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Hansjakob Furrer

Publications and source records attributed to Hansjakob Furrer.

52 records · Page 3Linked to original sources
PubMed2003

A prospective trial of structured treatment interruptions in human immunodeficiency virus infection.

BACKGROUND: According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead to low viremia after withdrawal of highly active antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease course than is currently recommended would like to discontinue, but it is unknown whether it is safe to do so. OBJECTIVES: To determine whether repeated treatment interruptions of HAART (1) stimulated the cytotoxic HIV-specific immune response and whether such stimulation correlated with low viremia off treatment, and (2) were safe with respect to clinical complications, development of viral resistance, and decline in CD4 cell counts. DESIGN: Interventional study with before-after comparison. SETTING: Outpatient clinics of university hospitals in Switzerland and Spain. PATIENTS: A total of 133 patients receiving HAART, with a median CD4 cell count of 740/ microL, and whose viral load had been undetectable for a median of 21 months. INTERVENTIONS: HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After 4 such cycles, treatment was indefinitely suspended 40 weeks after study entry. MAIN OUTCOME MEASURES: HIV-specific cytotoxic T-cell responses were evaluated by interferon gamma enzyme-linked immunospot analysis. The proportion of "responders" (viral load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and CD4 cell counts were recorded. RESULTS: Seventeen percent of patients (95% confidence interval, 11%-25%) were responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased between week 0 (median, 343 spot-forming cells per million peripheral blood lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there was an inverse correlation between response and the number of spot-forming cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and 55 (41%) for at least 56 weeks. The median CD4 cell count decreased from 792/ microL to 615/ microL during the first 12 weeks without treatment, but stabilized thereafter. One patient (0.75%) developed drug resistance necessitating salvage treatment. There were no AIDS-related clinical complications. CONCLUSIONS: Results of this study do not favor the autovaccination hypothesis. Treatment interruptions did not provoke clinical complications, and there was little drug resistance. Comparative trials will have to show what benefit, if any, is associated with intermittent, as opposed to continuous treatment.

Adult↗
PubMed2003

Low incidence of community-acquired pneumonia among human immunodeficiency virus-infected patients after interruption of Pneumocystis carinii pneumonia prophylaxis.

We compared the incidence of bacterial pneumonia among 336 patients who discontinued trimethoprim-sulfamethoxazole (TMP-SMX) as prophylaxis against Pneumocystis carinii pneumonia (PCP) with that among 75 patients who fulfilled the criteria for discontinuation but continued receiving prophylaxis. The difference in the overall incidence rates for the 2 groups (1.2 events per 100 person-years) was not statistically significant. Discontinuation of TMP-SMX prophylaxis against PCP is not associated with a significant increase in the incidence of bacterial pneumonia among patients with a sustained CD4 cell count increase to >200 cells/microL.

AIDS-Related Opportunistic Infections↗
PubMed2003

Herpes simplex virus hepatitis 4 years after liver transplantation.

If not promptly recognized and treated, herpes simplex virus (HSV) hepatitis is associated with a high mortality. A patient transplanted for primary sclerosing cholangitis required, 4 years later, a colectomy for a steroid-resistant flare of ulcerative colitis. He subsequently developed fever, with genital and oral ulcerations. He was hospitalized for diabetic decompensation with massive elevation of serum aminotransferases. Examination revealed vesicles on the hands. Liver biopsy showed Cowdry type B inclusions. Therapy with acyclovir was immediately initiated and the patient recovered. This case illustrates the diagnostic importance of mucocutaneous lesions in the assessment of complications after liver transplantation.

Acyclovir↗
PubMed2003

Retinal microangiopathy in human immunodeficiency virus infection is related to higher human immunodeficiency virus-1 load in plasma.

PURPOSE: To evaluate the prevalence of retinal microangiopathy in human immunodeficiency virus (HIV)-1-infected patients and its association with virologic, immunologic, and sociodemographic parameters. DESIGN: Single-center cross-sectional study. PARTICIPANTS: One hundred eighty-eight HIV-1-positive individuals from a single outpatient clinic. METHODS: Human immunodeficiency virus-positive patients were screened for signs of HIV-associated retinal angiopathy. Plasma HIV-1 RNA and CD4-positive cell counts were monitored within 3 months of the ophthalmologic assessment. The absence or presence of angiopathy or of opportunistic viral retinitis was then correlated to data respecting CD4-positive cell count, plasma viral load of HIV-1, and sociodemographic parameters. MAIN OUTCOME MEASURES: Association between CD4-positive cell count, HIV-1 plasma viral load, sociodemographic parameters, and the manifestation of retinal microangiopathy. RESULTS: At the baseline consultation, 130 (69%) patients exhibited no retinal pathologic features, 45 (24%) manifested retinal angiopathy, and 13 (7%) had opportunistic viral retinitis. In univariate analysis, retinal angiopathy was associated with lower CD4-positive cell count and higher HIV-1 plasma viral load. In a multivariate logistic model, the presence of retinal microangiopathy was associated with higher age (P = 0.02) and higher viral load of HIV-1 (P < 0.005), but not with lower CD4 cell counts (P > 0.05). CONCLUSIONS: Human immunodeficiency virus-associated retinal microangiopathy is likely a multifactorial condition. Its presence is associated with higher age and higher replication of HIV-1 as measured by plasma HIV-1 RNA levels. In contrast to opportunistic infectious retinitis, the degree of immunodeficiency does not seem to be independently correlated with retinal angiopathy.

Adult↗
PubMed2002

Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy.

BACKGROUND: The safety of interrupting maintenance therapy for previous opportunistic infections other than Pneumocystis carinii pneumonia among patients with HIV infection who respond to potent antiretroviral therapy has not been well documented. OBJECTIVE: To assess the safety of interrupting maintenance therapy for cytomegalovirus (CMV) end-organ disease, disseminated Mycobacterium avium complex (MAC) infection, cerebral toxoplasmosis, and extrapulmonary cryptococcosis in patients receiving antiretroviral therapy. DESIGN: Observational study. SETTING: Seven European HIV cohorts. PATIENTS: 358 patients taking potent antiretroviral therapy (> or =3 drugs) who interrupted maintenance therapy at a CD4 lymphocyte count greater than 50 x 10(6) cells/L. MEASUREMENTS: Recurrence of opportunistic infection after interruption of maintenance therapy. RESULTS: 379 interruptions of maintenance therapy were identified: 162 for CMV disease, 103 for MAC infection, 75 for toxoplasmosis, and 39 for cryptococcosis. During 781 person-years of follow-up, five patients had relapse. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted when the CD4 lymphocyte count was less than 100 x 10(6) cells/L or when only one recent measurement exceeded this value. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted once CD4 counts were greater than 100 x 10(6) cells/L for 10 and 8 months, respectively. One relapse (toxoplasmosis) was diagnosed after maintenance therapy interruption at a CD4 lymphocyte count greater than 200 x 10(6) cells/L for 15 months. The overall incidences of recurrent CMV disease, MAC infection, toxoplasmosis, and cryptococcosis were 0.54 per 100 person-years (95% CI, 0.07 to 1.95 per 100 person-years), 0.90 per 100 person-years (CI, 0.11 to 3.25 per 100 person-years), 0.84 per 100 person-years (CI, 0.02 to 4.68 per 100 person-years), and 0.00 per 100 person-years (CI, 0.00 to 5.27 per 100 person-years), respectively. CONCLUSION: Maintenance therapy against previous infection with CMV, MAC, Toxoplasma gondii, or Cryptococcus neoformans in patients with HIV infection can be interrupted after sustained CD4 count increases to greater than 200 (or possibly 100 to 200) x 10(6) cells/L for at least 6 months after the start of potent antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2002

Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 x 10(6) /l.

OBJECTIVE: To evaluate the efficacy of early initiation of highly active antiretroviral therapy (HAART), we compared the clinical course of two nested, matched cohorts within the Swiss HIV Cohort Study. METHODS: We selected all asymptomatic patients who started HAART between 1 January 1996 and 31 December 1999 with a CD4 cell count > 350 x 10(6)/l. We then matched them with asymptomatic participants who were seen at around the same time and who remained untreated during the following 12 months. This control group was further matched for age, sex, CD4 cell count, viral load, and HIV risk category, generating 283 pairs of treated versus untreated patients. RESULTS: During observation of median 3.19 versus 2.66 years, CDC stage B/C occurred in 6.4% versus 21.2%, AIDS in 1.8% versus 5.3%, death in 2.1% versus 6.4%, and AIDS or death of 'natural' causes in 2.8% versus 6.7% of the treated versus untreated patients. In multivariable Cox regression analysis, treatment reduced the risk of clinical progression by a factor of four- to five fold. During follow-up, the treated group had significantly higher CD4 counts and lower HIV-1 RNA levels. Intolerance/adverse events led to change or stop of at least one drug in 35% of treated patients. The entire regimen was interrupted at least once by 41% of patients, and 24% had no treatment anymore at the end of follow-up. CONCLUSIONS: The initiation of HAART in asymptomatic patients with CD4 cell count > 350 x 10(6)/l significantly delayed clinical progression. However, the risk of severe clinical events with deferred therapy was low and must be counter balanced against the burden and toxicity of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed2002

A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection.

This randomized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens (n=79) or a change to the simplified regimen of abacavir-lamivudine-zidovudine (n=84) in patients with suppressed human immunodeficiency virus type 1 (HIV-1) RNA for > or = 6 months who did not have the reverse transcriptase 215 mutation. After a median follow-up of 84 weeks, virologic failure was 6% in the continuation and 15% in the simplified group (P=.081). Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure. Study treatment was discontinued because of adverse events in 20% of the continuation and 7% of the simplified group (P=.021). Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels; however, this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Impact of occasional short interruptions of HAART on the progression of HIV infection: results from a cohort study.

OBJECTIVES AND DESIGN: To investigate the clinical consequences of occasional and short ( or= 50 x 106/l] were studied in relation to the number of interruptions that occurred. In order to focus on short interruptions exclusively, observations of patients with a treatment interruption of > 3 months were censored. The CD4 cell count and viraemia were treated as time-dependent variables because of the importance of these factors when an interruption occurs. RESULTS: Between 1 January 1996 and 31 October 2000, 4720 Swiss HIV Cohort Study participants initiated HAART, which was interrupted at least once by 1299 participants. The main reasons for the interruptions were social factors. Interruptions did not increase significantly the risk of HIV-associated morbidity and mortality, except for a marginally increased risk for a CDC stage C event after the first interruption. The first interruption decreased significantly the likelihood of increasing the CD4 cell count. Subsequent interruptions had no further significant effect. High CD4 cell count and low viraemia, assessed as baseline and as longitudinal variables, were associated with a decreased risk of clinical progression. CONCLUSIONS: Occasional treatment interruptions of < 3 months neither worsen nor improve disease outcome on an average term (3-4 years). Our results suggest that interruptions might be non-risky, particularly when viraemia is low and CD4 cell count is high. These results require confirmation.

Adult↗
PubMed2002

Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study.

BACKGROUND: HIV-1-infected patients vary considerably by their response to antiretroviral treatment, drug concentrations in plasma, toxic events, and rate of immune recovery. This variability could have a genetic basis. We did a pharmacogenetics study to analyse the association between response to antiretroviral treatment and allelic variants of several genes. METHODS: In 123 patients, we did PCR analyses of the gene for the multidrug-resistance transporter (MDR1), which codes for P-glycoprotein, of genes coding for isoenzymes of cytochrome P450, CYP3A4, CYP3A5, CYP2D6, and CYP2C19, and of the gene for the chemokine receptor CCR5. We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia. FINDINGS: Median drug concentrations in patients with the MDR1 3435 TT, CT, and CC genotypes were at the 30th, 50th, and 75th percentiles, respectively (p=0.0001). In patients with CYP2D6 extensive-metaboliser or poor-metaboliser alleles, median drug concentrations were at percentiles 45 and 62.5, respectively (p=0.04). Patients with the MDR1 TT genotype 6 months after starting treatment had a greater rise in CD4-cell count (257 cells/microL) than patients with the CT (165 cells/microL) and CC (121 cells/microL) genotype (p=0.0048), and the best recovery of naïve CD4-cells. INTERPRETATION: The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment. This finding suggests that P-glycoprotein has an important role in admittance of antiretroviral drugs to restricted compartments in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Management of Opportunistic Infection Prophylaxis in the Highly Active Antiretroviral Therapy Era.

Prophylaxis and maintenance therapy against opportunistic infections are a mainstay of management of HIV-infected patients and have led to a significant improvement in quality of life and survival. Antiretroviral combination therapy (ART) has markedly changed the natural course of HIV infection. Incidence of opportunistic infections (OIs) has declined and survival after an OI has improved. Achieving a CD4 count of 200 cells/L after 6 months of ART is a valuable marker for low risk of OI afterwards. Therefore, recommendations on prophylaxis and maintenance therapy need to be redefined. Criteria for discontinuation, such as a CD4 count rise above threshold values and time above threshold values as response to ART, should be evaluated for the most frequent OIs. Reliable data in favor of discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia, toxoplasmic encephalitis, and Mycobacterium avium infection have been published. Discontinuation of maintenance therapy against P. carinii pneumonia is possible, and may be safe against cytomegalovirus retinitis, M. avium, and cryptococcosis and toxoplasmosis in selected patients. Pharmacologic interactions between drugs used for OI prophylaxis and antiretroviral drugs need to be taken into account.

Journal Article↗
PubMed2002

Cytotoxic HIV-1 p55gag-specific CD4+ T cells produce HIV-inhibitory cytokines and chemokines.

CD4+ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8+ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4+ T cell help. In order to investigate the function of HIV-specific CD4+ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR Vbeta gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4+ TCC produced substantial amounts of IFN-gamma and MIP-1alpha/beta were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4+ T cells suggest that they may exert direct antiviral activity.

Anti-HIV Agents↗
PubMed2002

Opportunistic infections: an update.

With highly active antiretroviral therapy (HAART), the overall incidence of opportunistic infections (OIs) has declined and survival after an AIDS-defining event has improved. However, rates of mycobacterial diseases and cytomegalovirus (CMV) disease remain high for the first 3 months before declining. Achieving a CD4 count of 200 cells/ micro l after 6 months of HAART is a valuable marker for a subsequent low risk of OIs. Different clinical manifestations of OIs may be attributable to immunopathogenic mechanisms linked to immune reconstitution on HAART. The recommendations on prophylaxis and maintenance therapy need to be redefined to allow for the decreased risk of OIs in HAART-treated patients. There are strong data in favour of discontinuing primary prophylaxis against Pneumocystis carinii pneumonia, toxoplasma encephalitis and Mycobacterium avium infection.

AIDS-Related Opportunistic Infections↗
PubMed1997

Low doses of zidovudine plus didanosine are less effective than higher doses of didanosine monotherapy: a randomized trial in patients pretreated with zidovudine.

OBJECTIVE: To compare the clinical efficacy and tolerance of didanosine (ddl) monotherapy with low-dose zidovudine/didanosine (AZT/ddl) therapy among HIV-infected patients previously treated with AZT. METHODS: A randomized controlled trial was carried out of ddl 400 mg daily versus AZT/ddl 300/200 mg daily among patients with CD4 cell counts </=350 mm3 and prior AZT treatment for at least 16 weeks. Fifty eight patients received ddl monotherapy and 66 combined treatment. RESULTS: Patients were similar with respect to demographic, clinical and laboratory characteristics, and prior AZT treatment. Median duration of follow-up was 17.3 months. In the ddl group, 20 patients (34%) discontinued treatment because of toxicity, compared to 19 (29%) in the AZT/ddl group (p=0.38). There was no statistically significant difference in CD4 change between the two groups. In the ddl group, 16 patients (28%) developed a clinical endpoint (death or AIDS-defining opportunistic infection), compared to 33 (50%) in the combined therapy group (relative risk 1.8; 95% confidence interval 1.1-2.9; p=0.01). CONCLUSIONS: For fairly advanced AZT-pretreated patients, monotherapy with ddl was clinically and statistically superior to the low-dose AZT/ddl combination in preventing AIDS-defining illness and death. When access to drugs is limited, e.g. in under-resourced countries, combining available drugs and reducing dosage may be less effective than a single drug at the conventional dosage.

Journal Article↗
PubMedDate not supplied

Tenofovir-containing nucleoside/nucleotide-only antiretroviral maintenance therapy: decision making and virological outcome.

OBJECTIVE: To assess the virological outcome of patients with undetectable human immunodeficiency (HI) viremia switched to tenofovir (TDF)-containing nucleosideonly (NUKE-only) treatments and to investigate the factors influencing the physicians' decision for application of a nonestablished therapy. METHOD: Patients' characteristics and history were taken from the cohort database. To study the decision-making process, questionnaires were sent to all treating physicians. RESULTS: 49 patients were changed to TDF-containing NUKE-only treatment and 46 had a follow-up measurement of HI viremia. Virological failure occurred in 16 (35%) patients. Virological failure was associated with previous mono or dual therapy and with a regimen including didanosine or abacavir. No failure occurred in 15 patients without these predisposing factors. The main reasons for change to TDF-containing NUKE-only treatment were side effects and presumed favorable toxicity profile. The rationale behind this decision was mainly analogy to the zidovudine/lamivudine/abacavir maintenance therapy. CONCLUSION: TDF-containing NUKE-only treatment is associated with high early failure rates in patients with previous nucleoside reverse transcriptase inhibitor mono or dual therapy and in drug combinations containing didanosine or abacavir but not in patients without these predisposing factors. In HIV medicine, treatment strategies that are not evidence-based are followed by a minority of experienced physicians and are driven by patients' needs, mainly to minimize treatment side effects.

Adenine↗