Matthias Stoll

Impaired glucose tolerance, beta cell function and lipid metabolism in Hiv patients under treatment with protease inhibitors

OBJECTIVES To evaluate metabolic abnormalities, beta-cell function, lipid profile and vascular risk factors in HIV patients on protease inhibitors (PI). DESIGN Prospective cross-sectional study. METHODS Thirty-eight HIV-1-infected patients receiving at least one PI were compared with 17 PI-naive HIV patients in an oral glucose tolerance test (OGTT). Serum glucose, insulin, proinsulin, and C-peptide were determined. The fasting lipid pattern was analysed using electrophoresis and the assessment of apolipoproteins including lipoprotein (a). Fibrinogen, homocysteine, and anticardiolipin antibodies were also assessed. RESULTS Twenty-seven (71%) of the PI-treated group had detectable hyperlipidaemia. Isolated hypertriglyceridaemia was present in 12 patients (44%), two (7%) of them had type V and 10 (37%) subjects had type IV hyperlipidaemia (Frederickson classification). Type IIb hyperlipidaemia defined as an increase of both very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) was found in 10 (36%) subjects, and five (18%) patients presented with isolated hypercholesterolaemia (type IIa). PI treatment was associated with significant higher fasting cholesterol, triglycerides, LDL and VLDL levels. Apolipoprotein B and E concentrations were significantly increased in patients receiving PI. Elevated concentrations of lipoprotein (a) (> 30 mg/dl) were detected in six (16%) of the hyperlipidaemic patients on PI. Eighteen (46%) patients on PI had impaired oral glucose tolerance and five (13%) had diabetes. Although four (24%) of the PI-naive patients were glucose intolerant, none had diabetes. Fasting concentrations and secretion response of insulin, proinsulin, and C-peptide to glucose ingestion was significantly increased in the PI-treated group suggesting a beta-cell dysfunction in addition to peripheral insulin resistance. Beta-cell abnormalities were associated with the abnormal lipid pattern and PI treatment. CONCLUSION Combination drug regimens including PI are accompanied by impaired glucose tolerance, hyperproinsulinaemia as an indicator for beta-cell dysfunction, and lipid abnormalities proved to be significant risk factors for coronary heart disease. Moreover, PI may have an impact on the processing of proinsulin to insulin.

GB Virus C/Hepatitis G Virus Infection: A Favorable Prognostic Factor in Human Immunodeficiency Virus-Infected Patients?

To investigate a possible influence of GB virus C (GBV-C) in immunocompromised patients, the prevalences of GBV-C RNA and anti-E2 antibody in 197 human immunodeficiency virus (HIV)-infected patients and in 120 control blood donors were studied. GBV-C RNA was detected in 33 of 197 HIV-infected patients (16.8%) compared with 1 in 120 blood donors (0.8%) (P < .001). Previous exposure to GBV-C (anti-E2 antibody-positive) was shown in 56.8% of HIV patients and in 9% of blood donors. GBV-C viremia was not associated with hepatitis. Despite approximately equal duration of HIV infection in all subgroups, the CD4 cell counts were significantly higher in GBV-C-viremic patients (344 cells/microL) compared with exposed (259 cells/microL) and unexposed (170 cells/microL) patients (P = .017 and P < .001). Furthermore, Kaplan-Meier analysis demonstrated significantly better cumulative survival in GBV-C RNA-positive HIV-infected patients, suggesting that GBV-C might be a favorable prognostic factor in HIV disease.

Safety and Immunogenicity of an Adjuvanted Herpes Zoster Subunit Candidate Vaccine in HIV-Infected Adults: A Phase 1/2a Randomized, Placebo-Controlled Study

Background. Human immunodeficiency virus (HIV)–infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative. Methods. This phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ≥18 years were enrolled: 94 ART recipients with a CD4+ T-cell count of ≥200 cells/mm3, 14 ART recipients with a CD4+ T-cell count of 50–199 cells/mm3, and 15 ART-naive adults with a CD4+ T-cell count of ≥500 cells/mm3. Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6. Results. One month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4+ T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4+ T-cell count was noted following vaccinations. Conclusions. HZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults. Clinical Trials Registration. NCT01165203.

Short-Term Monotherapy in HIV-Infected Patients with a Virus Entry Inhibitor Against the gp41 Fusion Peptide

An optimized derivative of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide shows antiviral potency and minimal side effects in a Phase I/II clinical trial. Anchors Away: Blocking HIV Entry Combination antiretroviral therapy has been very successful for treating infection with the human immunodeficiency virus (HIV-1), which causes AIDS. However, drug resistance is emerging and there is a need to develop new antiretroviral drugs that work earlier in the virus life cycle, for example, by preventing HIV-1 from entering host cells. Two such virus entry inhibitors, maraviroc and T-20, are in clinical use, but both have drawbacks. Forssmann, Kirchhoff and their colleagues have now developed a new virus entry inhibitor called VIRIP (VIRus-Inhibitory Peptide), a 20-peptide fragment of α1-antitrypsin, an abundant circulating serine protease inhibitor. VIRIP and its optimized derivative VIR-576 are so-called anchoring inhibitors because they prevent the gp41 fusion peptide of HIV-1 from inserting itself into the host cell membrane. This then blocks the next step in the virus life cycle, which is fusion of the virion envelope with the host cell membrane. Forssmann and co-workers now report on a Phase I/II clinical trial in which 18 HIV-1–infected patients who were not on any other antiretroviral therapy were treated for 10 days with three different doses of VIR-576 (0.5, 1.5, 5.0 g/day). They show that VIR-576 reduced the viral load in the plasma of patients on the highest dose by an order of magnitude and that the drug was well tolerated. Previous studies have shown that the gp41 fusion peptide is essential for HIV-1 entry into host cells, and suggest that it may be difficult for HIV-1 to develop resistance to VIR-576 because the fusion peptide is highly conserved and hardly tolerates changes without loss of function. This anchoring inhibitor, unlike other HIV entry inhibitors, is also active against many different HIV strains and has a different target (the gp41 fusion peptide). Thus, VIR-576 represents a potential new class of HIV entry inhibitor. However, VIR-576 does have some drawbacks too. Because VIR-576 is a peptide, it will be costly and time-consuming to produce and it must be administered intravenously. This has prompted Kirchhoff and colleagues to start searching for a small molecule that would block the gp41 fusion peptide in the same way as VIR-576 but would have the advantage that it could be made cheaper and given orally. To infect host cells, most enveloped viruses must insert a hydrophobic fusion peptide into the host cell membrane. Thus, fusion peptides may be valuable targets for developing drugs that block virus entry. We have shown previously that a natural 20-residue fragment of α1-antitrypsin, designated VIRus-Inhibitory Peptide (VIRIP), that binds to the gp41 fusion peptide of HIV-1 prevents the virus from entering target cells in vitro. Here, we examine the efficacy of 10-day monotherapy with the optimized VIR-576 derivative of VIRIP in treatment-naïve, HIV-1–infected individuals with viral RNA loads of ≥10,000 copies per ml. We report that at the highest dose (5.0 grams per day), intravenous infusion of VIR-576 reduced the mean plasma viral load by 1.23 log10 copies per ml without causing severe adverse effects. Our results are proof of concept that fusion peptide inhibitors suppress viral replication in human patients, and offer prospects for the development of a new class of drugs that prevent virus particles from anchoring to and infecting host cells.

Clinical impact of Hiv-related lipodystrophy and metabolic abnormalities on cardiovascular disease

Metabolic complications and altered fat distribution associated with HIV infection and antiretroviral therapy may lead to accelerated coronary artery disease (CAD). The high prevalence of multiple cardiovascular risk factors in a significant number of HIV patients is a cause for concern in both patients and physicians. Non-invasive strategies to measure subclinical CAD have been inconclusive. Long-term studies are underway to determine cardiac event rates, intervention strategies and consequences for the clinical management of HIV disease. In the present paper, we summarize the most prevalent risk factors in individuals with HIV infection receiving highly active antiretroviral therapy by focusing on the clinical implications of metabolic abnormalities and HIV-related lipodystrophy on CAD.

Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy.

We studied natural immunity mediated by natural killer (NK) cells in 62 HIV-1 infected individuals, 54 HIV-1 infected individuals receiving highly active antiretroviral therapy (HAART) for more than one year and 8 HIV-1 infected individuals without antiretroviral therapy. 22 individuals had a complete suppression of viral replication characterized by viral load values <50 copies/ml, whereas 32 individuals presented with persistent viral replication. The 8 untreated patients had an indication to start antiretroviral treatment. Lytic activity of NK cells was measured in a 51chromium release assay. In patients with persistent viral replication under HAART NK cell activity was significantly decreased compared to patients with effective control of HIV viremia. Patients with complete suppression of HIV replication displayed a similar NK activity to healthy control persons. Differences in antibody-dependent cellular cytotoxicity (ADCC) were not observed. Further studies will investigate whether decreased NK cell activity is a reason for or the consequence of persistent viral replication.

Calculation of Direct Antiretroviral Treatment Costs and Potential Cost Savings by Using Generics in the German HIV ClinSurv Cohort.

Background/Aim of the Study The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART,-regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios. Methods Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study centres have been investigated since 1996. Biannual data cART,-initiation, cART-changes, surrogate markers, clinical events and the Centre of Disease Control- (CDC)-stage of HIV disease are reported. Treatment duration was calculated on a daily basis via the documented dates for the beginning and end of each antiretroviral drug treatment. Prices were calculated for each individual regimen based on actual office sales prices of the branded pharmaceuticals distributed by the license holder including German taxes. Results During the 13-year follow-up period, 21,387,427 treatment days were covered. Cumulative direct costs for antiretroviral drugs of €812,877,356 were determined according to an average of €42.08 per day (€7.52 to € 217.70). Since cART is widely used in Germany, the costs for an entire regimen increased by 13.5%. Regimens are more expensive in the advanced stages of HIV disease. The potential for cost savings was calculated using non-nucleotide-reverse-transcriptase-inhibitor, NNRTI, more frequently instead of ritonavir-boosted protease inhibitor, PI/r, in first line therapy. This calculation revealed cumulative savings of 10.9% to 19.8% of daily treatment costs (50% and 90% substitution of PI/r, respectively). Substituting certain branded drugs by generic drugs showed potential cost savings of between 1.6% and 31.8%. Conclusions Analysis of the data of this nationwide study reflects disease-specific health services research and will give insights into the cost impacts of antiretroviral therapy, and might allow a more rational allocation of resources within the German health care system.

Estimating Trends in the Proportion of Transmitted and Acquired HIV Drug Resistance in a Long Term Observational Cohort in Germany

Objective We assessed trends in the proportion of transmitted (TDR) and acquired (ADR) HIV drug resistance and associated mutations between 2001 and 2011 in the German ClinSurv-HIV Drug Resistance Study. Method The German ClinSurv-HIV Drug Resistance Study is a subset of the German ClinSurv-HIV Cohort. For the ClinSurv-HIV Drug Resistance Study all available sequences isolated from patients in five study centres of the long term observational ClinSurv-HIV Cohort were included. TDR was estimated using the first viral sequence of antiretroviral treatment (ART) naïve patients. One HIV sequence/patient/year of ART experienced patients was considered to estimate the proportion of ADR. Trends in the proportion of HIV drug resistance were calculated by logistic regression. Results 9,528 patients were included into the analysis. HIV-sequences of antiretroviral naïve and treatment experienced patients were available from 34% (3,267/9,528) of patients. The proportion of TDR over time was stable at 10.4% (95% CI 9.1–11.8; p for trend = 0.6; 2001–2011). The proportion of ADR among all treated patients was 16%, whereas it was high among those with available HIV genotypic resistance test (64%; 1,310/2,049 sequences; 95% CI 62–66) but declined significantly over time (OR 0.8; 95% CI 0.77–0.83; p for trend<0.001; 2001–2011). Viral load monitoring subsequent to resistance testing was performed in the majority of treated patients (96%) and most of them (67%) were treated successfully. Conclusions The proportion of TDR was stable in this study population. ADR declined significantly over time. This decline might have been influenced by broader resistance testing, resistance test guided therapy and the availability of more therapeutic options and not by a decline in the proportion of TDR within the study population.

Patient preferences for HIV/AIDS therapy - a discrete choice experiment

ObjectivesAn increasing emphasis on patient-centred health care and shared decision making requires an intensive consideration of patient preferences. In the present study, patient preferences regarding treatment of HIV/AIDS were explored using direct assessment and discrete choice experiment (DCE).MethodsBased on literature research about preferences of HIV/AIDS patients we conducted a qualitative pre-study. The results were used to compose a questionnaire on relevant aspects of HIV/AIDS treatment which underwent a pre-test. In the subsequent quantitative study phase presented here, the following data were collected online or on paper including socio-demographic data, SF12v2, data on HIV/AIDS, antiretroviral treatment and patient preferences for therapy characteristics using direct measurement, as well as a discrete choice experiment.Results218 patients completed the quantitative main study, 82% of these on paper. 86% were male and the most frequent age group was between 45 and 54 years (37.6%). The SF12v2 showed a mean value of 43 points for the “mental health” component sum score. In the direct measurement the most relevant therapy characteristics were “Self-application of the drug (at home or on-the-go) possible”, “Drug has very high efficacy (reduction of viral load)” and “Long term (hidden) damage (e.g. organ damage) is unlikely”. Based on a factor analysis, six treatment characteristics were selected and used to generate eight virtual therapies. To evaluate the patient assessments a random effect logit model was employed. All of the characteristics were statistically significant predictors of the model of patient preference. The most important therapy characteristic was that the disease is not obvious for others.ConclusionsThe main result is the high impact of quality of life, in particular the emotional quality of life on patient preferences on the selection of treatments. Thus, the selection of particular treatment options should be accompanied by a deliberate consideration of treatment features, which need to be considered in order to maximize patient adherence and compliance.

Orthotopic Liver Transplantation in Human-Immunodeficiency-Virus-Positive Patients in Germany

Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41–86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.