H. J. Stellbrink

SYSTEMIC PENICILLIUM MARNEFFEI INFECTION IN A GERMAN AIDS PATIENT

Section of Infectious Diseases, Hospital de Galdakao, 48960 Vizcaya, Spain. thrombocytopenic purpura associated with human immunodeficiency virus infection: demonstration of p24 antigen in endothelial cells. Clinical Infectious Diseases 1993, 17: 360-363. 12. Lafeuillade A, Aiessi MC, Poizot-Martin I, Boyer-Newmann C, Zandotti C, Quilichini R, Aubert L, Tamalet C, Juhan-Vague Y, Gastaut JA: Endothelial cell dysfunction in HIV infection. Journal of the Acquired Immune Deficiency Syndromes 1992, 5: 127-131. 13. Salem G, Terebelo H, Raman S: Human immunodeficiency virus associated with thrombotic thrombocytopenic purpura: successful treatment with zidovudine. Southern Medical Journal 1991, 84: 493-495. 14. Routy JP, Beaulieu R, Monte M, Saint-Louis J, Sauvageau G, Toma E: Immunologic thrombocytopenia followed by thrombotic thrombocytopenic purpura in two HIV-1 patients. American Journal of Hematology 1991, 38: 327-328.

Comparison of Changes in Bone Density and Turnover with Abacavir-Lamivudine versus Tenofovir-Emtricitabine in HIV-Infected Adults: 48-Week Results from the ASSERT Study

BACKGROUND Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. METHODS In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. RESULTS A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001). CONCLUSIONS This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study

BACKGROUND Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1. METHODS SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824. FINDINGS 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance. INTERPRETATION The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients. FUNDING ViiV Healthcare.

The changing pattern of Kaposi sarcoma in patients with HIV, 1994-2003: the EuroSIDA Study.

The introduction of highly active antiretroviral therapy (HAART) has radically changed the clinical course of human immunodeficiency virus (HIV) infection. The goals of the current study were to assess the change in the incidence of Kaposi sarcoma (KS) among European patients with HIV since the introduction of HAART and to identify the factors associated with the development of KS among patients receiving HAART.

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

ABSTRACT 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.

Changes in hospital admissions across Europe: 1995-2003. Results from the EuroSIDA study

To describe changes in the proportions of patients admitted to hospital and the duration of admission during the month of March between 1995 and 2003 and to describe the factors related to admission for 9802 patients from EuroSIDA, a pan‐European, observational cohort study.

Randomised, Multicentre Phase III Study of Saquinavir plus Zidovudine plus Zalcitabine in Previously Untreated or Minimally Pretreated HIV-Infected Patients

AbstractBackground: PISCES (SV14604) was the largest study of antiretroviral therapy to assess clinical end-points. The study data provides a repository of important information, much of which remains relevant today. This paper reviews the results of the PISCES study, placing the findings in context with today’s treatment practices. Objective: To determine the antiretroviral efficacy of saquinavir hard gelatin capsule (SQV; Invirase®) plus two nucleoside analogues [zidovudine (ZDV) and zalcitabine (ddC)] using clinical end-points. Design: Prospective, randomised, double-blind international study. Patients: HIV-1-infected individuals (CD4 50 to 350 cells/μl) who were anti-retroviral-naïve or minimally pretreated with zidovudine (ZDV; ≤16 weeks) were randomised. Interventions: Patients received: (i) SQV + ZDV + ddC, (ii) SQV + ZDV, (iii) ZDV + ddC, or (iv) ZDV for ≥80 weeks or until the common closure date, at daily oral dosages of SQV 1800mg, ddC 2.25mg and ZDV 600mg. After 14 months, ZDV monotherapy patients were reallocated to receive additional SQV + ddC in a double-blinded manner. Main Outcome Measure: Time to clinical end-point of first AIDS-defining event (ADE) or death. Results: A total of 3591 patients were randomised, and 3485 received therapy. Median duration of study therapy was 58.4 to 63.3 weeks and mean duration of follow-up was 73.9 to 75.6 weeks. The time to first ADE or death was significantly reduced with triple therapy relative to ZDV + ddC (p = 0.0001, log rank test). The proportion of patients progressing to the primary clinical end-point was 8.0% for the triple therapy group compared with 15.1 % for ZDV + ddC. Initiating triple therapy reduced the risk of progression by 50% relative to ZDV + ddC [risk ratio 0.502; (95% CI 0.379-0.663) p = 0.0001). Patients with prior ZDV therapy for <8 weeks achieved the greatest clinical benefit. HIV-1 RNA was reduced more by triple therapy than by either dual therapy (p = 0.0001), and this reduction explained 64% of the treatment effect. In an exploratory analysis, the primary end-point was reached by 8.0% of patients receiving immediate triple therapy, compared with 17.8% receiving initial ZDV monotherapy followed by triple therapy (p = 0.0001). Conclusions: This study was the first to show the benefit of triple therapy over dual therapy using clinical outcome measures; treatment with SQV + ZDV + ddC producing a statistically significant prolongation of time to first ADE or death in antiretroviral-naïve/minimally pretreated patients, compared with combined nucleoside analogues only. The study also confirms the outcome benefit (time to first ADE or death) of immediate triple therapy over delayed triple therapy and the prognostic value of monitoring HIV-1 RNA (but not CD4 count). The potential of patient/clinician perception of therapy to influence study outcome was also demonstrated.

A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine

Objective: Zidovudine (ZDV) is the only antiretroviral drug which has been shown to reduce mortality in patients with symptomatic HIV disease, but its use is restricted by intolerance in a significant proportion of patients. Additionally, the efficacy of ZDV therapy appears to decrease after prolonged treatment particularly in the advanced stage of HIV disease. Therefore, alternative antiretroviral regimens for patients are needed. In this study, didanosine (ddl; 2′,3′‐dideoxyinosine), another HIV reverse transcriptase inhibitor, was evaluated. Design: A total of 426 patients with AIDS or AIDS‐related complex (ARC) who were intolerant to or clinically progressing on ZDV therapy and who had CD4+ cell counts ≤ 150 × 106/l were randomized to receive either a high (750 mg for bodyweight ≥ 60 kg or 500 mg for bodyweight < 60 kg) or a low (200 mg and 1 34 mg, respectively) dose of ddl daily. Setting: The patients were recruited from 31 German and Austrian AIDS clinical primary‐care centres. Results: The study was stopped after the second interim analysis due to a statistically significant difference in the incidence of pancreatitis (nine versus 26; relative risk, 2.92; P = 0.003) and neuropathy (28 versus 43; relative risk, 1.55; P = 0.05) in favour of the low dose. There was no difference between the low and high dosage groups in survival rate at 6 (80 versus 80%) and 12 months (61 versus 65%), number of deaths [82 (43.6 per 100 patient‐years) versus 84 (44.4 per 100 patient‐years)], progression from ARC to AIDS or to AIDS or death, or average number of new/recurrent opportunistic infections (2.8 versus 3.0 per patient). Conclusions: This study cannot conclude on ddl efficacy but it shows that in patients with advanced HIV disease for whom no alternative antiretroviral therapy is available and ddl therapy is considered, daily doses < 750 mg should be administered. AIDS 1995, 9:463‐469

Rapid clearance of human immunodeficiency virus type 1 from ventricular cerebrospinal fluid during antiretroviral treatment.

To understand the pathogenesis of human immunodeficiency virus–induced neuropathology, it is critical to know the dynamics of viral replication in the central nervous system. Viral decay kinetics were mathematically analyzed from multiple serial specimens of ventricular cerebrospinal fluid and plasma during antiretroviral therapy in a patient with asymptomatic human immunodeficiency virus infection and an external ventricular catheter for hydrocephalus. A rapid exponential decay of virus with an elimination half‐life of 4.2 days in ventricular cerebrospinal fluid and 2.3 days in plasma was found. Sequencing the V3 loop‐encoding envelope gene of virus in both compartments revealed high sequence homology. The combined data suggest that virus in ventricular cerebrospinal fluid is at least partly contributed by rapidly replicating virus‐producing cells recruited from the circulation. Ann Neurol 2000;47:816–819

HIV-induced immune activation - pathogenesis and clinical relevance. Summary of a workshop organised by the German AIDs Society (DAIG e.v.) and the ICH Hamburg, Hamburg, Germany, November 22, 2008

This manuscript is communicated by the German AIDS Society (DAIG) http://www.daignet.de. It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V.).