Chronic hepatitis C patients prior to broad access to interferon-free treatments in Germany.

In 2014, the first interferon-free treatment options for chronic Hepatitis C (CHC) became available in Europe introducing a new era of highly effective and well tolerated oral treatment options for CHC. The data from the cross-sectional study CURRENT-C highlights the epidemiological characteristics of patients with CHC in Germany. During the period that the study was conducted, the approval of the combination drugs for the treatment of CHC was imminent.Between June and November 2014, 1471 CHC-patients not receiving anti-HCV treatment were included nationwide in 40 German centers specializing in viral hepatitis. The mean age was 52.4 years with 41.2 % of the patients being female. Presumed route of infection in male patients was most frequently drug use (46.2 %) and blood products in females (22.8 %). The route of infection was unknown in 28.2 % of male and 43.1 % of female patients. Compared to male patients, female patients were older (55.6 vs. 50.1 years) and longer diagnosed with HCV (18 vs. 15 years). First language of the patients was most frequently German (72.2 %), followed by Russian (14.2 %), and Polish (2.9 %). HCV genotype (GT) 1 was found in 73.8 % (1a 29.0 %, 1b 38.4 %), GT2 in 3.5 %, GT3 in 18.3 %, GT4 in 4.2 %, GT5 in 0.2 %, and GT6 in 0.3 %. Liver cirrhosis was diagnosed in 15.7 % of the patients (17.1 % male, 13.7 % female). 43.2 % of the patients had already received HCV treatment, most frequently dual therapy with pegIFN + RBV (75.8 %) or triple therapy with telaprevir or boceprevir (20.3 %). Compared to treatment-naïve patients, pretreated HCV patients were older (55.1 vs. 50.3 years) and more frequently had liver cirrhosis as clinical diagnosis (22.2 % vs. 10.8 %). Patients scheduled for HCV treatment within the next 3 months had higher rates of pre-treatment (49.4 % vs. 37.0 %), and liver cirrhosis (21.4 % vs. 10.0 %).Compared to epidemiological data of Hüppe et al. 1 from 2003 to 2006, Klass et al. 2 stated in 2012 in a comparable setting that the German CHC population were older and had more advanced liver disease. The current data seem to support this ongoing trend towards more difficult to treat patients with an urgent need for new treatment options.

[Cost of Illness of HIV Patients under Anteretroviral Therapy in Germany - Results of the 48-Week Interim Analysis of the Prospective Multicentre Observational Study 'CORSAR']. / Krankheitskosten von HIV-Patienten unter antiretroviraler Therapie in Deutschland - Ergebnisse einer 48-Wochen-Interimsanalyse im Rahmen der prospektiven multizentrischen Kohortenstudie "CORSAR".

BACKGROUND: With the introduction of highly active combined antiretroviral therapy (c-ART) mortality and morbidity of HIV patients declined substantially. Earlier studies reported that c-ART was able to save health-care costs due to a reduction of other direct medical costs, particularly for inpatient treatments and concomitant medication. To date, analyses of costs and health-related quality of life (HRQOL) of patients under c-ART are lacking in Germany. Hence, this study aims to estimate the current cost of illness and HRQOL of HIV-patients under c-ART in different treatment lines. METHODS: A multicenter, prospective observational study was carried out in 12 specialised German centres for infectious diseases: 8 private practices/outpatient centres and 4 specialised hospitals offering both inpatient and outpatient services. Demographic, clinical and medication data were derived from patient records. Resource utilisation, information on productivity, out of pocket costs and HRQOL (EQ-5D) were collected every 12 weeks via a patient questionnaire. All costs were calculated based on price information from publicly accessible databases. RESULTS: N=1,154 patients were included in the analysis. Mean direct disease-related costs of -patients under c-ART amounted to 22,563 Euro/year. Patients beyond the 3(rd) line of treatment -incurred considerably higher costs 24,654 Euro/year. In the 1(st) treatment line, c-ART accounted for 83.2% of the total direct costs, in the 2(nd)/3(rd) line for 80.8% and in >3(rd) line for 83.4%, respectively. Indirect costs due to impaired productivity were higher in the 2(nd)/3(rd) treatment line (2,843 Euro) compared to the 1(st) (1,604 Euro) and >3(rd) (1,752 Euro) treatment lines, respectively. The average HRQOL (EQ-5D) varied between 0.77 (self-assessment via visual analogue scale) and 0.91 (utility score based on the German time trade-off tariff). CONCLUSIONS: Over the last decade, cost of illness of HIV patients under c-ART decreased slightly with average costs per year still being substantial. Main cost driver of overall costs is c-ART. There have been, however, noticeable shifts between different cost domains.

Impact of GB virus C viraemia on clinical outcome in HIV-1-infected patients: a 20-year follow-up study.

OBJECTIVES: The impact of coexisting GB virus C (GBV-C) infection on the clinical course of HIV infection remains controversial. Early data from HIV-1 infected patients attending the Hannover Medical School in 2001 suggested prognostic benefit in GBV-C viraemic patients. The aim of this study was to evaluate patterns in long-term mortality and morbidity outcomes in this cohort. The impact of the introduction of antiretroviral therapy (ART) on the perceived benefits of GBV-C viraemia was subsequently investigated. METHODS: A retrospective follow-up analysis of data in this cohort was performed. GBV-C status (GBV-C RNA positive, antibodies against GBV-C envelope protein E2 or no evidence of GBV-C exposure) had been determined at enrolment, with several markers of HIV disease progression (such as viral load and CD4 cell count) being collated from 1993/1994, 2000 and 2012. These eras were chosen to reflect variations in treatment strategies within the cohort. In addition, mortality and HIV-related morbidity data were collated for all patients. RESULTS: Complete data were available for 156 of 197 patients (79%). In highly active antiretroviral therapy (HAART)-naïve patients, GBV-C RNA positivity conferred significant improvements in the course of HIV infection and mortality as well as lower rates of HIV-related diseases. E2 positivity alone conferred no significant advantage. With the advent of HAART, however, the benefits GBV-C RNA positivity disappeared. CONCLUSIONS: Although GBV-C coinfection appears to inherently improve morbidity and mortality in HIV-infected patients, modern HAART has eradicated these advantages. Evidence of synergy between GBV-C status and HAART response exists, with further studies examining the role of GBV-C in existing treatment de-escalation strategies being required.

Impaired CD4+ cell recovery during antiretroviral therapy in patients with HIV resistance mutations.

Antiretroviral therapy is limited by the development of human immunodeficiency virus (HIV) resistance mutations. Although resistance testing is recommended during therapy failure, little is known about the optimal time points for testing or its impact on treatment. In this study, we investigated HIV polymorphisms and mutations and assessed their influence on the outcome of highly active antiretroviral therapy (HAART). We focused on viral load and CD4+ cell counts as the most important parameters for therapy response. Resistance mutations were present in 19% of all patients prior to antiretroviral treatment. Mutations causing direct antiretroviral drug resistance were observed in 10%. Analyzing therapy response, we found a significant correlation between resistance mutations and impaired CD4+ cell recovery six months after the initiation of antiretroviral treatment. Lower CD4+ cell counts were also observed in a subgroup of patients infected with a virus presenting mutations that directly lowered drug susceptibility.

High prevalence of comorbidities and use of concomitant medication in treated people living with HIV in Germany - results of the BESIDE study.

Due to demographic changes in people living with HIV (PLHIV), physicians are challenged with age-related comorbidities and their management. In the absence of comprehensive data collection, the burden of comorbidities and co-medication in addition to antiretroviral therapy (ART) remains unclear for the German real-world setting. BESIDE was an observational, cross-sectional study evaluating the prevalence of comorbidities and use of co-medication in treated PLHIV. Regional distribution of study centers (n = 20), consecutive patient recruitment, and age-stratified sampling in alignment with national epidemiologic data aimed to ensure a representative sample (n = 453). The overall prevalence of comorbidities was 91.2%; 31.6% of patients had ≥4 comorbidities. The most common diagnoses were vitamin D deficiency (29.1%), depressive episode (27.8%), arterial hypertension (16.3%), and hypercholesterolemia (10.8%). 83.7% of patients were on co-medication; 21.2% taking ≥4 medications. The most common medications or supplements were vitamins (31.6%), anti-inflammatory agents (16.1%), renin-angiotensin system agents (12.1%), acid suppressants (11.7%), lipid modifying agents (10.8%); 1.3% of patients were on co-medication that should not be co-administered with ART, 41.5% on co-medication with potential for drug-drug interactions. The prevalence of comorbidities and use of co-medication among treated PLHIV in Germany is consistently high and increases across age groups, illustrating the complexity of HIV care involving appropriate ART selection.

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.

Progressive reduction of CMV-specific CD4+ T cells in HIV-1 infected individuals during antiretroviral therapy.

Visualization of antigen-specific T cells has become an important tool in studying immune responses. The aim of this study was to analyze CMV-specific CD4+ T cells in healthy and HIV-infected individuals. Peripheral blood mononuclear cells (PBMC) were examined for antigen-induced intracellular cytokine responses. We found significant numbers of CMV-specific CD4+ T cells detectable in most CMV-IgG+ HIV-1 infected individuals, whereas CMV-specific CD4+ T cells could not be demonstrated in CMV-IgG- patients. Median frequency of CMV-specific CD4+ T cells were lower in HIV-infected subjects who had been treated with highly active antiretroviral therapy (HAART) for more than 1 year than in untreated HIV-infected individuals. In patients under therapy for less than 1 year median CMV-specific CD4+ T cell responder frequency was higher than in subjects treated for more than 1 year but lower than in untreated subjects. HIV suppression with HAART might lead to a progressive reduction of CMV-specific CD4+ T cells indicating an efficient elimination of an opportunistic pathogen.

Immunologic and virologic studies in long-term nonprogressors with HIV-1 infection.

BACKGROUND: It is not known whether clinical latency in long-term nonprogressors (LTNP) with HIV-1 infection is due to a strong HIV-1 specific immune response of the host or to virologic factors. - METHODS: Peripheral blood mononuclear cells (PBMC) of 6 LTNP were analyzed for their phenotype, proliferation rates, natural killer (NK) cell activity, antibody dependent cellular cytotoxicity (ADCC), and CCR5 chemokine receptor genotype. Furthermore sequence analyses of the HIV-1 gene were performed. - RESULTS: Phenotypic analyses of lymphocyte subsets revealed increased CD8+ as well as HLA-DR+ expressing cells in LTNP and patients with progressive disease (PRO). Proliferation assays in LTNP and PRO showed a reduction of stimulation by polyclonal mitogens (PHA, ConA, PWM) of up to 60%. NK activity was within normal ranges in LTNP but reduced in PRO. 1 LTNP exhibited heterozygosity for CCR5-D32. A mutant HIV nef gene was not discovered by PCR in any of the LTNP. HIV-V3 loop PCR in 5 LTNP revealed the HIV-1B (NSI) subtype. In 2 patients further sequence analyses of the HIV-1 genome showed homozygous mutations in the Sp1 and NF-kB binding sites. CONCLUSION: The non-progression of HIV-1 infection in some LTNP seems to be due to single mutations in the viral genome resulting in a less replicative HIV-1 subtype or to a mutant chemokine receptor leading to a reduced HIV-1 entry into CD4+ cells. NK cell activity might be an additional contributing factor in controlling viremia.

[Lipodystrophy syndrome. Therapeutic progress is still pending]. / Lipodystrophie-Syndrom. Der therapeutische Durchbruch steht noch aus.

A common problem seen with the long-term use of highly active antiretroviral therapy (HAART) is the HIV-associated lipodystrophy syndrome. Clinical signs include a loss of peripheral subcutaneous fatty tissue, an increase in visceral or local fat, and altered glucose and lipid metabolism. The physical changes frequently impair quality of life, and the patient's adherence to treatment regimens. Metabolic changes may possibly represent cardiovascular risks with incalculable consequences over the long term. Although the lipodystrophy syndrome was first described in 1998. It still lacks a definition. So far, therapeutic strategies have remained ineffective or have had only limited success. Proposed treatments include general recommendations (diet, physical exercise, etc.), changing the antiretroviral therapy, and treatment with metabolically active medication.

[Immune reconstituted inflammatory syndrome. Pitfalls of antiretroviral therapy]. / Immunrekonstitutionelle inflammatorische Syndrome. Das Janusgesicht der antiretroviralen Therapie.

The pandemic HIV infection, the more frequent use of immunosuppressive treatment, and the improved long-term prognosis of immunocompromised patients due to better supporting therapies have resulted in an increase in the prevalence of immunodeficiencies. Highly active antiretroviral therapy (HAART) can improve immunocompetence in HIV patients, even when the immunodeficiency is far advanced. This has resulted in an impressive and lasting lowering of the morbidity and mortality associated with HIV infection. However, immune reconstitution may exacerbate subclinical opportunistic infections or autoimmune diseases, or result in an unexpected, paradoxical aggravation of intercurrent inflammatory diseases. The atypical inflammatory conditions have a number of synonymous names: immune restoration disease (IRD), immune reconstitution syndrome (IRS), or immune reconstitution inflammatory syndrome (IRIS). In the light of specific differential therapeutic consequences, it is important to distinguish the clinical presentation from that of corresponding opportunistic infections. However, diagnostic and therapeutic standards for IRIS have not yet been worked out. The present overview also points to possible diagnostic pitfalls, and makes suggestions for a possible classification of the condition and the therapeutic options.

[Immunologic control of HIV-1 infection. Fantasy or soon reality?]. / Immunologische Kontrolle der HIV-1-Infektion. Wunschtraum oder bald Realität?

The human immunodeficiency virus-1 (HIV-1) preferentially infects CD4+ cells, leading to their destruction. In contrast to other viral infections, the immune system is unable to keep the HIV infection under permanent control in most cases. This failure ultimatively results in immunodeficiency with occurrence of AIDS-defining diseases. In recent years, highly active antiretroviral therapy (HAART) has become available, and the number of AIDS cases and deaths have decreased dramatically. However, limitations of HAART become more apparent, demanding greater emphasis on search for alternative approaches. Stimulation and modulation of the immune response to HIV are new and promising strategies. A prerequisite, however, is the knowledge about immunologic defense mechanisms against HIV. In this article, the major factors of innate and acquired immune responses to HIV are described.

[Helper cells, viral load, genetic factors, co-infections. Prognostic factors in HIV-1 infection]. / Helferzellzahl, Viruslast, genetische Faktoren, Koinfektionen. Prognosefaktoren bei der HIV-1-Infektion.

The ideal time to initiate antiretroviral therapy in asymptomatic patients with chronic HIV infection remains to be defined. The most relevant laboratory parameter is the CD4 cell count. Therapy should be started before the CD4 cells drop below 200/microliter and the immune system becomes compromised. In contrast to past recommendations, viral load should not be used as a single laboratory parameter for initiation of antiretroviral therapy in asymptomatic untreated patients. The determination of genetic factors to assess the prognosis of HIV patients has not yet been incorporated into daily clinical practice. While co-infection with GBV-C is a prognostically favorable factor for the course of the HIV infection, replicative hepatitis C is associated with increased mortality.

A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial.

OBJECTIVE: The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen. DESIGN: Multicenter, randomized, open-label, phase III clinical trial. SUBJECTS: Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48. RESULTS: In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48. CONCLUSIONS: ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication.

Cytotoxic CD4 T cells in viral hepatitis.

CD4+ T cells are thought to contribute to antiviral immune responses by secretion of cytokines thereby providing help to CD8+ T and B cells. However, perforin-positive cytotoxic CD4+ T cells have been described in human immunodeficiency virus-positive patients suggesting a role not only of CD8+ but also of CD4+ T cells for killing virus-infected cells. We investigated 76 patients with viral hepatitis [15 hepatitis B virus (HBV), 22 HBV/hepatitis D virus and 17 hepatitis C virus (HCV)] for cytotoxic CD4+ T cells. The frequency of perforin-positive CD4+ T cells in viral hepatitis was highly variable ranging from < 1% to more than 25%. Perforin-positive CD4+ T cells displayed the phenotype of terminally differentiated effector cells (CD28-, CD27-). The highest frequencies of CD4+ cytotoxic T lymphocytes (CTLs) were found in patients with delta hepatitis (P = 0.04 vs HBV and HCV patients), and the presence of CD4+ CTLs was associated with elevated aspartate aminotransferase levels (P = 0.01) and decreased platelet counts (P = 0.03). Perforin-positive CD4+ T cells decreased in two individuals during spontaneous clearance of acute hepatitis C. Significant associations were found between the frequency of perforin-expressing CD4+ cells and age (P = 0.04), perforin-positive CD8+ cells (P < 0.001) and perforin-positive CD4-/CD8- lymphoid cells (P = 0.002). Differentiated CD27- effector CD4+ CTLs can be detected in patients with viral hepatitis. In particular in patients with more advanced liver disease, the accumulation of perforin-positive T cells with age could be one correlate for the more severe course of viral hepatitis in elderly individuals.

Pre-TCR signaling components trigger transcriptional activation of a rearranged TCR alpha gene locus and silencing of the pre-TCR alpha locus: implications for intrathymic differentiation.

A rearranged TCR alpha transgene remains transcriptionally inactive in rag-2-/- thymocytes but can be induced by CD3-mediated signals with concomitant maturation of double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. Reciprocally, the same signals silence pre-TCR alpha (pT alpha) expression. In normal C57BL/6 thymocytes, TCR alpha expression is not detected in DN thymocytes while, in contrast, TCR beta expression is initiated at the most immature c-kit+CD44+CD25- stage and continues throughout thymocyte development. pT alpha expression is first detected at the intermediate c-kit +/- CD44+CD25+ DN stage, increases during transition to the more mature c-kit-CD44-CD25+ stage and is lost at the DP stage. Thus, although TCR beta and pT alpha expression are independent, the pre-TCR complex mediates signals controlling the appearance of alpha beta TCR through selective regulation of TCR alpha and pT alpha genes.

A subset of CD16-natural killer cells without antibody-dependent cellular cytotoxicity function.

The low affinity IgG receptor, CD16 (Fc gamma RIII), is expressed on almost all peripheral blood natural killer (NK) cells. A small subset of CD3- CD16- CD56+ NK cells, representing less than 1% of peripheral blood lymphocytes, expands during in vivo IL-2 treatment. To analyze this CD16- NK cell subset in more detail, NK clones have been generated. One of them (TNK2) has been used to study the function of these cells in more detail. It is demonstrated that TNK2 exerts normal NK activity and displays large granular lymphocyte morphology. Since this clone lacks CD16 expression, antibody-dependent cellular cytotoxicity cannot be exerted. CD16 monoclonal antibodies fail to induce cytotoxic activity against NK-resistant target cells. These studies reveal that the lack of CD16 detection is not due to the modulation or the stage of activation of these NK cells. TNK2 is representative of this small subset of peripheral blood NK cells, expanded during IL-2 treatment, which does not express Fc gamma RIII and therefore cannot perform antibody-dependent cellular cytotoxicity.

T lymphocyte development in the absence of Fc epsilon receptor I gamma subunit: analysis of thymic-dependent and independent alpha beta and gamma delta pathways.

During fetal development, early thymocyte progenitors transiently express low affinity Fc receptors for IgG (Fc gamma R) of both Fc gamma RII and III isoforms. Only the Fc gamma RIII isoform requires association of an Fc gamma RIII (CD16) alpha subunit with an Fc epsilon RI gamma homodimer for surface expression. To address the role of Fc gamma R in ontogeny, we studied thymic development in Fc epsilon RI gamma-/- mice. We fine that day 14.5 CD4-CD8- double-negative (DN) fetal thymocytes of Fc epsilon RI gamma-/- mice express mRNA of both Fc gamma RIIb1 and Fc gamma RIII. Surface expression of Fc gamma RII/III is readily detected on these cells. It appears that Fc gamma RIIb1, whose surface expression is Fc epsilon RI gamma independent, replaces Fc gamma RIII during thymic development in these animals. Moreover, subsequent development into CD4+CD8+ double-positive and CD4+CD8- and CD4-CD8+ single-positive subsets appears normal even in the absence of Fc epsilon RI gamma. However, alterations were noted in adult animals among the DN alpha beta TCR+ thymocytes and peripheral splenic DN T cells as well as CD8 alpha alpha + intestinal intraepithelial lymphocytes (iIEL). In contrast to conventional T lymphocytes, which do not express either Fc gamma RIII or Fc epsilon RI gamma, DN alpha beta TCR+ thymocytes and extrathymically derived alpha beta TCR+ and gamma delta TCR+ CD8 alpha alpha + beta- iIEL express TCR which incorporate Fc epsilon RI gamma as one of their subunits. Consistent with this, the TCR levels of these cells are lower than the TCR levels on cells from wild-type C57BL/6 mice. Despite the reduction in the level of surface TCR, the development of these cells was unaltered by the absence of Fc epsilon RI gamma. Thus, we observed alterations in adult DN alpha beta TCR+ thymocytes, splenic DN alpha beta TCR+ and DN gamma delta TCR+ large granular lymphocytes (LGL), and alpha beta TCR+ and gamma delta TCR+ CD8 alpha alpha+beta- iIEL, but no detectable changes in their major fetal thymic developmental pathways. Cultivation of peripheral DN alpha beta TCR+ and DN gamma delta TCR+ cells from Fc epsilon RI gamma-/- mice with interleukin-2 generates LGL which mediate natural killer activity. Unlike LGL from wild-type C57BL/6 mice, LGL from Fc epsilon RI gamma-/- mice lack Fc gamma RIII expression and could not mediate antibody-dependent cellular cytotoxicity through Fc gamma RIII.