Sarah H. Cheeseman

Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of ‘covert’ virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

Kawasaki Syndrome: Description of Two Outbreaks in the United States

Investigation of two outbreaks of Kawasaki syndrome (KS) in the United States in 1979 and in 1980 revealed no evidence of person-to-person transmission or of a common-source exposure among patients. Questionnaire data showed that KS was more likely to occur in children of middle and upper socioeconomic status than in those of lower status (P less than 0.05 and P less than 0.001 for the respective outbreaks) and that patients with KS had a higher incidence of an antecedent, primarily respiratory illness than did controls matched for age, sex, and race (83% of patients in the first outbreak vs. 30% of one control group, P less than 0.01, and vs. 36% of another control group, P less than 0.02; and 56% of patients in the second outbreak vs. 32% of their controls, P less than 0.02). However, laboratory studies did not identify an etiologic agent for either KS or for the antecedent illness that may be a risk factor for KS.

Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus

In these Phase I/II open-label clinical trials, 62 persons with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ cell counts < 400/mm3 received nevirapine at doses of 12.5, 50, and 200 mg/day, alone or in combination with zidovudine, 200 mg q8h. Nevirapine was well tolerated in the doses tested. Mean steady-state trough levels were 0.23, 1.1, and 1.9 micrograms/ml for the 12.5, 50, and 200 mg/day doses, respectively. Early suppression of p24 antigen levels and increase in CD4+ cell count were reversed following rapid emergence of virus less susceptible to nevirapine. Resistant strains were isolated from all participants by 8 weeks. Nevertheless, reduction of p24 antigen levels to < 50% of baseline values persisted for 12 weeks or more in four of seven persons who received 200 mg nevirapine/day in combination with zidovudine: these individuals had been antigenemic on long-term zidovudine therapy. This study demonstrates a direct relationship between drug resistance and effects on surrogate markers in HIV-1 infection.

Pharmacokinetics of nevirapine: initial single-rising-dose study in humans.

Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.

Influenza in Human Immunodeficiency Virus-Infected Patients during the 1997–1998 Influenza Season

A cluster of cases of severe influenzal disease was recognized in HIV-infected individuals during the 1997-1998 influenza season. Both primary influenza pneumonia and concomitant viral and bacterial pneumonia were found.

Prophylaxis with Weekly Versus Daily Fluconazole for Fungal Infections in Patients with AIDS

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Virologic studies in a case of transfusion-associated AIDS.

The authors present the case of a 60-year old woman who developed acquired immunedeficiency syndrome (AIDS) 43 months after a blood transfusion. The blood donor was identified as a sexually active homosexual man who frequently used intravenous drugs. Although he was asymptomatic, physical examination revealed generalized lymphadenopathy of cervical, axillary, and inguinal areas. 47 months after his blood donation, the donor underwent lymph node biopsy which revealed follicular hyperplasia. He was seropositive for antibodies to human T-lymphotropic virus type III (HTLV-III) and had serologic evidence of prior infection with cytomegalovirus, Epstein-Barr virus, and hepatitis B virus. On the other hand, he had a normal total lymphocyte count and normal T-cell subsets. Striking was the difference between the seropositivity of the high-risk donor and the seronegativity of the patient with transfusion-associated AIDS with respect to cytomegalovirus, Epstein-Barr virus, and hepatitis B virus. The demonstration of apparent transmission of HTLV-III by blood transfusion and the inability to detect evidence of infection with other viruses strongly indicate a primary etiologic role for this virus in the pathogenesis of AIDS. The high-risk blood donor continues to be an asymptomatic carrier of HTLV-III. The authors are currently comparing the HTLV-III isolates obtained from the blood donor with the HTLV-III-related RNA sequences detected in the spleen of the patient in order to determine whether molecular changes occurred after transmission of the virus that might be related to the development of AIDS.

Hemophiliac immunodeficiency: Influence of exposure to factor VIII concentrate, LAV/HTLV-III, and herpesviruses

The relationship between hemophiliac immunodeficiency and exposures to factor VIII concentrate, LAV/HTLV-III retrovirus, and infection with Epstein-Barr virus and cytomegalovirus was examined. Exposure to factor VIII concentrate was significantly correlated with decreased percentages of T helper/inducer cells, decreased T helper/suppressor cell ratios, and decreased proliferative responses to plant mitogens. LAV/HTLV-III seropositivity was the primary predictor of increased percentages of HLA-DR-bearing mononuclear cells and decreased proliferative responses to pokeweed mitogen. Epstein-Barr virus and cytomegalovirus infections acted in a synergistic manner with LAV/HTLV-III to produce immunoregulatory defects. Increased percentages of T suppressor cells and decreased delayed cutaneous hypersensitivity skin test responses were observed in LAV/HTLV-III seropositive hemophiliacs infected with Epstein-Barr or cytomegalovirus. We conclude that hemophiliacs receiving commercial factor VIII concentrate experience several stepwise incremental insults to the immune system: alloantigens in factor VIII concentrate, LAV/HTLV-III infections, and herpesvirus infections.

Methicillin-Resistant Staphylococcus intermedius Pneumonia Following Coronary Artery Bypass Grafting

virus DNA in cerebrospinal fluid from immunocompetent individuals with brain disorders. Microbiologica 1998;21:77–9. 8. Studahl M, Bergström T, Hagberg L. Acute viral encephalitis in adults— a prospective study. Scand J Infect Dis 1998;30:215–20. 9. Tang YW, Espy MJ, Persing DH, Smith TF. Molecular evidence and clinical significance of herpesvirus coinfection in the central nervous system. J Clin Microbiol 1997;35:2869–72.

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062).

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.