M. Elaine Eyster

A Randomized Trial Comparing Fluconazole with Clotrimazole Troches for the Prevention of Fungal Infections in Patients with Advanced Human Immunodeficiency Virus Infection

Background Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. Methods We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. Results After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the cl...

Acid-Labile Alpha Interferon: A Possible Preclinical Marker for the Acquired Immunodeficiency Syndrome in Hemophilia

Many homosexual men with the acquired immunodeficiency syndrome (AIDS) have an unusual acid-labile form of human leukocyte, or alpha, interferon in their serum. Male patients with classic hemophilia treated with lyophilized clotting-factor concentrates are also at high risk for the development of AIDS. To determine whether the level of alpha interferon may be a preclinical marker of early subclinical disease, we examined stored plasma and serum from three hemophilic patients with AIDS. Persistently elevated levels of the acid-labile form of alpha interferon were found in all three patients. In two patients the appearance of circulating alpha interferon preceded the onset of clinical disease by 3 to 10 months. In contrast, alpha-interferon levels were not elevated in 43 of 46 unselected patients with hemophilia; three of these patients had transient elevations. These results suggest that acid-labile alpha interferon may be a marker that can be used to identify affected asymptomatic members of high-risk groups before the onset of clinical disease.

RISK OF AIDS AFTER HERPES ZOSTER

In a closed internal medicine practice for homosexual men in Central Manhattan herpes zoster developed in 112 men between 1980 and mid-1986. In these patients the incidence of acquired immunodeficiency syndrome (AIDS) was high: Kaplan-Meier survival analysis indicated cumulative incidences of AIDS of 22.8% within 2 years after herpes zoster, 45.5% within 4 years, and an estimated 72.8% after 6 years. Severity of zoster (relative risk, RR = 4.6), degree of pain (RR = 3.4), and zoster of the cranial or cervical dermatomes (RR = 2.2) were all associated with a poor outcome. Oral thrush, oral hairy leucoplakia, amoebiasis, and superficial (tinea) fungal infections also indicated an increased risk of AIDS among zoster patients. Oral thrush and oral hairy leucoplakia manifestations were diagnosed an average of 1.2 and 1.1 years, respectively, after the diagnosis of herpes zoster; thus zoster is an early indicator of an impaired immunity. Herpes zoster can be used as a predictor of AIDS and in AIDS risk groups should be regarded as a poor prognostic sign.

Cryptosporidiosis in a Patient with Hemophilia, Common Variable Hypogammaglobulinemia, and the Acquired Immunodeficiency Syndrome

A 36-year-old man had chronic, debilitating diarrhea due to cryptosporidiosis. This patient had longstanding common variable hypogammaglobulinemia and recurrent bacterial infections. Immunologic evaluation after discovery of Cryptosporidium showed lymphopenia with persistently reduced numbers of helper/inducer cells (OKT-4), variable numbers of suppressor/cytotoxic cells (OKT-8), OKT-4/OKT-8 ratio of 0.09, and increased levels of serum alpha-interferon, all of which describe the acquired immunodeficiency syndrome. Oocysts of Cryptosporidium were found in feces from the patients cat, thus identifying a possible source of his infection. The patient had disseminated candidiasis, cytomegalovirus pneumonia, and cryptosporidiosis when he died.

Lack of Association of Hepatitis C Virus Load and Genotype with Risk of End-Stage Liver Disease in Patients with Human Immunodeficiency Virus Coinfection

In hepatitis C virus (HCV) infection, virus load and the risk for HCV-related end-stage liver disease (ESLD) are increased among persons with human immunodeficiency virus (HIV) coinfection. To clarify these relationships, 42 hemophilic patients who developed ESLD and random samples from 164 hemophilic patients with HCV infection alone and 146 with HCV-HIV coinfection were tested for HCV load and genotype. HCV genotype was unrelated to HIV and age. In contrast, HCV load was higher with older age (P(trend)=.0001) and with HIV coinfection (6.2 vs. 5.9 log(10) genome equivalents/mL, P=.0001). During 16 years of follow-up of dually infected patients, ESLD risk was unrelated to HCV load overall (P(trend)=.64) or separately to HCV genotype 1 and genotypes 2 or 3 (P(trend)> or =.70). Irrespective of virus load, incidence of ESLD was marginally increased 2-fold (95% confidence interval, 0.8-5.6) with HCV genotype 1. Understanding the discordance between HCV load and ESLD, despite HIVs link to each of these, may help clarify the pathogenesis of HCV-related disease.

HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia†

Hepatitis C virus (HCV) treatment response rates remain low in HCV/HIV‐1‐coinfected individuals compared with those with HCV alone. Persons with inherited coagulation disorders have high rates of HCV and HIV‐1 infection, but HCV treatment trials in this patient population are scarce. We hypothesized that differences by infection status in HCV viral kinetics would be associated with differences in HCV quasispecies complexity over time and with treatment response disparities. Coinfected and monoinfected patients were enrolled in a treatment trial for pegylated‐interferon alpha‐2a (peg‐IFN) + ribavirin. Patients were treated for 48 weeks and followed for an additional 24. Quantitative HCV RNA was tested at multiple times during and after treatment. Viral kinetic parameters associated with response were estimated with a mathematical model. Quasispecies emergence was determined via heteroduplex complexity assay. Twenty‐two patients were HCV RNA‐positive at baseline, with no significant demographic or virological differences by infection status. Five of eleven (45%) of monoinfected and 3 of 11 (27%) of coinfected patients achieved sustained viral response (SVR). Peg‐IFN efficacy (ε) of 90% or greater was associated with probability of end‐of‐treatment response (ETR) (P = .001) and SVR (P = .06). Patients with SVR had lower baseline quasispecies complexity than those without SVR (P = .07). Those with ε of 90% or greater also had lower baseline complexity (P = .07). Coinfection status mediated changes in complexity over time (P = .04). In conclusion, low pretreatment quasispecies complexity may predict peg‐IFN response; early peg‐IFN response is critical for sustained HCV clearance and is altered in coinfection. Further studies are warranted. (HEPATOLOGY 2006;44:1146–1157.)

Suppression of hepatitis C virus (HCV) replication by hepatitis D virus (HDV) in HIV-infected hemophiliacs with chronic hepatitis B and C

Most hemophiliacs who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have high serum levels of HCV RNA. To study the impact of multiple hepatitis virus infections, we evalated all eight chronic carriers of hepatitis B surface antigen (HBsAg) from a previously studied cohort of 99 hemophiliacs with chronic HIV and HCV infections. Stored serum or plasma samples were tested for antibody to hepatitis D virus (anti-HDV) by ELISA; qualitatively for HCV RNA, HBV DNA, and HDV RNA by the polymerase chain reaction (PCR); and quantitively for HIV RNA, HCV RNA, and hepatitis B virus (HBV) DNA by a quantitative branched DNA signal amplification assay. HCV RNA was detected in only one of five patients with HDV infections on a cross-sectional study, and this individual had low levels (<3.5×105 genome eq/ml) of HCV RNA. In contrast, all three without HDV infections had high levels (>1.5×107 genome eq/ml) of HCV RNA. HIV RNA was present in all eight patients. There was no correlation between the level of HIV RNA and the presence of hepatitis viruses. Three of the eight patients (38%) died of liver failure and another has hypersplenism with hypoprothrombinemia. We conclude that HDV infection appears to suppress HCV replication and that liver failure is common in adult HIV-infected hemophiliacs with chronic HCV and HBV infections. These findings have implications for the therapy of HCV-infected hemophiliacs who are HBsAg positive.

A study of prospective surveillance for inhibitors among persons with haemophilia in the united states

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person‐years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003

Summary.  Before the mid‐1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV‐1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV‐seropositive patients, age 13–88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross‐sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV‐1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV‐1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV‐1‐positive participants had ≥200 CD4+ cells μL−1, only 59% were on HAART. HIV‐1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti‐HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV‐1‐positive than HIV‐1‐negative participants (85% vs. 70%, P < 0.0001). HIV‐1‐positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV‐negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self‐reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non‐Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV‐1, HCV or both.

Adverse Reactions to Factor VIII Infusions

Excerpt To the editor: In a 15-month period during which time 4 700 000 units of factor VIII were used by 70 hemophiliacs known to us, fifteen adverse reactions were reported. Excluding surgical us...