[HIV-1 therapy in the Netherlands; virological and immunological response to antiretroviral therapy]. / Behandeling van HIV-1 in Nederland: virologische en immunologische respons op antiretrovirale therapie.

OBJECTIVE: To evaluate the effect of treatment of HIV-1 infection with combination therapy consisting of since 1996 in the Netherlands available protease and reverse transcriptase inhibitors. DESIGN: Prospective cohort study. METHODS: In an observational clinical cohort of HIV-1-infected individuals, the short-term successful treatment end point of antiviral therapy including at least one antiretroviral drug licensed in the Netherlands since July 1, 1996 (protease inhibitors and reverse transcriptase inhibitors), was HIV-1 RNA plasma levels < or = 500 copies/ml (virological success). Cox proportional hazard models were used to identify prognostic markers for therapy success. The study included 2,148 infected individuals with a median follow-up of 135 weeks of treatment; 1,049 had been pre-treated with antiretroviral drugs before starting their new regimen and 1,099 were treatment naive. RESULTS: Plasma HIV-1 RNA levels < or = 500 copies/ml at 24 weeks of treatment were seen in 61% of all patients. The chance of therapy success for naive patients was twice that for pre-treated patients (relative risk: 1.8; p < or = 0.001). Following the first 24 weeks, the chance of virological success was higher in the naive group (78% versus 63%; p < or = 0.001), and the number of naive patients failing therapy after initial success was smaller compared to pre-treated patients (22% versus 45%; p < or = 0.001). In the naive group, the CD4+ T-cell number increased from 239 to 440 (x 10(6) cells/l) in case of success, and decreased from 150 to 320 in case of treatment failure. HIV-1 related morbidity declined from 0.26 to 0.05 and mortality dropped from 0.07 to 0.03 per person-year of follow-up. Regimens were changed at least once in 76% of patients. Toxicity and therapy failure were the main reasons for regimen changes in naive and pre-treated patients, respectively. CONCLUSION: A combination of antiretroviral drugs, including at least one of the drugs licensed since 1996, led to a drop in HIV-1 plasma concentrations. Morbidity and mortality also decreased. The chance of a better immunological and virological response to the new drug regimens was greatest in therapy-naive patients.

Local treatment of facial lipodystrophy in patients receiving HIV protease inhibitor therapy.

Localized facial lipodystrophy is a socially disabling complication affecting many HIV-seropositive patients receiving triple combination therapy. The exact pathogenesis is not well understood and proper therapy is not available. The purpose of this pilot-study was to determine whether a hyaluronic acid get, used to treat wrinkles for cosmetic reasons, would be a safe and effective treatment for facial lipodystrophy in patients receiving triple combination therapy. Seven patients were treated with intradermal gel injections after skin tests. There were no immediate or late allergenic reactions or other side effects. Within the limitations of the product, overall satisfaction regarding the results was high.

A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of twice-daily indinavir + ritonavir regimens DESIGN: A cohort-based survey of HIV-infected patients who either used indinavir 800 mg + ritonavir 100 mg twice daily or indinavir 400 mg + ritonavir 400 mg twice daily. METHODS: Data were extracted from a database of samples sent to our laboratory for measurement of indinavir + ritonavir plasma concentrations. Patient characteristics, safety, and efficacy measurements were collected by retrospective chart review. RESULTS: 100 Patients using 800-mg indinavir + 100-mg ritonavir twice daily and 32 patients using 400-mg indinavir + 400-mg ritonavir twice daily were eligible. Median peak and trough concentrations of indinavir were 6.8 and 0.77 mg/L in the 800/100 group and 2.6 and 0.45 mg/L in the 400/400 group. The most frequently found side effects were nausea and vomiting, which occurred in 22.1% and 34.9% of the patients in the 800/100 and the 400/400 groups, respectively. Viral load data were analyzed for patients who switched from 800-mg indinavir three times daily to one of the indinavir + ritonavir twice daily regimens. At the time of switch 63% (800/100 group) and 60% (400/400 group) had an undetectable viral load and this increased to 77% and 70%, respectively, during follow-up. Patients who switched to the 400/400 group discontinued treatment more frequently than patients who switched to the 800/100 group (70% vs. 26%, p =.008). CONCLUSIONS: Indinavir + ritonavir regimens show improved pharmacokinetic properties, allowing twice-daily dosing with food. Clinical data suggest that safety and efficacy is at least as good as with indinavir three-times-daily regimens without ritonavir. Prospective, comparative trials are needed to properly assess the role in HIV therapy of these twice-daily indinavir + ritonavir regimens.

Generalized mycobacterium genavense infection in HIV-infected patients: detection of the mycobacterium in hospital tap water.

We describe 3 HIV-infected patients with disseminated M. genavense infection. The use of corticosteroids possibly favoured colonization and dissemination of atypical mycobacteria in these patients with low CD4 cell counts and may have masked symptoms of infection. The fact that these patients were treated with highly active antiretroviral therapy (HAART) together with antimycobacterial therapy may explain that 1 patient was free from mycobacteria 16 months after the end of specific treatment. Hospital tap water contained M. genavense at a concentration of >10 bacteria/l as examined by PCR. This species caused 12% of cases of non-tuberculous disseminated mycobacteriosis in HIV-infected patients at our hospital.

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.

Hepatitis E virus antibodies among patients with hemophilia, blood donors, and hepatitis patients.

The presence of antibodies to hepatitis E virus (HEV) was studied among hemophiliacs, blood donors, and hepatitis patients. Four of 296 (1.4%) hemophiliacs and 5 of 1,275 (0.4%) donors were confirmed as positive for HEV antibodies (difference was not significant: P = 0.07). Parenteral transmission of HEV to hemophiliacs was thus rare or nonexistent. Seven of 187 hepatitis patients were found with HEV antibodies (IgG and IgM). Six persons fell ill shortly after arriving from HEV-endemic countries. The seventh patient, without a history of travel, represents a case of nontropical hepatitis E. Consequently, hepatitis E should be considered in patients suffering from acute non-ABC hepatitis, even in industrialized countries.

Detection of HIV-1 RNA in plasma by isothermal amplification (NASBA) irrespective of the stage of HIV-1 infection.

Using an experimental assay for isothermal amplification of HIV RNA in plasma (NASBA, Organon Teknika, Boxtel, The Netherlands), 70 samples from 59 HIV-1-infected persons and 29 samples from 28 uninfected volunteer blood donors were tested for the presence of HIV-1 RNA. The HIV-1-positive plasma samples were drawn from patients at various stages of infection: two samples from persons with signs of acute HIV infection (CDC stage I); 29 samples from 25 symptom-free persons (CDC stage II) and 39 samples from 32 persons with AIDS-related symptoms (CDC stage IV). All samples from HIV-1-infected persons had HIV-1 RNA, irrespective of the stage of infection (100% sensitivity). Testing the donor samples in duplicate, initially 54/58 samples (93%) tested negative for HIV-1 RNA. Repeated testing of the 4 samples with inconsistent test results showed all samples to be negative (specificity 100%). Detection of HIV-1 RNA in plasma by isothermal amplification (NASBA) promises to be a valuable alternative to the detection of HIV-1 RNA or DNA by the polymerase chain reaction.

Detection of HIV-1 DNA in leukocytes using a commercially available assay.

Recently, an assay for detection of proviral HIV-1 DNA in leukocytes became commercially available. This assay (Amplicor HIV-1 test, Roche Diagnostic Systems) multiplies HIV-1DNA up to a detectable level, using the polymerase chain reaction. We studied performance of this assay on 74 samples from HIV-1-infected patients and on 41 samples from healthy blood donors. Twice a negative control sample appeared to be erroneously reactive. However, sensitivity and specificity on the patient and donor samples both were 100%. To avoid false-positive results, we advise to repeat initially reactive samples if no other data confirm HIV-infection.

[Treatment of AIDS patients with zidovudine]. / Behandeling van patiënten met AIDS met zidovudine.

During 20 months 49 AIDS patients treated with zidovudine were followed prospectively. The 12-month cumulative probability of survival was 73% and the 18-month probability of survival was 51%. The probability of survival was significantly higher when, at the start of therapy, the Karnofsky score was 70 or higher (p less than 0.001) or the CD4 cell count was 0.05 x 10(9)/l or higher (p less than 0.05). The general condition, Karnofsky score, body weight, number of CD4 positive cells and the lymphocyte stimulation in vitro improved during therapy, but the beneficial effects lasted only 6-9 months. Anaemia (Hb less than 6 mmol/l) developed in 21 (43%) of the patients. (Pan)cytopenia prompted dose reduction in 14 patients, in 5 patients with pancytopenia therapy was withdrawn. The length of stay in hospital was 885 days for the whole group of patients, equivalent to 20 days per patient year.

Incidence and significance of heartmuscle antibodies in patients with acute myocardial infarction and unstable angina.

The incidence of heartmuscle antibodies was studied prospectively in 136 patients consecutively admitted for acute myocardial infarction (AMI) and in 95 patients with unstable angina. Heartmuscle antibodies were determined with the indirect immunofluorescence technique on days 1, 10, 20 and 30 in patients with AMI and on days 1 and 10 in patients with unstable angina. Heartmuscle antibodies were found in 16/136 AMI patients (12%) and in 3/95 (3%) with unstable angina. None of the AMI patients developed post-myocardial-infarction syndrome in the 2--4 weeks after infarction or during the one-year follow-up. The AMI patients with and without heartmuscle antibodies were comparable with respect to age, sex, site and size of infarction, incidence of early pericarditis and previous infarction.

Conservative surgical management of urological complications after cadaveric renal transplantation.

Review of a consecutive series of 85 cadaveric renal transplants revealed urinary fistulas in 7 cases. Bladder fistulas originated from the anterior cystostomy suture line in 3 patients and required secondary closure in every case. Ureteral fistulas from the donor ureter often required a multistaged operation. In every case the end result has been satisfactory, with closure of the fistula and preservation of renal function.

Inferior myocardial infarction in a patient with mirror-image dextrocardia and situs inversus totalis.

A case of inferior wall myocardial infarction in a patient with mirror-image dextrocardia and situs inversus totalis is presented. The clinical and electrocardiographic findings are discussed.