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Biomedical subjects

J Gerstoft

Publications and source records attributed to J Gerstoft.

At least 73 records · Page 4Linked to original sources
PubMed1997

[HIV quantification--how and why].

The principals of four methods for measurements of viral load (HIV endpoint dilution, NASBA, bDNA and Amplicor PCR) are outlined. HIV quantification has increased our knowledge about the natural history of the HIV infection and the influences of exogenous factors on HIV replication. Furthermore measurements of HIV RNA early in the course of the infection have proven to be prognostic for the clinical outcome of the infection. Last but not least, HIV quantification has been shown to be a good marker for the efficacy of antiretroviral treatment and will hence be a valuable tool for the monitoring and management of anti-retroviral treatment.

DNA Probes↗
PubMed1997

Prognostic value of serum HIV-RNA levels at virologic steady state after seroconversion: relation to CD4 cell count and clinical course of primary infection.

The objectives of this study were to evaluate the prognostic value of a single serum HIV-RNA measurement 6-24 months after HIV seroconversion, and to investigate whether any differences in outcome related to the clinical course of primary infection could be explained by presumed steady-state HIV-RNA levels at 6-24 months after seroconversion. Disease progression was analyzed by life tables and Cox proportional hazard models. A total of 93 HIV seroconverters followed for a median of 76 months (range, 19-143 months) were included in the study. The main outcome measures were development of AIDS stratified by age, the year of seroconversion, serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The proportion of patients who developed AIDS was 36% (95% confidence interval, 22%-50%) at 8 years and 50% (26%-75%) at 10 years. In the unadjusted analyses, clinical progression was significantly associated with serum HIV-RNA levels, CD4 cell counts, and duration of primary illness. The adjusted analyses indicated that HIV-RNA was the strongest predictor. Patients with long-lasting symptoms associated with primary infection had significantly higher serum HIV-RNA levels than those with less severe presentations (median counts, 11,660 vs. 2880 copies/ml, p = 0.001). It is concluded that the serum HIV-RNA level in early HIV infection is a strong independent predictor of clinical progression. Patients with long-lasting primary illnesses reach a higher viral load in steady state after seroconversion, which is probably the main reason for the poorer prognosis observed in this group of patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus encodes a chemokine called vMIP-II. This protein displayed a broader spectrum of receptor activities than any mammalian chemokine as it bound with high affinity to a number of both CC and CXC chemokine receptors. Binding of vMIP-II, however, was not associated with the normal, rapid mobilization of calcium from intracellular stores; instead, it blocked calcium mobilization induced by endogenous chemokines. In freshly isolated human monocytes the virally encoded vMIP-II acted as a potent and efficient antagonist of chemotaxis induced by chemokines. Because vMIP-II could inhibit cell entry of human immunodeficiency virus (HIV) mediated through CCR3 and CCR5 as well as CXCR4, this protein may serve as a lead for development of broad-spectrum anti-HIV agents.

Amino Acid Sequence↗
PubMed1997

HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group.

The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.

CD4 Lymphocyte Count↗
PubMed1997

Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin.

BACKGROUND: Low serum concentrations of mannose-binding lectin (MBL) are associated with increased susceptibility to recurrent infection. Three variant alleles in the MBL gene (B, C, and D), cause low serum concentrations of the protein. We investigated whether variant alleles of MBL affect susceptibility to infection with HIV and progression of AIDS. METHODS: Between 1983 and 1986, all men who attended two clinics in Copenhagen for HIV screening were invited to take part in our study. We investigated the prevalence of variant alleles of MBL (detected by PCR) and assessed the prognostic value of these alleles and the corresponding serum MBL concentrations (measured by ELISA) in 96 homosexual men with HIV infection and in two control groups (123 healthy adults and 36 HIV-negative homosexual men at high risk of HIV infection because of their sexual behaviour). Follow-up was for up to 10 years. FINDINGS: Eight (8%) of the HIV-infected men were homozygous for the variant MBL alleles compared with one (0.8%) of the healthy controls (p = 0.005) and none of the high-risk homosexual controls (p = 0.05). We found no significant association between MBL genotype and time from first positive HIV test to progression of AIDS (p = 0.8). However, in the 61 HIV-infected men who developed AIDS, the median survival time was significantly shorter after the AIDS diagnosis for men who were carriers of the variant alleles (both homozygous and heterozygous) than for men homozygous for the normal MBL allele (11 [IQR 4-21] vs 18 months [9-44], p = 0.007). Among men who developed AIDS, there was a significant difference in survival time between those with serum MBL concentrations below the lower quartile, those within the IQR, and those above the upper quartile (p = 0.02). Multivariate analysis showed that men who developed AIDS and had low serum MBL concentrations had an increased rate of rapid death, independently of CD4 T-cell counts at AIDS diagnosis. INTERPRETATION: Our findings suggest that homozygous carriers of variant MBL alleles are at increased risk of HIV infection, either directly or indirectly because of increased susceptibility to coinfections. These alleles are also associated with a significantly shorter survival time after a diagnosis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Decreased short-term production of tumor necrosis factor-alpha and interleukin-1beta in human immunodeficiency virus-seropositive subjects.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured by ELISA in 4.5-h, lipopolysaccharide-stimulated whole blood cultures of 347 human immunodeficiency virus type 1-infected patients and 107 healthy seronegative controls. The production of TNF-alpha was decreased in both AIDS and non-AIDS patients, whereas the production of IL-1beta was decreased in AIDS patients only. The production of TNF-alpha and IL-1beta was positively affected by the concentrations of CD14+ monocytes and CD8+ lymphocytes; however, in patients, the concentration of CD4+ lymphocytes and the presence of AIDS had a negative effect on cytokine production as determined by multiple linear regression analysis. It is concluded that low whole blood cytokine production is mainly caused by low numbers of cells, but a functional defect may also exist.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Survival of AIDS patients according to type of AIDS-defining event. The AIDS in Europe Study Group.

BACKGROUND: There are known to be wide differences in the prognosis of patients with a diagnosis of AIDS. In this study of 6578 patients with AIDS form 17 European centres, we develop a ranking of AIDS-defining illnesses, and determine how well this ranking holds after adjustment for potential confounding variables. METHODS: Survival from each AIDS-defining event was calculated and ranked using Kaplan-Meier estimation of median survival. Cox proportional hazards models with each disease modelled as a time dependant covariate were used to determine the risk of death after each diagnosis, before and after adjustment for potential confounders. RESULTS: Median survival after an initial AIDS-defining diagnosis of progressive multifocal leukoencephalopathy and malignant lymphoma was particularly poor (2 and 5 months respectively), while the longest median survival occurred after initial AIDS-defining illnesses of Kaposi's sarcoma and extrapulmonary tuberculosis (17 and 22 months respectively) Patients diagnosed with a primary brain lymphoma had shorter median survival times than patients with a peripheral lymphoma (median survival of 1 month and 4 months respectively P < 0.0001). In general, median survival in patients with cutaneous Kaposi's sarcoma (skin, oral) was between two and four times longer than patients with systemic involvement The ranking of diseases was found to be generally similar after adjustment for all potential confounders. CONCLUSIONS: AIDS-defining events can be grouped into three categories with median survival after diagnosis of < 6 months. 6-12 months and > 12 months. The assigned ranking of disease would not be altered by prognostic factors such as age or CD4 lymphocyte count. These results have important implications in the design of clinical trials and patient management.

AIDS-Related Opportunistic Infections↗
PubMed1997

Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals.

OBJECTIVE: Recently, it has been shown that a homozygous 32 base-pair deletion in the gene encoding CKR-5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1. We have investigated whether HIV-seropositive individuals who were heterozygous for the CKR-5 deletion had a different course of the disease. DESIGN: Thirty-five high-risk HIV-seronegative and 99 HIV-seropositive Danish homosexual men followed form 1985 to 1996 and 37 blood donors were analysed for their CKR-5 genotype by polymerase chain reaction. RESULTS: Two (6%) of the 35 HIV-seropositive subjects at high-risk of infection were homozygous and seven (20%) were heterozygous for the CKR-5 deletion. This was not significantly different from the distribution in normal donors. Twenty-two (22%) of the 99 HIV-seropositive subjects were heterozygous and none was homozygous. Two subgroups of patients who had an opposite course of the HIV disease were identified. Of nine long-term non-progressors, six (66%) were heterozygous for the deletion. This frequency is significantly higher than in nine rapid progressors of whom non was heterozygous. The frequency of heterozygotes in long-term non-progressors was also significantly higher than in the cohort as a whole. A Kaplan-Meier plot of the HIV-seropositive subjects, of whom 57 developed AIDS, showed a significantly better prognosis within the first 7 years of follow-up for those who were heterozygous for the deletion. Heterozygous individuals also had a significantly slower decrease in CD4 T-cell count per year. CONCLUSION: Individuals who are heterozygous for the 32-base-pair deletion in the CKR-5 gene have a slower decrease in their CD4 T-cell count and a longer AIDS-free survival than individuals with the wild-type gene for up to 11 years of follow-up.

CD4 Lymphocyte Count↗
PubMed1997

Alternating treatment with didanosine and zidovudine versus either drug alone for the treatment of advanced HIV infection. The Alter Study. Nordic HIV Therapy Group.

The efficacy and safety of an alternating regime with zidovudine and didanosine versus treatment with either drug alone were investigated in a randomized, open, controlled trial, 552 patients with advanced HIV infection, 47% of whom had received prior treatment with zidovudine, were enrolled. The patients were randomly assigned to zidovudine 600 mg/day, didanosine 400 mg/day or 4-week alternations with the 2 drugs in the same dose. The study had a median length of follow-up of 88 weeks. In the overall analyses, time to death (p = 0.48) and time to death or new AIDA event (0.80) were equally distributed between the 3 treatment groups. In the subgroup of patients with a CD4 count < 100 x 10(6)/l the survival was longer in the alternating arm (p < 0.005) primarily because of differences among zidovudine naive patients. The alternating regime was better tolerated than the 2 monotherapies, with a longer time to dose reduction or withdrawal owing to side effects (p < 0.001).

Adult↗
PubMed1997

Toxoplasmosis in Danish AIDS patients.

Infection with Toxoplasma gondii was studied in 600 patients with AIDS, diagnosed in the eastern part of Denmark from 1980 up to and including 1990. The median age was 38 years, and 223 (44%) had anti-T. gondii IgG antibodies. Of the patients seropositive to T. gondii 61 (27%) developed toxoplasma encephalitis (TE). Few patients received prophylactic treatment with sulfamethoxazole-trimetoprim. In total, 66 patients were diagnosed with TE. One had no serological test performed, and of the remaining 65, 4 (6%) had no anti-T. gondii IgG antibodies. The predictive value of a negative Sabin-Feldman dye test was 99%. The geometric mean dye test titer was higher in patients with TE than in patients without TE. Of the patients with TE 34% had serological reactivation of their T. gondii infection at the time of TE diagnosis, and 34% had detectable T. gondii-specific antibodies in the cerebrospinal fluid. Specific IgM antibodies were found to have little value in the diagnosis of TE, as only 3% had detectable IgM antibodies. Acute toxoplasmosis was the AIDS-defining diagnosis for 23 (35%) of the patients with TE. The median CD4 count at the time of TE was 30 x 10(6)/l, and the median survival time from diagnosis of TE was 9 months.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome.

OBJECTIVE: To investigate the longitudinal changes in serum HIV RNA, and to clarify whether the viral load early in infection has a predictive value for the clinical outcome; also, to correlate viral phenotype at seroconversion and changes in CD4 cell counts with viral burden. DESIGN: Twenty seroconverters with HIV isolates available at seroconversion had HIV RNA quantified by polymerase chain reaction (PCR) at seroconversion and thereafter every 6 months. Mean follow-up time was 65 months. Patients were classified according to viral phenotype at seroconversion, time to AIDS progression, serum viral load within the first year (less or more than 1.5 x 10(4) copies/ml). RESULTS: High viral load at seroconversion was followed by a significant decline within the first months (P < 0.0005). Decline to < 1.5 x 10(4) copies/ml was correlated with slower progression to AIDS (P < 0.05). A correlation between the rate of CD4 decline and the median viral load during the ensuing viral load plateau phase was also shown (P < 0.05). Subsequent to this phase the viral burden increased. Rapid progressors had higher viral load than slow- or non-progressors; this was particularly pronounced late in infection. Harbouring syncytium-inducing (SI) virus at seroconversion was associated with faster progression to AIDS than non-SI (NSI; P < 0.005). The increased in vitro replication rate of SI over NSI was not translated into significantly higher serum HIV RNA. CONCLUSION: Serum HIV RNA is high around the time of seroconversion. A significant decline within the first months hereafter is followed by a plateau phase, which in turn is followed by an increase in HIV RNA. HIV RNA early in infection has a predictive value for the clinical outcome. The increased virulence of SI over NSI virus did not translate into significantly higher HIV RNA values.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Development of resistance of zidovudine (ZDV) and didanosine (ddI) in HIV from patients in ZDV, ddI and alternating ZDV/ddI therapy.

OBJECTIVE: To study development of phenotypic and genotypic resistance against zidovudine (ZDV) and didanosine (ddI) during 24 months of mono- and monthly alternating therapy. PATIENTS: Forty-six patients, not previously treated with antiretroviral drugs, were included in the study. METHODS: ZDV and ddI sensitivity were determined in a biological assay based on production of HIV antigen in cultures of CD4+ lymphocytes. The ZDV-associated mutations at codon 41 and 215, and the ddI-associated mutation at codon 74 of the reverse transcriptase (RT) gene were analysed using selective polymerase chain reaction on DNA from peripheral blood mononuclear cells. The biological phenotype [syncytium-inducing (SI)/non-SI(NSI)] of the viral isolates was assessed using a MT2 assay. RESULTS: Of the patients, 82% in ZDV therapy and 73% in alternating therapy developed phenotypic resistant HIV [median inhibitory concentration (IC50) > 0.1 microM]. Patients treated for 1 year with ddI (monotherapy or alternating) had significant higher ddI IC50 values than patients in ZDV monotherapy. During ZDV and alternating therapy, 67 and 75% of the patients, respectively, developed mutations in RT codon 41, whereas 83 and 75%, respectively, developed mutations in codon 215. In patients treated with ddI, 60% developed mutations in codon 74, whereas none of the patients in either alternating ZDV/ddI or ZDV therapy developed this mutation. Forty-six per cent of the patients had SI HIV at start of therapy. Four patients switched from SI to NSI during either ZDV, ddI or alternating therapy. Faster development of resistance was associated with the SI phenotype. CONCLUSIONS: No difference in either phenotypic ZDV or ddI resistance, or genotypic ZDV resistance could be demonstrated during monotherapy or monthly alternating ZDV/ddI therapy, whereas genotypic ddI resistance (mutation in RT codon 74) only were detected in patients in ddI monotherapy. In addition, we found that development of phenotypic and genotypic resistance was faster in patients harbouring SI isolates, and that switches from SI to NSI during therapy was independent of the type of therapy.

Anti-HIV Agents↗
PubMed1996

Assessments of plasma HIV RNA and CD4 cell counts after combined Pneumovax and tetanus toxoid vaccination: no detectable increase in HIV replication 6 weeks after immunization.

The influence of simultaneous vaccination with Pneumovax and tetanus toxoid on plasma human immunodeficiency virus (HIV) RNA and CD4 cell counts was assessed in patients with HIV infection. Six weeks after immunization plasma HIV RNA did not differ significantly from baseline values. A slight decline in CD4 cell counts after vaccination was detected. There was no correlation between the serological responses to pneumococcal vaccination and baseline CD4 cell counts, changes in HIV RNA or CD4 cell counts. In conclusion, immunization did not induce an increase in viral replication detectable 6 weeks after immunization.

Bacterial Vaccines↗