobilize spores in the bedclothes.

The significance of these findings is not entirely clear. It is sobering that these spores may settle on areas that are infrequently cleaned, but those areas are also probably infrequently touched, thus reducing their likelihood as a source of transmission. Furthermore, the overall number of spores cultivated from the air in this study was far less than that detected on solid surfaces. Finally, the revelation that C. difficile spores travel through the air does not necessarily mean that masks or face shields are indicated for health care worker protection.

Certainly, these results support the practice of meticulous environmental decontamination, gowning, gloving, and hand hygiene when caring for patients with symptomatic CDI. They may also help to explain C. difficile’s propensity to move beyond the bedside and across the wards, although direct contact with spores on hands and fomites still probably represents the lion’s share of that phenomenon.

(Best et al. Clin Infect Dis. 2010;50:1450-1457 and Donskey. Clin Infect Dis. 2010;50:1458–1461.)

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In 2008, people took more than 900 million international tourist trips, according to United Nations estimates. Nearly 10 percent were made by children, whose distinct needs for pre-travel consultation, differing behaviors during travel, and varied presentations on return may present unique management dilemmas for the travel medicine or infectious disease clinician. A study in the May issue of Pediatrics offers some guidance, describing the largest known series of returning child travelers who present to medical care.

Using data from the GeoSentinel Surveillance Network from 1997 through 2007, the authors identified 1,591 children presenting to medical care for travel-related illness. Clinical and demographic features were compared between three age groups: 0-5 years, 6-11 years, and 12-17 years. Data were also compared with 32,668 adult controls presenting during the same period. Only patients with probable or confirmed diagnoses were included in the study (87 percent of children and 86 percent of adults). 

Overall, children were more likely to seek care within seven days and to require hospitalization upon return than were adults. Only 51 percent of children who were tourist travelers and 32 percent of children visiting friends or relatives received pre-travel advice, compared with 59 percent of adults. Although regional variation occurred, the most common presentations were diarrhea (28 percent), dermatologic conditions (25 percent, largely animal/insect bites and cutaneous larva migrans), systemic febrile syndromes (23 percent, largely malaria and viral syndromes), and respiratory disorders (23 percent). Prolonged travel (> 30 days) increased the risk of systemic febrile syndrome (aOR 4.19; 95 percent CI 2.72-6.47) and decreased the risk of diarrheal illness (aOR 0.58; 95 percent CI 0.44-0.77). Vaccine-preventable diseases represented a small overall proportion of diagnoses (2 percent, mostly hepatitis A and Salmonella typhi infection).

Although subject to selection bias, this large systematic report of pediatric travel clinic usage provides a useful database of disease prevalence and perhaps a call to action to provide more complete travel advice for children. 

(Hagmann et al. Pediatrics. 2010; 125(5): e1072-80.)

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Standard therapy with pegylated interferon (pIFN) and ribavirin (RBV) can result in a sustained virologic response (SVR) in many patients with chronic hepatitis C (HCV) infection. There is a growing pool of patients, however, most with genotype 1 virus, who fall short of this sustained viral clearance, largely because their viral level remained detectable on treatment (non-responders) or returned after treatment cessation (relapsers). A phase II randomized-control trial, described in the April 8 issue of the New England Journal of Medicine, offers a potential option for these patients in telaprevir, an oral inhibitor of HCV nonstructural 3/4A protease.

Researchers randomized 465 patients into four treatment arms: telaprevir and pIFN with RBV for 12 weeks followed by 12 weeks of pIFN/RBV; telaprevir/pIFN/RBV for 12 weeks followed by 36 weeks of pIFN/RBV; telaprevir/pIFN for 24 weeks followed by pIFN alone for 24 weeks; and a control arm of current standard therapy with pIFN/RBV for 48 weeks.

The addition of telaprevir to pIFN and RBV clearly improved efficacy as measured by the primary end-point of SVR 24 weeks after the end of treatment. SVR rates were 51 percent and 53 percent, respectively, for the first two treatment arms compared with the control arm at 14 percent (P<0.001 for each). Patients who had a history of relapse tended to do better than those who had prior non-response. A lower SVR rate of 24 percent was observed in the third arm that contained telaprevir and pIFN in the absence of RBV. Emergence of HCV variants resistant to telaprevir occurred in most of the 12-13 percent of patients receiving telaprevir plus pIFN/RBV who experienced virologic breakthrough.

These findings are encouraging news for treatment-experienced patients who await new therapeutic options for HCV. Enthusiasm, however, may be tempered by the emergence of drug resistance as well as the fact that blacks, who are more likely to be treatment-refractory, comprised only a small minority (9 percent) of trial participants.

(McHutchinson et al. N Engl J Med. 2010; 362:1292-303.)

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