Biomedical subjects

S A Danner

Publications and source records attributed to S A Danner.

At least 37 records · Page 2Linked to original sources

PubMed2000

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

OBJECTIVE: To assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1 -infected patients. DESIGN: A multicentre, open-label, randomized controlled trial. METHODS: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. RESULTS: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. CONCLUSION: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

Adult↗

PubMed2000

T-cell progenitor function during progressive human immunodeficiency virus-1 infection and after antiretroviral therapy.

Impairment of T-cell renewal has been proposed as contributing to CD4(+) T-cell depletion in persons infected with human immunodeficiency virus-1. We analyzed the T-cell development capacity of progenitors using fetal thymus organ culture. Those who progressed to AIDS had a dramatic loss in T-cell development capacity shortly after seroconversion. In contrast, long-term nonprogressors retained progenitor capacity 8 years after seroconversion. Approximately 70% of patients experienced an improvement in T-cell development capacity after receiving 6 months of potent antiretroviral therapy. Improvement in T-cell development in fetal thymus organ culture correlated with an increase in the number of naive CD4(+) T cells in peripheral blood. Numbers of progenitors in blood and bone marrow after seroconversion or during therapy did not correlate with the change observed in T-cell development capacity. These data provide evidence that HIV-1 infection can interfere with T-cell renewal at the level of the progenitor cell. Interference with T-cell renewal may contribute to CD4(+) T-cell depletion.

Acquired Immunodeficiency Syndrome↗

PubMed2000

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals.

OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Non-compartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC[24h]), and the maximal (Cmax) and minimal plasma concentration (Cmin), the time to Cmax (t(max)), the plasma elimination half-life (t1/2), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. RESULTS: The exposure to nevirapine, as measured by the AUC[24h], was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t1/2 Cl/F and V/F were not significantly different between the two dosing regimens (P > or = 0.08). However, Cmax and Cmin were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for Cmax and Cmin as measured for the once daily and twice daily regimens were 6.69 and 5.74 microg/ml, respectively (P = 0.03), and 2.88 and 3.73 microg/ml, respectively (P < 0.01). CONCLUSION: These data show that the daily exposure to nevirapine, as measured by the plasma AUC[24h], is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, Cmax and Cmin are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established.

Adult↗

PubMed2000

Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir.

OBJECTIVE: To explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir. METHODS: The pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily. RESULTS: The first study day was 4-12 months (median 7 months) after the start of the current regimen. The second study day was 9-15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was -30% (range -79 to +11%; P = 0.06). Median change in maximum plasma concentration was -40% (range -62 to +34%; P = 0.09). The median change in area under the plasma concentration versus time curve over 0-8 h was -33% (range -53 to +21%; P = 0.06). CONCLUSION: The exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients.

Adult↗

PubMed2000

The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine. Prometheus Study Group.

OBJECTIVE: To evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/6 stavudine (D4T) or RTV/SQV alone, with treatment intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. DESIGN: Multicentre, open-label, randomized controlled trial. Two-hundred and eight patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks. RESULTS: In a strict intention-to-treat analysis, counting all dropouts as virological failures, 63% [95% confidence interval (CI), 54-73%] of subjects in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week 48, as compared with 69% (95% CI, 60-78%) in the RTV/SQV/D4T group (n = 104; P = 0.379). In the on-treatment analysis these percentages were 88 and 91% respectively. Thirty-one patients intensified their study medication according to the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events. CONCLUSION: The concept of starting with a simple, potent regimen, that could be intensified if necessary, showed good virological results after 48 weeks in this study, comparable to starting with more drugs from the beginning. Longer follow-up is needed to determine the long-term efficacy of this treatment strategy.

Adult↗

PubMed2000

Quality of life in asymptomatic- and symptomatic HIV infected patients in a trial of ritonavir/saquinavir therapy. The Prometheus Study Group.

OBJECTIVE: To compare the impact on quality of life (QoL) of treatment with ritonavir (RTV)/saquinavir (SQV) versus RTV/SQV/stavudine (d4T) in asymptomatic [Centers for Disease Control (CDC) class A] and symptomatic HIV-infected patients (CDC B and C) who did or did not receive antiretroviral therapy (ARVT) before entry into the study. DESIGN: A multicenter randomized clinical trial. PATIENTS: Protease inhibitor- and d4T-naive patients were allocated to RTV/SQV (n = 84) versus RTV/SQV/d4T (n = 83). MAIN OUTCOME MEASURE: Changes from baseline in QoL assessed by the Medical Outcomes Study Health Survey for HIV (MOS-HIV) and a symptom checklist administered at baseline and after 12, 24, 36 and 48 weeks. RESULTS: Changes in QoL were comparable in both treatments, although more neuropathy was reported in the RTV/SQV/d4T group. QoL improved significantly in both groups regarding health distress, energy/fatigue, mental health, health perceptions, physical function and overall QoL, despite an increase in reported symptoms. More favourable changes in cognitive and social function were observed in symptomatic compared with asymptomatic patients, with symptomatic patients showing an improvement and asymptomatic patients showing a decline in function after baseline. ARVT-naive patients showed more favourable changes in mental health, health distress and social function compared with patients with previous ARVT. CONCLUSION: RTV/SQV and RTV/SQV/d4T were equally effective in improving the QoL of patients over 48 weeks, despite an increase in reported symptoms. Symptomatic patients reported more QoL benefit than asymptomatic patients, and ARVT-naive patients benefitted more than those with previous ARVT. The impact on patients' QoL should be considered in the search for the optimal management of HIV infection.

Administration, Oral↗

PubMed2000

Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases.

Our objective was to describe clinical features and predisposing factors attributed to lactic acidosis in 4 HIV-infected patients on long-term nucleoside reverse transcriptase inhibitor (NRTI) therapy. All patients had received at least 6-20 months of NRTI-containing antiretroviral therapy: all used stavudine (d4T), in one combined with lamivudine (3TC), in the other 3 with didanosine (ddI); in one hydroxyurea was added. In all, the initial symptoms were gastrointestinal (nausea and vomiting), followed by tachypnoea preceding the lactic acidosis; death followed 6-22 days after admission (liver failure and uncontrollable arrhythmias). Treatment with riboflavin was unsuccessful in one patient. The only definite risk factor in all cases was NRTI-induced mitochondrial toxicity; one patient was concomitantly treated for Kaposi's sarcoma (with bleomycin and vinblastine) and one just recovered from pneumococcal sepsis. None of the patients had a history of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. In all patients, some sort of toxicity to other previously used NRTIs had occurred earlier. Lactic acidosis occurred after months of NRTI therapy in patients who had already suffered other forms of NRTI toxicity. Concomitant diseases or comedication might have aggravated the mitochondrial toxicity of the NRTIs. Screening methods to detect mitochondrial toxicity are necessary, since lactic acidosis occurs rather unexpectedly, with a rapid, fatal course.

Acidosis, Lactic↗

PubMed1999

Antigen-driven CD4+ T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy.

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.

Anti-HIV Agents↗

PubMed1999

Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.

In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

Animals↗

PubMed1999

Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection.

Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.

Anti-HIV Agents↗

PubMed1999

[Therapeutic options for HIV infection should lead to increased utilization of HIV tests].

Owing to the recent advances in drug therapy for HIV infected patients, HIV infection is no longer an untreatable condition. The Health Council of the Netherlands therefore considers the advantages of knowing a person's HIV status to outweigh the disadvantages, especially for pregnant women. The restrictive policy with respect to HIV testing should be discontinued.

Communicable Disease Control↗

PubMed1999

Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs.

OBJECTIVE: To identify genotypic drug resistance patterns of HIV-1 in patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral combination therapy. METHODS: Drug susceptibility of the viruses was tested by a phenotypic recombinant virus assay. Genotypic analysis of HIV resistance was performed by sequencing of the amino-terminal part of the corresponding reverse transcriptase (RT) gene (amino acids 1-280) for serum-derived and recombinant viruses. RESULTS: Among viruses from 92 patients studied, three (3%) viruses contained a T215Y amino-acid change as well as a previously unseen combination of an amino-acid change at codon 67 (N-->E/S) and a two amino-acid insertion between codons 68 and 69 of the RT gene of HIV-1. Phenotypic resistance analysis showed high levels of resistance to zidovudine, lamivudine and stavudine (in all patients) and moderate levels of resistance to didanosine and zalcitabine (in two patients), whereas neither serum-derived nor recombinant viruses contained previously known amino-acid changes conferring resistance to didanosine, zalcitabine, lamivudine and stavudine. However, all recombinant viruses contained an insertion of two amino acids between codons 68 and 69 of RT as well as an amino-acid change at codon 67, as was seen in the serum-derived viruses. CONCLUSIONS: Antiretroviral therapy including zidovudine may yield replicating viruses with a two amino-acid insertion in RT in combination with amino-acid changes at codons 67 and 215, which are highly resistant to lamivudine and stavudine on top of zidovudine and have unpredictable susceptibility to didanosine and zalcitabine despite lack of previously reported corresponding resistance-associated amino-acid changes. It is currently unknown what regimens can induce the emergence of this type of multidrug-resistant viruses. This will only be elucidated when resistance assays are capable of detecting these mutants.

Adult↗

PubMed1999

Antigen-specific T-lymphocyte proliferative responses during highly active antiretroviral therapy (HAART) of HIV-1 infection.

To evaluate functional T-cell recovery during combination therapy with ritonavir, lamivudine (3TC), and zidovudine (ZDV), peripheral blood mononuclear cells (PBMC) were obtained from 4 HIV-1 infected patients (baseline values: 40 403 CD4+ T-cells/microl; 4.6-6.4 log HIV-1 RNA copies/ml) before HAART administration (week -1) and after 5, 20, and 37 weeks of treatment on average. In vitro lymphoproliferative responses (LPR) to C. albicans, tetanus toxoid, and M. tuberculosis protein purified derivative (PPD), as recall antigens (Ag), and to recombinant HIV-1 Gag-p24 and p17 were measured by 3H-Thymidine incorporation. LPR to recall Ag, almost undetectable before therapy, appeared in all four patients during HAART soon after maximal load reduction was achieved. LPR to Gag-p17, but not to p24, became also detectable in three patients, even though remaining weak. In conclusion, improved T-lymphocyte function during HAART was achieved probably mostly as a result of lower virus inhibitory factors and cytokines.

Adult↗

PubMed1999

Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons.

The outcome and predictors of virologic treatment failure of highly active antiretroviral therapy (HAART) were determined for 271 human immunodeficiency virus (HIV)-infected protease inhibitor-naive persons. During a follow-up of 48 weeks after the initiation of HAART, 6.3% of patients experienced at least one new AIDS-defining event, and 3.0% died. Virologic treatment failure occurred in 40% (indinavir, 27%; ritonavir, 30%; saquinavir, 59%; ritonavir plus saquinavir, 32%; chi2, P=.001). Risk factors for treatment failure were baseline plasma HIV-1 RNA (odds ratio [OR], 1.70 per log10 copies increase in plasma HIV-1 RNA), baseline CD4 cell count (OR, 1. 35 per 100 CD4 cells/mm3 decrease), and use of saquinavir versus other protease inhibitors (OR, 3.21). During the first year of treatment, 53% of all patients changed (part of) their original HAART regimen at least once. This was significantly more frequent for regimens containing saquinavir (62%; 27% for virologic failure) or ritonavir (64%; 55% for intolerance) as single protease inhibitor.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Functional T cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy.

Lymphoproliferative responses (LPRs) to recall antigens (Ags) and human immunodeficiency virus type 1 (HIV-1) Gag and frequencies of circulating HIV-1-specific cytotoxic T lymphocyte precursors (CTLps) were measured in 12 patients undergoing highly active antiretroviral therapy (HAART) after long-standing HIV-1 infection. LPRs to at least 1 recall Ag became detectable or increased in all patients during HAART. No significant LPRs to Gag-p24 were observed, whereas 4 of 8 patients tested presented with Gag-p17-specific LPRs. HIV-1-specific CTLp frequencies became measurable or increased early during therapy in 6 of 10 patients tested and were maintained or decreased thereafter. Increasing HIV-1-specific CTLp frequencies were seen only in association with partial HAART failure in 1 patient. In conclusion, restoration of CD4+ T lymphocyte responsiveness to recall Ags is achieved during HAART. The data provide evidence for limited HIV-1-specific CD4+ memory T cells during advanced HIV-1 infection and suggest that both CD4+ and CD8+ HIV-1-specific T cells are poorly stimulated when viral load is suppressed.

Adult↗

PubMed1999

Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Common health problems in HIV-infected travelers to the (sub)tropics.

BACKGROUND: A study was conducted to estimate the incidence of health problems in HIV-infected travelers with various degrees of immunodeficiency to the (sub)tropics. METHODS: A retrospective questionnaire-based study among HIV-infected patients attending the outpatient department of a university hospital during three months in 1996 with a history of travel to (sub)tropical destinations in the proceeding 12 months. The outcome measures were incidences of and medical consultation rates for common travel-associated illnesses. RESULTS: Of 293 HIV-infected patients, 59 (20%) had traveled during the preceding 12 months; of these 36 (61%) responded. Ten (28%) had traveled more than once during this period. There were no significant differences between travelers and nontravelers regarding CD4 count and age. Fifteen respondents (42%) used cotrimoxazole (CTX) for PCP prophylaxis; 22 (61%) had sought pretravel health advice. Median duration of travel was 3 weeks. Respiratory infections were recorded by two respondents (6%, 95% confidence intervals 1-19%) and skin problems by 10 (28%, 14-45%). Of 31 respondents without diarrhea on departure, 10 recorded diarrhea (32%, 19-57%). The overall rate of medical consultation for travel-related complaints ws 5% abroad and 28% after return, respectively. There was no association between the risk of diarrhea and CD4 count or CTX prophylaxis, even after adjustment for differences in age, duration of travel and travel experience. CONCLUSIONS: Although numbers in this study are small, HIV-infected travelers tend to have a high rate of medical consultation for (possibly) travel-related illness. Diarrhea is the most frequent complaint, but shows no strong association with degree of immunodeficiency.

Adult↗

PubMed1998

Diversity of the T-cell receptor BV repertoire in HIV-1-infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during highly active antiretroviral therapy.

OBJECTIVES: Highly active antiretroviral therapy (HAART) induces a decline in viral load and a biphasic increase in peripheral blood CD4+ T-cell counts in HIV-infected patients. To evaluate the effect of HAART on T-cell receptor (TCR) diversity of repopulating naive and memory CD4+ T cells, complementarity determining region 3 (CDR3) spectratyping was performed. DESIGN: For four patients treated with HAART, CD45RO+ (memory) and CD45RA+ (naive) CD4+ T cells were isolated from peripheral blood leukocyte samples obtained 1 week before, 1-2 months after, and 9-11 months after start of treatment. METHODS: CDR3 regions were amplified by TCR-BV-specific nested PCR from CD4+ T-cell subsets. CDR3 size distributions and single-strand conformation polymorphism profiles were compared as an indication for TCR diversity. RESULTS: Increasing blood CD4+ T-cell counts during the first 2 months of treatment coincided with increased perturbation of CDR3 patterns in CD4+ T-cell subsets, suggesting an early oligoclonal repopulation. At later timepoints, CDR3 size diversity increased when T-cell counts did not substantially decrease. Memory and naive CD4+ T cells generally showed comparable levels of perturbation. CONCLUSION: Diversity of the TCR repertoire reflected biphasic T-cell repopulation during HAART, compatible with initial redistribution and later CD4+ T-cell production. Sustained elevation of T-cell counts will in principle result in restoration of TCR diversity.

Anti-HIV Agents↗