The use of protease inhibitors. A sampling of opinions. Interview by Deborah J Cotton.
Explore the source record for details and available documents.
Antiviral Agents↗
Biomedical subjects
L Corey
Publications and source records attributed to L Corey.
Virologic characteristics of subclinical and symptomatic genital herpes infections.
BACKGROUND: The frequency, pattern, and anatomical sites of subclinical shedding of herpes simplex virus (HSV) in the genital tract, along with factors that predict such shedding, have not been well characterized. METHODS: We studied prospectively the clinical and virologic course of genital herpes in 110 women. The women kept symptom diaries and provided daily samples from the vulva, cervix, and rectum for viral culture. RESULTS: During a median follow-up of 105 days, subclinical shedding of virus was identified in 36 of 65 women (55 percent) with HSV type 2 (HSV-2), in 16 of 31 women (52 percent) with HSV type 1 (HSV-1) and HSV-2, and in 4 of 14 women (29 percent) with only HSV-1. Among women with genital HSV-2 infection, subclinical shedding occurred on a mean of 2 percent of the days. The mean duration of viral shedding during subclinical episodes was 1.5 days, as compared with 1.8 days during symptomatic episodes. HSV was isolated from several sites in the genital tract and rectum in 17 percent of subclinical episodes and 22 percent of symptomatic episodes. Half the episodes of subclinical shedding of HSV occurred within seven days of a symptomatic recurrence. The risk of subclinical shedding increased with the frequency of symptomatic recurrences. Subclinical shedding was more frequent among women with more than 12 recurrences per year than among those with no symptomatic recurrences (odds ratio, 3.3; 95 percent confidence interval, 1.4 to 7.9); it was also more frequent among women who had recently acquired genital herpes (odds ratio for women with HSV acquired in the past year as compared with those who had had the infection for a year or more, 1.85; 95 percent confidence interval, 1.1 to 3.1). CONCLUSIONS: Among women with a history of genital herpes infection, subclinical shedding of HSV is common and accounts for nearly one third of the total days of reactivation of HSV infection in the genital tract. Women with frequent symptomatic recurrences also have frequent subclinical shedding and may be at high risk for transmitting HSV.
Adolescent↗
Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications.
OBJECTIVE: To compare two recently developed molecular techniques for quantitating the levels of hepatitis C virus (HCV) RNA in the serum of patients with a wide spectrum of chronic hepatitis C. DESIGN: Serum samples from 299 patients with HCV viremia, 101 control patients without HCV infection, and 19 consecutive patients receiving systemic interferon therapy were evaluated by a commercially available branched-chain DNA (bDNA) assay and a quantitative competitive polymerase chain reaction (PCR). SETTING: University-based hepatology clinics and reference virology laboratory. PATIENTS: Patients with HCV viremia as defined by results of qualitative RNA PCR, including 53 HCV-infected blood donors, 34 patients receiving renal dialysis, and 212 patients attending a hepatology clinic. RESULTS: Results of in vitro and in vivo experiments indicated that the sensitivity and dynamic range of the PCR assays were greater than those of the bDNA assay. Detection of HCV viremia by the bDNA assay was highly dependent on viral RNA titers, with a sensitivity of 5% at HCV RNA titers of 5.0 logs per mL or less and 94% at titers of 5.5 logs per mL or greater. The best correlation between assays was observed in specimens with HCV RNA titers between 6.0 and 7.5 logs per mL (r = 0.73). In patients with high-titer HCV viremia, including liver transplant recipients and patients with cirrhosis, quantitative PCR results were an average of 12-fold higher than bDNA assay results. Results of repetitive testing of discordant specimens showed that these discrepancies were caused by a high kit-to-kit coefficient of variation (112%) in the bDNA assay. Of 19 patients receiving interferon therapy, 9 (47%) became bDNA negative, but only 5 became quantitative PCR negative. The bDNA-negative, quantitative PCR-positive patients all had relapse when therapy was discontinued. CONCLUSIONS: The bDNA assay has a narrower linear range for quantitation of HCV viremia than quantitative PCR. Because persons with low HCV titers may respond well to therapy, seropositive persons with negative bDNA results should be retested with PCR-based assays. Similarly, the bDNA assay may underestimate the true degree of HCV viremia in persons with end-stage infection (> 10(7) RNA equivalents/mL of sera). Despite these limitations, the combination of bDNA- and PCR-based assays appears to be optimal for selecting and following patients during interferon therapy.
Case-Control Studies↗
A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity [corrected].
OBJECTIVE: To evaluate the safety and immunogenicity of a recombinant glycoprotein vaccine for herpes simplex virus type 2 (HSV-2), which contains glycoproteins gD2 and gB2 combined with the novel MF59 adjuvant emulsion, in HSV-2-seronegative persons. DESIGN: Integrated summary of two phase I and two phase II studies. SETTING: University and private outpatient clinics. PATIENTS: 137 persons seronegative for HSV-2 antibodies as determined by HSV Western blot assay. INTERVENTION: Open-label vaccine administration with a dose-escalating design (phase I) was followed by randomized vaccine administration (phase II). Vaccine was administered intramuscularly into the deltoid at 0, 1, and 6 months. MEASUREMENTS: Neutralizing, HSV-2-binding antibodies and HSV-2-stimulated proliferative responses were measured before and after immunization. RESULTS: Among HSV-seronegative patients, the gD2 and gB2 enzyme-linked immunosorbent assay (ELISA) and HSV-2-neutralizing antibody titers increased to levels equal to or higher than those seen in naturally acquired HSV-2 infection after the full three-dose immunization schedule. Among HSV-1-seropositive patients, one immunization produced increases in gD2 and gB2 ELISA antibody titers and HSV-2-neutralizing antibody titers that were 3 to 5 times greater than those in persons with naturally acquired HSV-2 infection. Among HSV-seronegative patients, frequency analysis assays showed a marked increase in the precursor frequency of gD2- and gB2-specific T cells after vaccination: T-cell responses after two immunizations were equal to the responses of HSV-2-seropositive patients and were sustained at day 180. The vaccine was well tolerated. CONCLUSIONS: This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.
Adjuvants, Immunologic↗
Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection.
In vitro, recombinant soluble CD4 (rsCD4) attaches to and inactivates human immunodeficiency virus (HIV). To determine if prolonged therapy with high-dose intravenous rsCD4 provides an in vivo benefit, we gave three HIV-1-infected patients with AIDS, whose isolates were susceptible in vitro to rsCD4, 10 mg/kg of rsCD4 for 4 weeks, 5 mg/kg for 4 weeks, and 1 mg/kg for 2 weeks. Single-dose pharmacokinetic studies performed prior to this showed transient in vivo decreases of HIV-1 plasma viremia in all three subjects. Surrogate markers of HIV activity, clinical status, HIV-1 p24 antigen, plasma HIV-1 titers, and peripheral blood mononuclear cell (PBMC) intracellular titers of virus were measured at entry, and every other week after onset of therapy. All subjects demonstrated rsCD4 concentration-dependent reduction in plasma viremia, with two subjects having complete neutralization of cell-free virus. The third subject's isolate was relatively resistant to the in vivo effects of rsCD4 and only partial reduction in plasma virus titers was obtained, even at the highest dose of 10 mg/kg. There was no change in the PBMC intracellular viral titer or surrogate markers of HIV-1 activity (including CD4 cell count and beta 2-microglobulin). There was subjective improvement in clinical symptoms, and all subjects gained weight with the highest doses of rsCD4. rsCD4 exhibited linear pharmacokinetics over the dose range studied. We conclude that high-dose intravenous rsCD4 can be safely given for up to 10 weeks and that it has a stable pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Seroprevalence of herpes simplex virus infections in a family medicine clinic.
OBJECTIVES: To determine the prevalence of herpes simplex virus (HSV) antibody in a general medical practice setting and to assess the frequency of subclinical infection. DESIGN: Prevalence study. SETTING: A family practice clinic at the University of Washington Medical Center, Seattle. PARTICIPANTS: Five hundred randomly selected patients between the ages of 18 and 45 years. MAIN OUTCOME MEASURES: Serum samples were tested by Western blot assay to detect the presence of antibody to HSV type 1 (HSV-1) and HSV-2. Demographic information and clinical history of oral and genital herpes were obtained. RESULTS: One hundred fourteen patients (23%) were seropositive for HSV-2 antibody, 277 patients (56%) were seropositive for HSV-1 antibody, 59 patients (12%) were seropositive for both HSV-2 and HSV-1 antibodies, and 163 patients (33%) were seronegative for both. Women were almost twice as likely as men to be seropositive for HSV-2 antibody (28% vs 15%, P < .001). Blacks had the highest rates of HSV-2 antibody seropositivity (60%) compared with whites (20%) and Asians (6%) (P < .001). Other demographic correlates of seropositivity included being older, having fewer years of education, and having public insurance. The specificity of a clinical history of genital herpes or sores for HSV-2 infection was high (99%), but the sensitivity was low (27%). CONCLUSIONS: Herpes simplex virus infection is common among patients seeking primary care. Women, blacks, and patients of lower socioeconomic status are most likely to be seropositive for HSV-2 antibody. The high frequency of unrecognized HSV infection has implications for primary care physicians in counseling patients regarding HSV infection and transmission.
Adult↗
A comparison between detailed and simple histories in the diagnosis of genital herpes complicating pregnancy.
OBJECTIVE: All women seropositive for herpes simplex virus-2 are at risk for asymptomatic viral shedding at the onset of labor and neonatal transmission of the virus. Unfortunately, only 20% to 35% of seropositive adults give a history consistent with genital herpes. We evaluated whether more detailed questioning during pregnancy might elucidate symptoms predictive of seropositivity and therefore better identify women at risk for herpes simplex virus shedding at delivery. STUDY DESIGN: During pregnancy 201 randomly selected women were asked in-depth questions about recurrent genital symptoms and whether they "currently have or have ever had genital herpes." An assessment was made whether the patient had a history compatible with genital herpes. This assessment and the "yes/no" history of genital herpes obtained by physicians at the initial prenatal visit were both compared with herpes simplex virus serologic studies by Western blot. RESULTS: Of 201 patients interviewed, 177 gave no history of genital herpes. Of these, 30.4% were seropositive for herpes simplex virus-2. Detailed histories on these 177 patients indicated that among the 159 subjects without suggestive symptoms or with somewhat suggestive symptoms the corresponding rates of seropositivity were 28% and 30%. Among the 18 (10.2%) subjects with highly suggestive symptoms, only 50% were seropositive. The positive predictive values for recurrent genital symptoms to predict herpes simplex virus-2 seropositivity ranged from 30% to 57%. CONCLUSION: A detailed history of genital symptoms is no better at identifying an herpes simplex virus-2 seropositive patient than is simply asking if she has ever had genital herpes. Serologic screening is a more accurate method of identifying women with past genital herpes or those who are at risk for acquiring genital herpes during pregnancy.
Adolescent↗
Automated microneutralization: method and comparison with western blot for type-specific detection of herpes simplex antibodies in two pregnant populations.
A novel method for the detection of microneutralization was compared to Western blot for detection of type-specific antibodies to herpes simplex virus in two pregnant patient populations in Vancouver. From an unselected group of women in labor in a tertiary care obstetric hospital (426) and another group of women specially referred for assessment of genital herpes in pregnancy (195) 20 and 88%, respectively, were seropositive for herpes simplex virus type 2 antibodies by Western blot. During the study period, 93 (48%) of the high-risk group were culture positive for HSV-2 and all but one case was verified serologically by Western blot. Therefore, the sensitivity for Western blot in this high seroprevalence group was 99%. The false-negative case had longstanding recurrent infection and on retest was found to be a laboratory error. For microneutralization, type-specificity was especially difficult to distinguish among patients with mixed viral type patterns. Comparing microneutralization to Western blot as the gold standard, sensitivity, specificity, positive and negative predictive values were 84, 78, 97 and 40% respectively, for the referred group and 73, 82, 51 and 92%, respectively, for the unselected group. Poor negative and positive predictive values for the referred group and unselected populations, respectively, demonstrate that microneutralizations are not clinically acceptable for type-specific antibody detection. By contrast, serology by Western blot is very sensitive and apparently highly specific.
Antibodies, Viral↗
Frequency and reactivation of nongenital lesions among patients with genital herpes simplex virus.
OBJECTIVE: To determine the frequency, recurrence patterns, and host factors associated with nongenital herpes simplex virus lesions. PATIENTS AND METHODS: In this cohort study at a referral clinic, 457 patients with first episodes of genital herpes were prospectively observed to evaluate the anatomic sites of herpetic lesions at the first and subsequent visits. Of these patients, 73 had primary genital herpes simplex virus (HSV) type 1, 326 had primary first episode genital HSV-2, and 58 had HSV-1 infection prior to acquisition of genital HSV-2. The median follow-up was 63 weeks. RESULTS: Nongenital lesions at the time of acquisition of genital herpes were observed in 25%, 9%, and 2% of patients with primary HSV-1, primary HSV-2, and nonprimary HSV-2, respectively. Half of the patients with concurrent genital and nongenital lesions subsequently had recurrences at a nongenital site. Twenty patients (6.5%) whose primary genital HSV-2 infection involved only the genitalia subsequently developed nongenital recurrences, primarily on the buttocks (12) and legs (4). Nongenital recurrences, especially buttock recurrences, tended to be less frequent but of longer duration than genital recurrences. CONCLUSIONS: Overall, 21% of patients with primary genital herpes will have or will subsequently develop a nongenital recurrence. Among patients with HSV-1, nongenital lesions tended to occur more often on the hand and face, whereas HSV-2 lesions appeared more often on the buttocks. Buttock lesions due to HSV recur less frequently but last longer than genital lesions.
Herpes Genitalis↗
Herpesvirus infections in persons infected with human immunodeficiency virus.
Herpesviruses are among the most common causes of infections of humans. Viruses in this family share the unique biological property of being able to establish latency and to recur. Furthermore, chronic excretion of virus is not uncommon. In the immunocompromised host, including persons with human immunodeficiency virus (HIV) infection, herpesvirus disease can be particularly severe, resulting in chronic, persistent, active infection and, in some cases, life-threatening disease. The most pathogenic of the herpesviruses in patients with AIDS include herpes simplex viruses, human cytomegalovirus, and varicella-zoster virus. Disease caused by Epstein-Barr virus, particularly opportunistic malignancies, has been recognized. A new herpesvirus that is associated with Kaposi's sarcoma was recently described. On the other hand, disease caused by human herpesviruses 6 and 7 in persons infected with HIV remains to be unequivocally recognized. Prevention of exposure to herpesviruses, disease, and recurrence requires different measures than those for some of the other opportunistic infections in HIV-infected patients; this is because herpesvirus disease develops in most of these individuals as a result of reactivation rather than primary infection. Thus, approaches to the prevention and control of herpesvirus infections must be individualized according to both the type of virus as well as the type of infection (i.e., primary or recurrent). We discuss recommended measures for the prevention and control of these infections.
HIV Infections↗
Cervical but not urinary excretion of cytomegalovirus is related to sexual activity and contraceptive practices in sexually active women.
The relationship between sexual activity and genitourinary excretion of cytomegalovirus (CMV) was evaluated in 1481 women at a sexually transmitted disease (STD) clinic. Among 951 who were CMV-seropositive, 16.6% had CMV isolated, from cervix alone in 9.4%, urine alone in 3.8%, and both sites in 4.2%. Isolation rates were highest in young women (P < .001). Compared with those with only cervical infection, women shedding from both cervix and urine were younger, began sexual activity when younger, had more recent partners, and a higher frequency of CMV-specific IgM, suggesting recent CMV infection. By logistic regression, cervical CMV excretion was associated with concomitant gonococcal infection (P = .008) and was less frequent in those using barrier contraception (P = .036). Isolated urinary excretion of CMV was not associated with sexual activity, concomitant cervical infections, or use of contraception. Cervical CMV infection is related to sexual activity, acquisition of other STDs, or exogenous reinfection, and urinary CMV is not.
Adolescent↗
Reducing T cell activation as a therapy for human immunodeficiency virus infection.
Explore the source record for details and available documents.
CD4 Lymphocyte Count↗
Seminal shedding of human immunodeficiency virus type 1 and human cytomegalovirus: evidence for different immunologic controls.
Contact with semen of seropositive men is important for sexual transmission both human immunodeficiency virus (HIV) type 1 and human cytomegalovirus (CMV), but the factors that determine shedding of either virus in semen are poorly understood. HIV was cultured from 36 (17%) of 215 semen specimens from 56 seropositive men, and CMV was cultured from 42 (30%) of 139 specimens. In logistic regression models, the CD8+ cell count in peripheral blood was the best predictor of HIV shedding in semen. Shedding of HIV was more closely associated with concomitant shedding of CMV than with CD4+ cell count, and antiretroviral therapy had minimal influence on shedding of HIV. In contrast, CD4+ cell count was the best predictor of CMV shedding in semen. Factors that determine shedding of viruses in semen may differ substantially from those that influence virus levels in the systemic immune compartment. Likewise, immunologic factors that determine shedding of HIV appear to differ from those that control shedding of CMV in semen.
Antiviral Agents↗
A randomized, double-blind, placebo-controlled trial of systemically administered interferon-alpha, -beta, or -gamma in combination with cryotherapy for the treatment of condyloma acuminatum.
One hundred fifty-two patients were enrolled in a study to evaluate 3 interferon (IFN) preparations used in combination with cryotherapy for treatment of anogenital warts. Subjects received subcutaneous injections (2 x 10(6) units/m2) of IFN-alpha n1, -beta, -gamma or placebo 3 times a week for 6 weeks and cryotherapy with liquid nitrogen. Subjects were followed < or = 1 year. Among patients followed > or = 12 weeks, two-thirds had a complete response. No significant differences in rates of complete response (P = .37) or reappearance of a wart at the initial site (P = .20) were noted among the treatment groups. However, patients who received IFN-beta or -gamma developed new warts at a significantly lower frequency (P = .02). IFN administration was associated with side effects but was well tolerated. IFN-beta was the least toxic of the 3 preparations and had the best therapeutic ratio.
Adult↗
Infection of Macaca nemestrina brain with human immunodeficiency virus type 1.
We previously reported that pigtailed macaques (Macaca nemestrina) became infected after intravenous inoculation with the LAI strain of human immunodeficiency virus type 1 (HIV-1), an isolate that replicates in both M. nemestrina lymphocytes and blood-derived monocyte/macrophages. In the current study we investigated the presence of HIV-1 and pathology in the postmortem brains of four of these macaques. Histopathological findings revealed focal lesions in white matter in the frontal and occipital lobes of one macaque, with myelin loss, nerve fibre loss, and gliosis within these lesions. Semi-quantitative, solution-based PCR revealed HIV-1 DNA in the brains of two of the other macaques. Using slide-based PCR-driven in situ hybridization, we studied these two macaques further and detected intranuclear, circular HIV-1 DNA in vascular endothelia and other non-neuronal brain cells. These findings indicate that M. nemestrina brain can be infected with HIV-1 in vivo and may provide a useful animal model for understanding early HIV-1 brain infection in humans.
AIDS Dementia Complex↗
Cytotoxic and proliferative T cell responses in HIV-1-infected Macaca nemestrina.
Macaca nemestrina has been described as an animal model for acute HIV-1 infection. This animal, unlike most infected humans, appears to contain HIV-1 replication. Therefore analysis of HIV-1-specific proliferative and cytotoxic T lymphocyte (CTL) responses following HIV-1 challenge of M. nemestrina may provide information into the role of such responses in both the control of acute HIV infection and protective immunity. Although CD4+ T cell responses to HIV-1 are generally difficult to detect in HIV-1-infected humans, early and persistent CD4+ T cell proliferative responses to HIV-1 antigens were detected in all HIV-1-inoculated M. nemestrina. HIV-1-specific CD8+ CTL responses were evaluated in PBMC by stimulation with autologous cells expressing HIV-1 genes, limiting dilution precursor frequency analysis, and T cell cloning. CTL reactive with gag, env, and nef were present 4-8 wk after infection, and persisted to 140 wk after infection. The presence of both CD4+ and CD8+ T cell responses before and after clearance of HIV-1 viremia is consistent with a role for these responses in the successful control of HIV-1 viral replication observed in M. nemestrina. Further studies of T cell immunity in these animals that resist disease should provide insights into the immunobiology of HIV-1 infection.
Animals↗
Persistent hepatitis C virus infection after liver transplantation: clinical and virological features.
We report a prospective clinical and virological study of 18 patients undergoing orthotopic liver transplantation, selected because of hepatitis C virus (HCV) RNA positivity before transplantation. Nine of the 18 patients (50%) developed chronic active hepatitis (CAH) in liver allografts during the first year posttransplantation; hepatitis was first observed between 6 and 25 weeks posttransplantation. HCV viremia was measured for all patients before transplantation and on posttransplantation days 3, 7, and 14, and months 1, 6, 12, and 24 to 41, by quantitative competitive RNA polymerase chain reaction (QC-PCR). HCV RNA levels on posttransplantation days 3, 7, and 14 were significantly higher among patients who subsequently developed CAH versus those who did not (P < .02 by t-test and Mann-Whitney test on all three dates). However, HCV RNA levels in sera obtained at 1, 6, and 12 months posttransplantation did not correlate with CAH at 1 year or with HCV genotype determined in posttransplantation sera. At least two serial liver biopsy specimens from each patient were stained for HCV nonstructural 4 (NS4) antigen by immunohistochemistry. The intensity of cytoplasmic staining of NS4 antigen was significantly higher for specimens with CAH versus those without CAH (P = .028 by chi 2). Three patients developed bridging fibrosis in liver allografts during the first year after transplantation; all three patients had intense (3+) immunostaining for NS4 antigen, and the infecting genotypes were 1a, 1b, and 1a plus 1b, respectively. In summary, the 18 patients all developed high-titer viremia by 1 month after liver transplantation, whereas CAH developed in 50% of allografts during the first year after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic Disease↗
Intermittent shedding of human immunodeficiency virus in semen: implications for sexual transmission.
PURPOSE: We attempt to increase our understanding of human immunodeficiency virus (HIV) shedding in semen. MATERIALS AND METHODS: We followed 16 seropositive men for up to 27 months by HIV cocultivation, with a subset evaluated using the polymerase chain reaction. RESULTS: The proportion with at least 1 HIV positive semen culture increased from 3 of 16 subjects (19%) at visit 1 to 10 (63%) by visit 5. Overall, HIV was cultured from 25 of 114 specimens (22%). Shedding was intermittent for each of the 10 men with at least 1 positive culture and seminal shedding patterns were highly variable. CONCLUSIONS: By culture and polymerase chain reaction, HIV is shed intermittently in the semen. If cultures are performed often enough most seropositive men shed HIV in the semen.
Base Sequence↗