James O. Kahn

A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection

BACKGROUND Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine. METHODS This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with less than or equal to 300 CD4 cells per cubic milliliter, or asymptomatic HIV infection with less than or equal to 200 CD4 cells per cubic milliliter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine. RESULTS There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P less than 0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group. CONCLUSIONS Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease.

Use of laboratory tests and clinical symptoms for identification of primary HIV infection

Objective To determine the sensitivity and specificity of symptoms, three HIV-1 RNA assays, a p24 antigen EIA and a third-generation enzyme immunoassay (EIA) antibody test for diagnosis of primary HIV infection (PHI). Design Prospective cohort in a university research program. Participants Of 258 eligible persons screened for PHI, 40 had primary/early infection (22 preseroconversion, 18 within 6 months of seroconversion) and 218 did not. Seven participants with preseroconversion HIV-1 from a second center were added for evaluating laboratory tests. Main outcome measure PHI, defined as a negative or indeterminate antibody test with subsequent conversion. Symptom analysis also included persons with antibody conversion of less than 6 months’ duration. Results The symptoms most strongly associated with PHI in multivariate analysis were fever [odds ratio (OR) 5.2; 95% confidence interval (CI) 2.3–11.7] and rash (OR 4.8; 95% CI 2.4–9.8). The sensitivity and specificity, respectively, for detecting preseroconversion HIV infection were: p24 antigen, 79% and 99%; third-generation EIA, 79% and 97%; HIV-1 RNA by branched chain DNA 100% and 95%; HIV-1 RNA by polymerase chain reaction 100% and 97%; HIV-1 RNA by transcription-mediated amplification testing, 100% and 98%. False-positive HIV-1 RNA tests were not reproducible and had values < 3000 copies/ml, while only one person with confirmed PHI was in this range. Conclusions Rash and fever indicated the highest risk of PHI. HIV-1 RNA tests are very sensitive for PHI but false-positive results occur. False-positive results can be reduced through duplicate testing and considering tests < 5000 copies/ml as indeterminate results requiring additional testing. p24 antigen was more specific than HIV-1 RNA testing but less sensitive.

Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial.

Thirty patients with human immunodeficiency virus (HIV)-associated non-Hodgkins lymphoma (NHL) receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomized to receive either subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) or no additional therapy. Recombinant rGM-CSF (at a dose of 10-20 micrograms/kg/d) was given on days 1 to 10 (early rGM-CSF) to the first five patients, but was changed to days 4 to 13 (delayed rGM-CSF) of each chemotherapy cycle in subsequent patients. Compared with the control group (N = 10), the delayed rGM-CSF group (N = 11) had higher mean nadirs of the absolute neutrophil count (0.36 v 0.89 x 10(9)/L; P = .009), shorter mean durations of neutropenia (4.9 v 1.3 days; P = .02), fewer chemotherapy cycles complicated by neutropenia and fever (67% v 27%; P = .001), fewer days hospitalized for fever and neutropenia (4.9 v 1.8; P = .004), fewer reductions in chemotherapy dosages, and less frequent delays in chemotherapy administration. No significant differences were observed between patients in the control group and those in the early rGM-CSF group (N = 5). Median levels of serum HIV-1 p24 antigen decreased to 18% and 17% of baseline values in control (N = 4) and rGM-CSF groups (N = 6), respectively, 1 week following administration of the first cycle of chemotherapy. In the third week after chemotherapy, median antigen levels remained below baseline in the control group, but rose to 243% of baseline values in the rGM-CSF group (P = .01), suggesting stimulation of HIV replication. The effect of this change in HIV activity on clinical outcome of treated patients could not be determined, and therefore the clinical significance of this finding remains unclear. Complete response rates of 67%, 70%, and 60% were observed in the control, delayed rGM-CSF, and early rGM-CSF groups, respectively, with corresponding survival times of 9.0, 11.4, and 8.0 months.

Feasibility of Postexposure Prophylaxis (PEP) against Human Immunodeficiency Virus Infection after Sexual or Injection Drug Use Exposure: The San Francisco PEP Study

The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection.

Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behavior

Background: The effectiveness of postexposure prophylaxis (PEP) following occupational exposure to HIV has prompted advocacy for PEP following sexual or drug-use exposures. Objective: To evaluate the concern that the availability of PEP for sexual or drug-use exposures might result in behavioral disinhibition. Design: Non-randomized trial of 397 adults with high-risk sexual or drug-use exposures within the prior 72 h. Interventions: Antiretroviral medication for 4 weeks and five counseling sessions. Main outcome measurements: Participants were followed for 12 months for repeat request for PEP and for changes compared with pre-enrollment in overall high-risk behavior and the acquisition of sexually transmitted diseases (STD) and HIV. Results: After 12 months following receipt of PEP, the majority of participants (83%) did not request a repeat course of PEP. At 12 months after exposure, 73% of participants reported a decrease compared with baseline in the number of times they had performed high-risk sexual acts; 13% reported no change, and 14% had an increase. Most participants (85%) had no change in the incidence of STD; 8.5% had a decrease and 6.8% an increase. Three homosexual men seroconverted for HIV (none associated with the presenting exposure) for a rate of 1.2/100 person-year, equivalent to rates in San Francisco among all homosexual men. Conclusions: After receipt of PEP consisting of antiretroviral medication and behavioral counseling following a potential sexual exposure to HIV, most individuals do not increase high-risk behavior. Coupled with prior safety and feasibility data, this lack of behavioral disinhibition suggests that use of PEP should be routinely considered following high-risk sexual exposures.

Risk behavior for HIV infection in participants in preventive HIV vaccine trials: a cautionary note.

We conducted a longitudinal study of participants in phase I and II HIV vaccine safety and immunogenicity trials to examine changes in sexual risk behavior that are associated with risk of HIV transmission. The participants were 48 HIV-negative men and women enrolled in one of two placebo-controlled HIV vaccine trials conducted at San Francisco General Hospital. There was a significant increase in insertive unprotected anal intercourse (UAI) from 9% at baseline (trial entry), to 13% at the month 6 assessment, to 20% at the month 12 assessment (p = .02). The primary predictor of either insertive or receptive UAI during the vaccine trials was having engaged in this behavior prior to entry (p = .001). Higher-risk behavior was also seen among participants who were younger and had multiple sexual partners (each, p = .06) and who indicated that one of their reasons for participation in the vaccine trial was hope of protection from HIV infection (p = .07). These findings indicate that despite instructions otherwise, participants with a history of high-risk behavior or who express hope of protection from HIV infection by enrolling in vaccine trials may be candidates for more intensive risk-behavior counseling prior to and during their participation.

Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems

Highly active antiretroviral therapy (HAART) delays disease progression and death. However, the treatments incompletely control HIV replication, only partially restore immune function, have significant shortand long-term toxicities, and eventually fail in many patients with consequent development of HIV drug resistance. Thus, there is increasing need for information to guide HIV-infected patients and their providers in making decisions regarding optimal use of antiretroviral therapies. Although clinical trials provide valuable information about efficacy and side effects of antiretroviral treatment, they have limited size, duration and power to detect effects on clinical outcomes, focusing instead on surrogate endpoints such as virologic failure, treatment discontinuation or composite outcome measures. Outside the clinical trial setting, there is tremendous heterogeneity among HIV-infected patients. The prevalence and impact of important health conditions such as hepatitis C virus (HCV) co-infection, mental illness and substance abuse likely contribute to increased toxicity and decreased clinical effectiveness of HAART regimens among the broader spectrum of patients treated in routine care. Cohorts with significant diversity in HIV disease severity, comorbidities and demographic distributions are required to provide information regarding long-term outcomes and complications of HIV infection in the modern HAART era. The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) was created to better define the relationship between patient and treatment factors and long-term clinical outcomes among HIV-infected patients in the HAART era. The CFARs are a national network of centres of excellence for HIV care and research established by the National Institutes of Health (NIH) whose mission is to support a multi-disciplinary environment for basic, clinical, epidemiologic, behavioural and translational research in the prevention, detection and treatment of HIV infection and AIDS. There are 19 CFARs located at academic and research institutions throughout the United States. The objective of the CNICS project is to integrate clinical data from the large and diverse population of HIV-infected persons receiving care at CFAR sites to investigate questions related to HIV disease management that cannot be readily addressed through traditional randomized controlled clinical trials and other cohort studies. Investigators with expertise in basic, clinical, translational and epidemiologic research, in addition to medical informatics, are collaborating on the CNICS project. The potential to build a comprehensive clinical data repository for HIV disease was greatly advanced by the work of CFAR investigators at the participating CNICS sites who had instituted point-of-care electronic medical record systems (EMRs) with the dual purpose of providing real-time clinical information to facilitate the delivery of HIV care and capturing standardized clinical data to support populationbased HIV research. The initial four CNICS sites were Case Western Reserve University, University of * Corresponding author. Center for AIDS Research, University of Washington, 325 9th Ave, MS 359931, Seattle, WA 98104, USA. E-mail: kitahata@u.washington.edu 1 Department of Medicine, University of Washington, Seattle, 98195, USA. 2 Department of Medicine, Case Western Reserve University, Cleveland, 44106, USA. 3 Department of Medicine, University of California, San Diego, 92110, USA. 4 Department of Medicine, Harvard University, Boston, 02115, USA. 5 Department of Medicine, Johns Hopkins University, Baltimore, 21218, USA. 6 Department of Medicine, University of Alabama, Birmingham, 35209, USA. 7 Department of Medicine, University of California, San Francisco, 94143, USA. Published by Oxford University Press on behalf of the International Epidemiological Association

Need for Annual Surveillance of Antimicrobial Resistance in Streptococcus pneumoniae in the United States: 2-Year Longitudinal Analysis

ABSTRACT Although changing patterns in antimicrobial resistance inStreptococcus pneumoniae have prompted several surveillance initiatives in recent years, the frequency with which these studies are needed has not been addressed. To approach this issue, the extent to which resistance patterns change over a 1-year period was examined. In this study we analyzed S. pneumoniaeantimicrobial susceptibility results produced in our laboratory with isolates obtained over 2 consecutive years (1997–1998 and 1998–1999) from the same 96 institutions distributed throughout the United States. Comparison of results revealed increases in resistant percentages for all antimicrobial agents studied except vancomycin. For four of the agents tested (penicillin, cefuroxime, trimethoprim-sulfamethoxazole, and levofloxacin), the increases were statistically significant (P < 0.05). Resistance to the fluoroquinolone remained low in both years (0.1 and 0.6%, respectively); in contrast, resistance to macrolides was consistently greater than 20%, and resistance to trimethoprim-sulfamethoxazole increased from 13.3 to 27.3%. Multidrug resistance, concurrent resistance to three or more antimicrobials of different chemical classes, also increased significantly between years, from 5.9 to 11%. The most prevalent phenotype was resistance to penicillin, azithromycin (representative macrolide), and trimethoprim-sulfamethoxazole. Multidrug-resistant phenotypes that included fluoroquinolone resistance were uncommon; however, two phenotypes that included fluoroquinolone resistance not found in 1997–1998 were encountered in 1998–1999. This longitudinal surveillance study of resistance inS. pneumoniae revealed that significant changes do occur in just a single year and supports the need for surveillance at least on an annual basis, if not continuously.

Seroconversion following nonoccupational postexposure prophylaxis against HIV

BACKGROUND The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverters virus. CONCLUSIONS As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Evaluation of Current Activities of Fluoroquinolones against Gram-Negative Bacilli Using Centralized In Vitro Testing and Electronic Surveillance

ABSTRACT Given the propensity for Enterobacteriaceae and clinically significant nonfermentative gram-negative bacilli to acquire antimicrobial resistance, consistent surveillance of the activities of agents commonly prescribed to treat infections arising from these organisms is imperative. This study determined the activities of two fluoroquinolones, levofloxacin and ciprofloxacin, and seven comparative agents against recent clinical isolates ofEnterobacteriaceae, Pseudomonas aeruginosa,Acinetobacter baumannii, and Stenotrophomonas maltophilia using two surveillance strategies: 1) centralized in vitro susceptibility testing of isolates collected from 27 hospital laboratories across the United States and 2) analysis of data from The Surveillance Network Database-USA, an electronic surveillance network comprising more than 200 laboratories nationwide. Regardless of the surveillance method, Enterobacteriaceae,P. aeruginosa, and A. baumannii demonstrated similar rates of susceptibility to levofloxacin and ciprofloxacin. Susceptibilities to the fluoroquinolones approached or exceeded 90% for all Enterobacteriaceae except Providenciaspp. (≤65%). Approximately 70% of P. aeruginosa and 50% of A. baumanii isolates were susceptible to both fluoroquinolones. Among S. maltophilia isolates, 50% more isolates were susceptible to levofloxacin than to ciprofloxacin. Overall, the rate of ceftazidime nonsusceptibility amongEnterobacteriaceae was 8.7%, with fluoroquinolone resistance rates notably higher among ceftazidime-nonsusceptible isolates than ceftazidime-susceptible ones. Multidrug-resistant isolates were present among all species tested but were most prevalent for Klebsiella pneumoniae andEnterobacter cloacae. No gram-negative isolates resistant only to a fluoroquinolone were encountered, regardless of species. Thus, while levofloxacin and ciprofloxacin have maintained potent activity against Enterobacteriaceae, the potential for fluoroquinolone resistance, the apparent association between fluoroquinolone and cephalosporin resistance, and the presence of multidrug resistance in every species examined emphasize the need to maintain active surveillance of resistance patterns among gram-negative bacilli.