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Biomedical subjects

J Gerstoft

Publications and source records attributed to J Gerstoft.

At least 55 records · Page 3Linked to original sources
PubMed2000

Effects of G-CSF on telomere lengths in PBMCs from human immunodeficiency virus-infected patients: results from a randomized, placebo-controlled trial.

Telomeres are unique terminal chromosomal structures, the length of which has been shown to decrease with cell division in vitro and with increased age in vivo for human somatic cells. In human immunodeficiency virus (HIV)-1 infection, decrease of telomere length is primarily found in CD8+ T cells, and not in CD4+ T cells. In this double-blind placebo-controlled study, we investigated the effect of granulocyte colony stimulating factor (G-CSF) treatment combined with highly active antiretroviral therapy (HAART) on mean telomere length in peripheral blood mononuclear cells (PBMC). The terminal restriction fragment (TRF) length showed no changes during G-CSF treatment although the number of lymphocytes increased significantly. The mean TRF length correlated positively (R = 0.552, P = 0.009) and negatively (R = -0.503, P = 0.02) to the proportion of CD4+ memory and naïve cells, respectively. Our data suggest that during G-CSF treatment lymphocytes are recruited by a combination of central and peripheral proliferation.

Adult↗
PubMed2000

The effect of long-term treatment with granulocyte colony-stimulating factor on hematopoiesis in HIV-infected individuals.

This randomized, placebo-controlled trial examine the long-term effect of granulocyte colony-stimulating factor (G-CSF) on absolute numbers of CD34+ progenitor cells and progenitor cell function in human immunodeficiency virus (HIV)-infected patients. G-CSF (300 microg filgrastim) or placebo was given three times weekly for 12 weeks to 30 HIV-infected patients that had been treated with HAART for at least 24 weeks and not yet achieved CD4 counts above 350 CD4+ cells/microl. Blood samples were collected at weeks 0, 2, 4, 8, and 12, and again 12 weeks after termination of the G-CSF treatment. Significant increase in absolute numbers of circulating CD34+ cells was detected in the treatment group (P = 0.006). The function of progenitor cells was examined in vitro using a colony-forming unit (CFU) assay, and increase in the number of CFU/ml was detected (P = 0.005). In order to estimate the effect of G-CSF on in vivo function of progenitors the white-blood count was determined. Significant increase in white-blood count was found (P < 0.001), while hemoglobin and platelet count decreased (P = 0.001 and P = 0.013, respectively). Significant increase in the CD4 count occurred, but correlation between the numbers of progenitors and the CD4 count was not found. These data suggest that G-CSF mainly increases the number and differentiation of myeloid progenitors.

Anti-HIV Agents↗
PubMed2000

Prognostic value of single measurements of beta-2-microglobulin, immunoglobulin A in HIV disease after controlling for CD4 lymphocyte counts and plasma HIV RNA levels.

The interrelationships between the CD4 lymphocyte count, plasma viral load [human immunodeficiency virus (HIV) RNA], beta-2-microglobulin (beta2-M) and immunoglobulin A (IgA) and the mortality risk was explored in 234 HIV-infected individuals (median CD4 count 230 cells/mm3, range 1-1,247). Product-moment correlation analysis was used to study the association between beta2-M, IgA and HIV RNA. A proportional hazards Cox model was used to estimate the relative hazard (RH) of death. Both beta2-M (r = 0.49, p < 0.0001) and IgA (r = 0.42, p < 0.0001) were positively correlated with HIV RNA. High beta2-M levels were associated with an increased risk of death in both univariate Cox analysis and after adjustment for HIV RNA, CD4 lymphocyte count and age [RH = 1.16 per 100 nmol/l higher beta2-M, 95% confidence interval (CI) 1.05-1.27]. Raised IgA levels were associated with shorter survival in individuals with a CD4 count above 50 cells/mm3 in univariate analysis as well as after adjusting for age and CD4 lymphocyte count (RH = 1.19 per 10 micromol/l higher IgA, 95% CI 1.01-1.39). However, this association was no longer significant after further adjusting for HIV RNA. In conclusion, beta2-M levels provided additional prognostic information for survival to the information obtained by CD4 count and HIV RNA levels, whereas serum IgA only was a weak prognostic marker in this fairly progressed cohort.

Adult↗
PubMed2000

Granulocyte colony-stimulating factor increases CD4+ T cell counts of human immunodeficiency virus-infected patients receiving stable, highly active antiretroviral therapy: results from a randomized, placebo-controlled trial.

Thirty human immunodeficiency virus (HIV)-infected patients with CD4+ T cell counts <350 cells/mm3 who had received stable, highly active antiretroviral therapy (HAART) for at least 24 weeks were randomized to receive either placebo or granulocyte colony-stimulating factor (G-CSF; 0.3 mg/mL 3 times a week) for 12 weeks. Blood samples were collected at specified time points. G-CSF treatment enhanced the total lymphocyte count (P=.002) and increased CD3+ (P=.005), CD4+ (P=.03), and CD8+ (P=.004) T cell counts as well as numbers of CD3-CD16+CD56+ NK cells (P=.001). The increases in CD4+ and CD8+ cell counts resulted from increases in CD45RO+ memory T cells and cells expressing the CD38 activation marker. Lymphocyte proliferative responses to phytohemagglutinin and Candida antigen decreased, whereas NK cell activity and plasma HIV RNA did not change during G-CSF treatment. After 24 weeks, all immune parameters had returned to baseline values. This study suggests that G-CSF treatment of HIV-infected patients receiving stable HAART increases the concentration of CD4+, CD8+, and NK cells without inducing changes in the virus load.

Adult↗
PubMed2000

Prevalence and characteristics of multinucleoside-resistant human immunodeficiency virus type 1 among European patients receiving combinations of nucleoside analogues.

The prevalence and the genotypic and phenotypic characteristics of multinucleoside-resistant (MNR) human immunodeficiency virus type 1 (HIV-1) variants in Europe were investigated in a multicenter study that involved centers in nine European countries. Study samples (n = 363) collected between 1991 and 1997 from patients exposed to two or more nucleoside analogue reverse transcriptase inhibitors (NRTIs) and 274 control samples from patients exposed to no or one NRTI were screened for two marker mutations of multinucleoside resistance (the Q151M mutation and a mutation with a 2-amino-acid insertion at codon 69, T69S-XX). Q151M was identified in six of the study samples (1. 6%), and T69S-XX was identified in two of the study samples (0.5%; both of them T69S-SS), but both patterns were absent among control samples. Non-NRTI (NNRTI)-related changes were observed in viral strains from two patients, which displayed the Q151M resistance pattern, although the patients were NNRTI naive. The patients whose isolates displayed multinucleoside resistance had received treatment with zidovudine and either didanosine, zalcitabine, or stavudine. Both resistance patterns conferred broad cross-resistance to NRTIs in vitro and a poor response to treatment in vivo. MNR HIV-1 is found only among multinucleoside-experienced patients. Its prevalence is low in Europe, but it should be closely monitored since it seriously limits treatment options.

Amino Acid Substitution↗
PubMed2000

Genotypic and phenotypic nevirapine resistance correlates with virological failure during salvage therapy including abacavir and nevirapine.

OBJECTIVE: To study the development of resistance during 8 weeks of salvage therapy with abacavir and nevirapine in combination with other reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). METHODS: Samples obtained at baseline and after 8 weeks of therapy from 16 heavily pretreated patients were analysed for genotypic and phenotypic resistance. Genotypic resistance was analysed in cell-associated DNA and plasma HIV-RNA using direct sequencing. Phenotypic resistance was analysed in a PBMC-based assay and in a recombinant virus assay. Plasma viral load was measured at baseline and after 2, 4 and 8 weeks of therapy. RESULTS: The majority of patients was genotypically and phenotypically resistant to lamivudine, abacavir, zidovudine and PIs, whereas 50% of the patients showed resistance to nevirapine at baseline in at least one of the methods used. After 8 weeks of salvage therapy, no additional development of resistance against nucleoside reverse transcriptase inhibitors and PIs could be detected. However, the amount of patients resistant to nevirapine increased to 83%. When the patients were divided into two groups according to baseline resistance against nevirapine, a significantly higher transient reduction in viral load was observed in patients with nevirapine-sensitive HIV at baseline compared to patients with resistant HIV at baseline. CONCLUSION: The transient effect of salvage therapy including abacavir and nevirapine was due to the effect of nevirapine. The lack of effect of abacavir was most likely due to cross-resistance between abacavir and lamivudine/zidovudine used in previous treatment.

Anti-HIV Agents↗
PubMed1999

Presence of multiple HIV subtypes and a high frequency of subtype chimeric viruses in heterosexually infected women.

The HIV-1 subtype distribution was determined in 41 HIV-positive women (-8% of all HIV-infected women in Denmark) belonging to different risk groups. HIV p17 gag and env gene subtypes were determined by DNA sequence analysis. Five different HIV subtypes were detected across all patients. Most HIV-1-positive women of Danish origin carried subtype B viruses, and a minority had virus belonging to subtypes A or C. All injecting drug users (IDUs) were infected with HIV subtype B viruses, whereas all non-B subtypes were present in cases linked to heterosexual transmission. In contrast, all women of African origin carried non-B HIV subtypes (subtypes A, C, D, or G) regardless of transmission mode. Of these women, 21% infected with non-B HIV subtypes appeared to be infected by subtype chimeric viruses and 7% were jointly infected with viruses belonging to two different subtypes (A and C). Data demonstrate a preferential representation of non-B HIV subtypes in women infected through heterosexual contact, as well as a high degree of recombination between viruses derived from endemic areas in which several HIV subtypes predominate. Combined with the increased incidence of heterosexual transmission of HIV, the results imply that an increased subtype diversity can be anticipated in newly infected individuals.

Female↗
PubMed1999

[Use of antiretroviral chemoprophylaxis after occupational HIV exposure].

The study describes the use of postexposure antiretroviral prophylaxis (PEP) after occupational exposure to HIV in Denmark in the period 1/1 1997-31/12 1998. Forty-seven accidentally exposed persons received PEP in this period, of whom 14 were nurses, 13 physicians and 11 were not employed in the health care system. In 23 cases side effects to PEP were described. In 18 cases the index person was i.v. drug abuser and in 11 cases homosexual/bisexual men. In 18 cases the HIV status of the index person was unknown at the time of exposure. Ten of these index persons were subsequently tested and all found HIV-negative. It is concluded, that the frequency of occupational exposure to HIV is unacceptably high. Further it is emphasised that in cases where the HIV status of the index person is unknown, PEP should only be instituted if the index person is at risk of being HIV infected and has signs of HIV infection.

Adolescent↗
PubMed1999

Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy?

BACKGROUND: In the 'USPHS/IDSA Guidelines for Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus', the indications for chemoprophylaxis are based on nadir CD4 cell count. Many patients have, however, experienced an increase in CD4 cell count after the introduction of highly active antiretroviral therapy (HAART). OBJECTIVES: To assess incidences of opportunistic infections after discontinuation of chemoprophylaxis in HIV-infected patients, who have experienced a HAART-induced increase in CD4 cell count. METHODS: The Danish guidelines for chemoprophylaxis against opportunistic infections in HIV-infected patients were revised in late 1997, allowing discontinuation of chemoprophylaxis after initiation of HAART if the CD4 cell count remained above a specified limit for more than 6 months. Consecutive patients were followed, and incidences of opportunistic infections after discontinuation of chemoprophylaxis were assessed. RESULTS: A total of 219 patients discontinued Pneumocystis carinii pneumonia (PCP)-chemoprophylaxis (12% maintenance therapy). One case of PCP was diagnosed within 174 person-years (PY) of follow-up, resulting in an incidence of 0.6 cases/100 PY follow-up (95% confidence interval, 0.0-3.2). No cases of cerebral toxoplasmosis, cytomegalovirus chorioretinitis, or disseminated Mycobacterium avium infection were observed. Follow-up time for these was, however, limited. CONCLUSION: PCP-chemoprophylaxis can be safely discontinued after HAART-induced increase in CD4 cell count to more than 200 x 10(6) cells/l. Among consecutive patients who discontinue chemoprophylaxis according to well-defined guidelines, the observed incidence of PCP is below those reported earlier in patients with similar CD4 cell count.

AIDS-Related Opportunistic Infections↗
PubMed1999

Nosocomial HIV-transmission in an outpatient clinic detected by epidemiological and phylogenetic analyses.

OBJECTIVE: To determine if a case of HIV-infection in a patient (GP) with common variable immunodeficiency, and with no known risk factors for HIV-infection, could be due to horizontal nosocomial transmission. METHODS: For determination of time of transmission stored serum-samples from GP were analysed for HIV RNA content. Patient records were used to identify patients, who had received intravenous therapy on the same day as GP. Samples from GP and these possible source patients were identified and phylogenetic analyses of the env, gag and RT-encoding region of pol were performed. Furthermore, routines in conjunction with intravenous therapy were examined. RESULTS: We identified a patient (FDL) harbouring virus almost indistinguishable from the virus isolated from GP. The pairwise nucleotide distance between the C2-V3-C3 region of the env and gag sequences from the two patients were 1.9 and 0.9% respectively. In addition, GP harboured HIV RNA with a foscarnet resistance mutation further lending support to virus from the foscarnet-treated FDL being the source of the infection. Interestingly, GP experienced increases in immunoglobulin production after contracting the HIV-infection, and decreases after antiretroviral-induced viral suppression. A clinical procedure which, under stressful conditions, could lead to breaches in infection control measures was identified. The source of the infection was most likely a contaminated multidose vial. CONCLUSION: Through epidemiological and phylogenetic analyses a case of horizontal nosocomial HIV-transmission was disclosed. Identification of multidose vials as possible vehicles for horizontal nosocomial transmission recently led to the recommendation of restriction of the use of multidose vials, a recommendation supported by the present study. The study underlies the importance of a constant survey of infection control precautions.

Ambulatory Care Facilities↗
PubMed1999

Immune function and phenotype before and after highly active antiretroviral therapy.

Immune functions represented by equal CD4 counts before and after highly active antiretroviral therapy (i.e., pre- and post-HAART) in the same HIV-infected patients, were examined. Twelve HIV-infected patients were included. Patients had equal CD4 counts pre- and post-HAART and were studied on average 30 months pre-HAART and 17 months post-HAART. Post-HAART, CD8+ T cells expressed greater amounts of CD28 (p < .02), smaller amounts of CD38 (p < .02), and a reduced proportion of CD4+CD28+ T cells expressed CD38+ (p < .01). Proliferation increased (p < 10) in lymphocyte cell cultures stimulated with pokeweed mitogens or Candida, and was correlated to expression of CD28 on T cells (p < .02). The proportion of CD3-CD16-CD56+ natural killer (NK) cells increased (p < .05) and CD3-CD16+CD56- NK cells declined (p < .01). Production of interferon-gamma increased (p < .10). The number of naive and memory T cells, the non-major histocompatibility complex (non-MHC)-restricted and HIV-specific MHC-restricted cytotoxicity and the production of macrophage inflammatory protein-1gamma were unchanged. The finding of increased expression of CD28, correlating to increased proliferation capacity, and diminished expression of CD38 on T cells, indicates that following long-term HAART, repopulation occurs with less activated cells with increased proliferative capacity. This finding may be of clinical importance in considering risk and vulnerability for progression of opportunistic infections post-HAART.

Anti-HIV Agents↗
PubMed1999

Natural immunity and HIV disease progression.

OBJECTIVE: To investigate the clinical implications of impaired levels of the natural immunity mediated by natural killer (NK) cells and lymphokine activated killer (LAK) cells during infection with HIV-1. DESIGN: Data used were from 172 individuals with an estimated measure of NK cell activity and 146 with an estimated measure of LAK cell activity. Patients had active HIV infection at the time of enrolment in the study and have been followed-up prospectively for a median of 3.0 years. METHODS: The lytic activity of NK cells and LAK cells, the CD4 T lymphocyte count, and the concentration of CD16/CD56 NK cells were measured at enrolment. HIV RNA in plasma was measured retrospectively. Survival analysis was performed considering three main endpoints: CD4 cell counts below 100 x 10(6) cells/l, clinical AIDS, and death. RESULTS: In unadjusted analysis and after adjustment for age, CD4 T lymphocyte count and plasma HIV RNA at enrolment, low LAK cell activity was significantly associated with higher risk of progression to a CD4 T lymphocyte count < 100 x 10(6) cells/l (crude P = 0.001; adjusted P = 0.04) and to death (crude P = 0.0002; adjusted P = 0.02). Patients with low NK cell responsiveness to interferon-alpha tended to be at higher risk of death (crude P = 0.04; adjusted P = 0.13) whereas unstimulated NK cell activity and the concentration of NK cells were of no prognostic value for patients in this cohort. CONCLUSIONS: The present study suggests that low LAK cell activity and low NK cell responsiveness to interferon-alpha may be important in the pathogenesis of HIV infection.

CD4 Lymphocyte Count↗
PubMed1999

Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial.

OBJECTIVES: To compare the efficacy and safety of indinavir 800 mg three times a day, ritonavir 600 mg twice a day, and a combination of ritonavir 400 mg twice a day and saquinavir 400 mg twice a day, when administered with two nucleoside analogues. DESIGN: A randomized, open-labelled, controlled trial. Two hundred and eighty-four patients started randomized treatment. The primary end-point was the proportion of patients with HIV RNA of 200 copies/ml or less (Roche Amplicor) and HIV RNA of 20 copies/ml or less (Roche ultradirect assay) at 6 months. Analysis was performed as intent-to-treat, and missing values were accounted for as failures. RESULTS: As of 1 May 1998, 269 patients should have completed 24 weeks of treatment. The proportion of patients with HIV RNA of 200 copies/ml or less was 71% (indinavir), 67% (ritonavir), and 82% (ritonavir + saquinavir), P = 0.07. In antiretroviral drug-naive patients (n = 119), the corresponding figures were 63, 57, and 89% (P < 0.01), whereas among drug-experienced patients (n = 165) 77, 74, and 77% had HIV RNA of 200 copies/ml or less (P = 0.90). The same pattern was observed in the ultradirect analysis. All three regimens were generally safe, but significantly more patients in the ritonavir group (37%) stopped treatment because of adverse drug reactions compared with the indinavir group (8%) and the ritonavir plus saquinavir group (16%) (P < 0.001). CONCLUSIONS: Treatment with saquinavir plus ritonavir in combination with two nucleoside analogues is generally safe, and has superior short-term antiviral efficacy compared with indinavir and ritonavir also combined with two nucleoside analogues in antiretroviral drug-naive patients. Further follow-up is needed to determine the durability of the viral response.

Adult↗
PubMed1999

Immunological changes in human immunodeficiency virus (HIV)-infected individuals during HIV-specific protease inhibitor treatment.

The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment including a protease inhibitor. Unstimulated and pokeweed mitogen (PWM)-, interleukin (IL)-2- and phytohaemagglutinin (PHA)-stimulated lymphocyte proliferative responses increased during follow-up reaching average levels from 1.3-fold (PHA) to 3.7-fold (PWM) above baseline values. The total CD4+ lymphocyte count increased mainly due to increases in numbers of CD4+ CD28+ and CD4+ CD45RO+ cells, whereas increases in numbers of CD4+ CD45RA+ cells contributed little to the increase in CD4+ cell count. The total cytotoxic T-cell (CTL) killing of autologous B cells infected with HIV-encoding recombinant Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed by an increase in lymphocyte proliferation and lymphocyte-mediated cytotoxicity. However, unchanged levels of specific HIV CTL and NK cell activity warn us that not all measures of immune function may respond simultaneously to anti-retroviral treatment.

Adult↗
PubMed1999

Bulk culture levels of specific cytotoxic T-cell activity against HIV-1 proteins are not associated with risk of death.

The ability of cytotoxic T lymphocytes (CTL) to control and influence the outcome of human immunodeficiency virus (HIV) infection is not fully understood. The association between HIV-CTL activity and disease progression was evaluated prospectively in 36 HIV-1-infected individuals with a median follow-up of 3.0 years. HIV-CTL activity was measured in a 4 h Cr* release assay using autologous target cells expressing HIV-1 BRU isolate gene products (gp-120, gag, pol, nef) and a bulk culture of autologous effector cells. The CD4 count was measured at enrolment and plasma HIV RNA was measured retrospectively. The present study failed to support the hypothesis that HIV-CTL activity, as measured using the present method, is important in reducing the risk of death in HIV-infected individuals. However, using other approaches and methods could possibly yield other conclusions, and further prospective studies are needed to examine the relationship between CTL and disease progression.

Adult↗
PubMed1999

Saquinavir hard gel suppresses viral load insufficiently in HIV-infected patients naive to anti-retroviral therapy: a retrospective cohort study.

Protease inhibitors are important components in anti-retroviral regimens. In this retrospective study 29 HIV-infected patients treated with a regimen of zidovudine, lamivudine and saquinavir hard gel in 1 centre in Denmark were compared with 58 patients treated with zidovudine, lamivudine and ritonavir or indinavir followed at 5 other centres in Scandinavia. All patients were naive to anti-retroviral therapy prior to institution of the actual anti-retroviral regimen and were followed for a median of 1.3 and 1.4 y respectively. The 2 groups did not differ significantly with respect to age, gender, route of infection, ethnic background, viral load, CD4 count, AIDS at baseline or frequency of clinical controls. Six and 12 months after initiating anti-retroviral therapy, 31% and 34% of the patients on the saquinavir regimen obtained HIV-RNA < or = 500 compared with 76% and 73% in the control group (p < 0.001). In contrast to viral load, the increase in CD4 count did not differ significantly between the 2 groups. In conclusion, we found that with respect to suppression of viral load a regimen of saquinavir, zidovudine and lamivudine seemed to be inferior to a regimen of zidovudine, lamivudine and ritonavir or indinavir.

Adult↗