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Biomedical subjects

H F Günthard

Publications and source records attributed to H F Günthard.

At least 19 recordsLinked to original sources
PubMed2005

[Primary HIV-1 infection in Zurich: 2002-2004].

Acute HIV-infection mostly presents with unspecifc symptoms. Thus the acute retroviral syndrome is often not readily recognized. Here we present an interim analysis of a prospective study from 62 patients with documented acute HIV infection acquired between January 2002-August 2004 in the greater Zurich area. 61.5% of patients were infected by homosexual contacts, mostly with HIV-1 subtype B, 34% acquired infection by heterosexual contacts, often with non-B-virus subtypes. Transmission occurred in all sexually active age groups (18-72 years). Clinical symptoms presented as follows: fever (77%), pharyngitis (56%), fatigue (52%), gastrointestinal symptoms (45%), rash (39%). On first physician contact, an ARS was only suspected in 27% of the cases. Patients primarily called on their family doctors (37.5%), went to see larger walk in clinics or emergency rooms (37.5%), and 16% were hospitalised. In 16% of patients other sexually transmitted diseases were diagnosed contemporaneously. Drug resistant virus (single class resistance) was transmitted in only one patient.

Acute Disease↗
PubMed2005

Efavirenz intoxication due to slow hepatic metabolism.

We describe a human immunodeficiency virus-positive woman who presented with severe psychosis while she was receiving therapy with efavirenz. Her plasma efavirenz level was excessively high. Genetic investigation showed that she was homozygous for the CYP2B6 G516T allele, resulting in slow hepatic metabolism. After the dosage of efavirenz was lowered, all neuropsychiatric symptoms subsided.

Adult↗
PubMed2005

Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy.

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

AIDS Dementia Complex↗
PubMed2004

[Unexpected complication in an elderly lady suffering from rheumatoid arthritis].

A 66-year old female suffering from rheumatoid arthritis was treated with methotrexate and intra-articular steroid injections. She had gone through pulmonary tuberculosis at the age of 2 years, also, surgery had been performed 2 years ago because of perforated sigmoid diverticulitis. The patient now presented with episodes of abdominal pain and diarrhea as well as occasional night sweats. Laboratory investigation (normal BSR, CRP and white blood cell counts) did not indicate the presence of an inflammatory process, such as reoccurrence of diverticulitis. However, leukocyturia was repetitively found in this patient with the conventional urine culture yielding no significant bacterial growth. Further urine investigation did not indicate infection with Chlamydia trachomatis or Neisseria gonorrhoeae. Ziehl Neelson stains of morning urinary samples did not show acid-fast rods, however, Mycobacterium tuberculosis was finally isolated by culture. Thus, urogenital tuberculosis was finally diagnosed in this patient. Infection, hematogenic dissemination, and spontaneous remission of pulmonary tuberculosis had occurred more than 60 years ago. After a long latent period, reactivation of tuberculosis happened during drug-induced immunosuppression. The patient was successfully treated with an anti-tuberculosis triple-drug therapy during 2 months followed by a double-drug therapy during 4 months.

Aged↗
PubMed2003

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence.

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Antiretroviral Therapy, Highly Active↗
PubMed2003

[25-year-old therapy naive patient with 3 class resistant HIV infection].

The wide use of potent antiretroviral therapy has significantly reduced mortality and morbidity in patients infected with the HI-Virus. Good individual tolerance and regular intake of an adequate drug regimen often lead to a substantial recovery of impaired immunologic function. In a substantial fraction of patients drug resistant virus is emerging. In the last decade transmission of such viruses to newly infected patients has been reported in several countries. Especially transmission of multidrug-resistant virus is of major concern. We report a case of a 25 year-old Swiss man with a newly diagnosed HIV-infection with a multidrug-resistant virus. In connection to this case we discuss the importance of resistance testing in newly diagnosed patients.

Adult↗
PubMed2003

Aortic homograft endocarditis caused by Rhodotorula mucilaginosa.

Serious infections caused by Rhodotorula spp. are rare and usually occur in immunocompromised people, especially in patients with tumors and long-time use of indwelling central venous catheters. We report a case of Rhodotorula mucilaginosa homograft endocarditis in an otherwise healthy man, which was successfully treated by surgery in combination with amphotericin B and subsequently intraconazole.

Antifungal Agents↗
PubMed2003

Gonococcal tonsillar infection--a case report and literature review.

Oral gonococcal infection is an uncommon but well-described manifestation of gonococcal infection, usually described as pharyngitis in the literature. Tonsillitis is much rarer and its role in the clinical presentation in oral gonorrhea is less clear. We describe a case of oral gonorrhea presenting with tonsillitis and a discrete cervical lymphadenopathy and present a review of the literature from 1961 to 2002. Of the 512 reported cases of oral gonococcal infection, only 61 have been described to be tonsillitis. The tonsils were invariably enlarged and infected. A whitish-yellow exudate in the cryptae was described in 12 cases (20.6%). Fever and cervical lymphadenopathy appear to be rather uncommon, since they have been described in only five (8.2%) and six (9.3%) of the 61 patients with tonsillitis, respectively. Gonococcal tonsillitis should be included in the differential diagnosis of tonsillitis in sexually active patients.

Adult↗
PubMed2001

Prevalence and predictive value of intermittent viremia with combination hiv therapy.

CONTEXT: In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown. OBJECTIVE: To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL). DESIGN AND SETTING: Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995). PATIENTS: Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine. MAIN OUTCOME MEASURES: Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up. RESULTS: Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance. CONCLUSIONS: Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Anti-HIV Agents↗
PubMed2001

Evidence for positive selection driving the evolution of HIV-1 env under potent antiviral therapy.

In HIV-infected individuals treated with potent antiretroviral therapy, viable virus can be isolated from latently infected cells several years into therapy, due to the long life of these cells, ongoing replication replenishing this population, or both. We have analysed the V3 region of the HIV-1 env gene isolated from six patients who have undergone 2 years of potent antiretroviral therapy without frank failure of viral suppression. We show that in two (and possibly three) patients, the sequence changes between baseline virus and virus isolated from infected cells persisting 2 years into infection result from positive selection driving adaptive evolution, occurring either prior to or during therapy. Our analyses suggest low-level replication despite absence of drug resistance due to drug sanctuary sites, or to low-level ongoing replication in the presence of alterations in the selective environment during therapy, perhaps due to a decline in HIV-specific immune responsiveness or changes in target cell pools. In one patient, genetic divergence between baseline plasma and infected cells isolated during therapy may reflect the long half-life of some of these persistent cell populations and the divergence of viral subpopulations that occurred prior to therapy.

Amino Acid Sequence↗
PubMed2001

Quantification of in vivo replicative capacity of HIV-1 in different compartments of infected cells.

Based on a mathematical model, we analyze the dynamics of CD4+ cells, actively, latently, persistently, and defectively infected cells and plasma virus after initiation of antiretroviral therapy in 14 HIV-1-infected asymptomatic patients. By simultaneous fitting of our model to clinical data of plasma HIV-1 RNA, peripheral blood mononuclear cell (PBMC)-gag RNA, proviral DNA, and CD4+ cell counts, we estimate kinetic parameters to determine the basic reproductive rate (R0) of the virus in different infected cell compartments as a measure of the replicative capacity of the virus in vivo. We find that the basic reproductive rate is larger than 1 before treatment only in actively infected cells (mean R0(act) approximately 2.46) indicating that only in this compartment the virus can maintain an ongoing infection. In latently and persistently infected cells the basic reproductive rate is considerably smaller (R0(lat) approximately 0.03 and R0(pers) approximately 0.008, respectively) indicating that these compartments contribute little to the total basic reproductive rate and cannot maintain an ongoing infection in absence of actively infected cells.

Anti-HIV Agents↗
PubMed2001

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years.

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.

Cohort Studies↗
PubMed2001

Direct ex vivo analysis reveals distinct phenotypic patterns of HIV-specific CD8(+) T lymphocyte activation in response to therapeutic manipulation of virus load.

Therapeutic intervention with antiretroviral therapy (ART) enables the modulation of HIV virus load and hence provides a unique opportunity to study the consequences of varying antigen load on the phenotype of virus-specific CD8(+) T lymphocytes in a persistent human viral infection. The recent advent of tetrameric peptide / HLA class I complexes has enabled the direct phenotypic characterization of antigen-specific T cell populations ex vivo. Here, we use this technology to examine directly ex vivo the consequences of therapeutic manipulation of HIV virus load on the phenotype of HIV-specific CTL. Our observations show that: (1) distinct sequential activation patterns of CD8(+) T cells are associated with increasing virus load; (2) T cell receptor (TCR) down-regulation without apoptosis represents an early event during the generation of a T cell response in a natural infection and precedes the emergence of two distinct antigen-specific CD8(+) T cell populations which differ in TCR and CD8 expression levels. Clear differences in surface Annexin V staining were observed between these populations. The observation that CTL activation, demonstrated by TCR and CD8 down-regulation, in response to rising levels of virus load, co-segregates with apoptosis only during later stages of the response indicates that antigen-associated cell death is restricted to distinct subpopulations of CTL.

Annexin A5↗
PubMed2000

Impact of TNFalpha, LTalpha, Fc gammaRII and complement receptor on HIV-1 trapping in lymphoid tissue from HIV-infected patients.

OBJECTIVES: To investigate HIV trapping mechanisms in patients with acute infection and in asymptomatic individuals prior to and during antiretroviral therapy. To determine the role of complement receptor (CR), Fc gamma receptor II (Fc gammaRII), tumour necrosis factor alpha (TNFalpha), and lymphotoxin alpha (LTalpha) expression in HIV trapping efficiency. METHODS: Lymphoid tissues from three acutely HIV-infected patients and six asymptomatic, chronically HIV-infected patients collected prior to and during antiretroviral therapy were compared with lymphoid tissues from six HIV-seronegative subjects. HIV, TNFalpha and LTalpha RNA expression was detected and quantified by fluorescence in situ hybridization. CR, Fc gammaRII and HIV p24 antigen were detected and quantified by fluorescence immunohistochemistry. RESULTS: The amount of trapped HIV did not differ significantly between patients with acute HIV infection and asymptomatic individuals, and was independent of the presence of CR or Fc gammaRII expression. However, in patients with acute infection, the amount of trapped virus was correlated inversely with the number of HIV-infected cells (P = 0.0092) and with the size of the light zone (P = 0.037). In these patients, the number of TNFalpha-expressing cells was correlated inversely with the amount of trapped virus (P = 0.014) and positively correlated with the size of the light zone in germinal centers (P = 0.041). No correlations were observed between TNFalpha or LTalpha expression and Fc gammaRII or CR expression. CONCLUSION: This report provides the first evidence that in humans TNFalpha is involved in the development of lymphoid follicles, HIV trapping, and, consequently, in early host immune responses. A model is proposed for early events in patients during acute HIV infection.

Acute Disease↗
PubMed2000

Residual HIV-RNA levels persist for up to 2.5 years in peripheral blood mononuclear cells of patients on potent antiretroviral therapy.

The long-term response of 10 asymptomatic, antiretroviral therapy-naive HIV-1-infected patients to potent combination antiretroviral therapy was characterized by monitoring levels of HIV-1 RNA in plasma, peripheral blood mononuclear cells (PBMC), and lymphoid tissue using highly sensitive HIV-1 RNA assays. Although plasma viral loads were continuously suppressed to levels below 50 HIV-1 RNA copies/ml for up to 2.5 years (60-128 weeks), HIV-1 RNA was still detectable at very low levels (1 to 49 HIV-1 RNA copies/ml) in 25% of the samples. In corresponding PBMC specimens, residual HIV-RNA was detectable in as much as 91% of samples tested (1 to 420 HIV-1 RNA copies/microg total RNA). Similarly, HIV-1 RNA levels in lymphoid tissue also remained detectable at a high frequency (86%). A highly significant correlation was demonstrated between therapy-induced change in PBMC HIV-1 RNA levels and change in plasma HIV-1 RNA levels (r2 = 0.69; p = 0.003). These findings support the concept that measurement of HIV-1 RNA in the easily accessible PBMC compartment is relevant for evaluating the potency of current and future antiretroviral therapies.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy.

OBJECTIVE: To determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy. METHODS: Amino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks. RESULTS: Numbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 601 + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks. CONCLUSIONS: Use of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Treatment-induced decline of human immunodeficiency virus-1 p24 and HIV-1 RNA in lymphoid tissue of patients with early human immunodeficiency virus-1 infection.

We report detailed quantitative analysis of human immunodeficiency virus-1 (HIV-1) p24 and HIV-1 RNA in tonsil biopsies from 13 patients with early, asymptomatic HIV infection before and during combination antiretroviral therapy. Using fluorescent microscopy in conjunction with reverse transcriptase-polymerase chain reaction of frozen tissue sections, we show that plasma and tissue viral loads decreased by approximately 3 logs during the 1-year treatment period, with good correlation between the HIV-1 p24 and HIV-1 RNA response in tissue. The decrease of tissue viral load was delayed compared to plasma viral load, possibly explained by the observation that the amount of follicular dendritic cell-associated virus correlated best with the area under the curve of plasma HIV-1 RNA throughout the last 12 weeks. Before and during treatment, the relative proportions of HIV-1 on follicular dendritic cells and within mononuclear cells remained constant, suggesting similar decay characteristics in these two lymphoid tissue compartments. However, viral p24 or RNA remained almost always detectable in tissue despite full suppression of HIV-1 RNA in plasma, and increased even after short-term rebounds in plasma viral load. Thus, full and sustained suppression of viral replication was required to efficiently decrease viral load in lymphoid tissue, but complete abolition of residual viral replication was not achieved.

Anti-HIV Agents↗