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Background and Aims: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis., Methods: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA., Results: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis., Conclusion: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease., (© 2023. The Author(s).)

Background: Improved treatment options of HIV have resulted in regular physical activities of many HIV-infected patients. However, data on effects of sports in HIV-patients are scarce., Methods: 21 HIV-infected persons were monitored prospectively while preparing for a marathon run. Multiple parameters with regard to immunology, quality of life and metabolism were measured at 4 time points (at baseline 1 year before the marathon run, 3 and 6 months after beginning of training, and immediately before marathon)., Results: 13 out of 21 participants completed the marathon (12 male, 1 female; median age 42 years [27-50]; CD4 = 620/μl [146-1268]; 11 were on ART since 3.5 years [1-7]). 8 participants ceased training early. All reasons for stopping (besides one pre-existing metatarsal fracture) were not regarded as training-related (e.g. time limitation n = 3; newly diagnosed anal cancer n = 1; personal reasons/unknown n = 3). We observed a significant increase in absolute CD4-T-cells (620/μl [146-1268] vs. 745 [207-1647]; p = 0.001) with simultaneous decrease of CD4-T-cell apoptosis (53% [47-64] vs. 32% [14-42]); p < 0.01). No effects on viral load independent of ART occurred. Systolic blood pressure and cholesterol improved significantly, although moderate and normal at baseline (cholesterol 185 mg/dl [98-250] vs. 167 [106-222], p = 0.02; RRsys 125 mmHg [100-145] vs. 120 [100-140], p = 0.01). Blood count, liver enzymes, creatinine and CK remained unchanged., Conclusions: The results of this pilot study indicated improved metabolic and immunologic parameters in HIV-infected patients undergoing moderate endurance training. Although training effects or ART cannot be ultimately separated as underlying mechanisms, we conclude that marathon training is safe for HIV-infected patients and potentially improves general health., Trial Registration: DRKS00011592 (retrospectively registered on February 9th 2017).

Introduction: We present two consensus definitions of advanced and late stage liver disease being used as epidemiological tools. These definitions can be applied to assess the morbidity caused by liver diseases in different health care systems. We focus is on hepatitis B and C virus infections, because effective and well tolerated treatments for both of these infections have greatly improved our ability to successfully treat and prevent advanced and late stage disease, especially if diagnosed early. A consensus definition of late presentation with viral hepatitis is important to create a homogenous, easy-to-use reference for public health authorities in Europe and elsewhere to better assess the clinical situation on a population basis., Methods: A working group including viral hepatitis experts from the European Association for the Study of the Liver, experts from the HIV in Europe Initiative, and relevant stakeholders including patient advocacy groups, health policy-makers, international health organisations and surveillance experts, met in 2014 and 2015 to develop a draft consensus definition of late presentation with viral hepatitis for medical care. This was refined through subsequent consultations among the group., Results: Two definitions were agreed upon. Presentation with advanced liver disease caused by chronic viral hepatitis for medical care is defined as a patient with chronic hepatitis B and C and significant fibrosis (≥ F3 assessed by either APRI score > 1.5, FIB-4 > 3.25, Fibrotest > 0.59 or alternatively transient elastography (FibroScan) > 9.5 kPa or liver biopsy ≥ METAVIR stage F3) with no previous antiviral treatment. Late stage liver disease caused by chronic viral hepatitis is clinically defined by the presence of decompensated cirrhosis (at least one symptom of the following: jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or hepatocellular carcinoma., Conclusion: These consensus definitions will help to improve epidemiological understanding of viral hepatitis and possibly other liver diseases, as well as testing policies and strategies.

The International AIDS Society convened the 3rd International HIV/Viral Hepatitis Co-Infection Meeting on 17 July 2016 as part of the pre-conference program preceding the 21st International AIDS Conference held in Durban, South Africa. The meeting brought together a diversity of scientific, technical and community interests to discuss opportunities and challenges for increased prevention, diagnosis and treatment of viral hepatitis in people living with HIV, particularly in low- and middle-income settings. The objectives of the meeting were:i.To review the latest therapeutic developments in viral hepatitis;ii.To identify challenges such as high cost of medications for hepatitis C virus (HCV) and risk of developing viral resistance, and successes, such as the provision of HCV treatment in community-based settings, movements to reduce drug costs and increasing access, in relation to scaling up diagnosis, screening, antiviral treatment and prevention of viral hepatitis;iii.To advance the agenda for elimination of viral hepatitis as a public health problem. Discussions centred around the six key interventions outlined by the World Health Organization Global Health Sector Strategy on Viral Hepatitis 2016-2021: hepatitis B virus (HBV) vaccination (including birth dose); safe injection practices plus safe blood; harm reduction among people who inject drugs; safer sex practices; hepatitis B treatment; and hepatitis C cure. This article summarizes the main issues and findings discussed during the pre-conference meeting. One of the recommendations from the meeting delegates is universal implementation of birth dose vaccination for HBV without further delay to prevent mother-to-child transmission of infection. There is also the need to implement screening and treatment of hepatitis among pregnant women. A call was made for concerted efforts to be put together by all stakeholders towards addressing some of the structural barriers, including criminalization of drug use, discrimination and stigma that people living with viral hepatitis face. Finally, the need for greater advocacy was highlighted to enable access to therapy of viral hepatitis at lower cost than currently prevails. Implementation of these resolutions will help in achieving the target of eliminating viral hepatitis as a public health threat.

Background: About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available., Methods: This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212., Results: The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies., Conclusion: This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable., Trial Registration: Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868.

Morbidity and mortality from co-morbid hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of hepatitis co-infection in HIV is now one of the most important clinical challenges. Therefore, the development of direct acting antivirals (DAAs) for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in co-infected individuals. Indeed, the availability of the first HCV protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients has changed the gold standard of treating hepatitis C allowing for substantially improved HCV cure rates under triple HCV-PI/pegylated interferon/ribavirin therapy. Moreover, numerous other new DAAs are currently being studied in co-infected patient populations, also exploring shorter treatment durations and interferon-free treatment approaches promising much easier and better tolerated treatment regimens in the near future. Nevertheless, numerous challenges remain, including choice of patients to treat, potential for drug-drug interactions and overlapping toxicities between HIV and HCV therapy. The dramatically improved rates of HCV cure under new triple therapy, however, warrant evaluation of these new treatment options for all co-infected patients.

Objective: HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rs12979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection., Methods: In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rs12979860 genotypes were analysed in 84 HCV/HIV co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rs12979860 C/T genotypes over two years., Results: 82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047)., Conclusion: Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.

Objectives: To estimate the cancer risk of HIV-infected patients in the HAART era with respect to a general reference population and to determine risk factors for malignancy., Methods: Long term (1996-2009) cancer incidence of the Bonn single centre HIV cohort was compared to the incidence of the reference population of Saarland using standardized incidence ratios (SIR). Poisson regression analysis was used to identify predictors of cancer risk., Results: 1,476 patients entered the cohort, enabling 8,772 person years of observation. 121 tumours in 114 patients, 7 in-situ and 114 invasive cancers, were identified. Malignancies associated with infectious agents such as Kaposi sarcoma (SIRs: male: 5,683; female: 277), non-Hodgkin lymphoma (SIRs male: 35; female: 18), anal cancer (SIRs male: 88; female: 115) as well a cervical carcinoma (SIR female: 4) and Hodgkin?s disease (SIR male: 39) and liver cancer (SIR male: 18) were substantially more frequent in HIV-infected patients than in the general population (p< 0.001, each), whereas all other types of cancer were not increased. Poisson regression identified HAART (incidence rate ratio IRR (95% CI): 0.28 (0.19-0.41), p<0.001), CD4 count (IRR per 100 cells/μl increase: 0.66 (0.57-0.76), p<0.001), hepatitis B (IRR: 2.15 (1.10-4.20), p = 0.046) and age (IRR per 10 year increase: 1.23 (1.03 - 1.46), p = 0.023) as independent predictors for the occurrence of any type of cancer., Conclusions: HAART and preserved CD4 cells preferentially reduce the risk of malignancies associated with oncogenic infections.

The success of first-line antiretroviral therapy can be challenged by the acquisition of primary drug resistance. Here we report a case where baseline genotypic resistance testing detected resistance conferring nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-associated mutations, but no primary mutations for protease inhibitor (PI). Subsequent PI-based HAART with boosted saquinavir led to virological treatment success with persistently undetectable viral load. After treatment simplification from saquinavir to an atazanavir based PI-therapy and no change in backbone therapy rapid virological breakthrough occurred. Retrospective analysis displayed preexisting gag cleavage site mutations which may have reduced the genetic barrier in a clinical relevant manner in combination with the already existing NRTI resistance mutations. Alternatively, this effect could be explained with a different antiviral potency for the respective PIs used.

Objective: This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated., Methods: Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2)., Results: 168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209)., Conclusions: Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.

The introduction of integrase inhibitors as a new drug class for treatment of HIV have added a very potent and extremely well tolerated new treatment option to the HIV-armentarium. Particularly in patients with previously developed drug resistance, the availability of new active drugs offers great hope. Moreover, the in general excellent safety profile offers numerous opportunities for all lines of therapy and special patient populations. Clearly more data is needed to further explore and define the future role of integrase inhibitors in HIV-care.

Chronic HCV co-infection is present in up to one third of HIV-positive patients in Europe. In recent years, apart from the traditional transmission route of intravenous drug abuse, outbreaks of sexually transmitted acute HCV infections, mainly among HIV-positive men who have sex with men, have contributed to the overall disease burden. - Because the natural course of HCV infection is substantially accelerated in HIV-co-infection, end-stage liver disease has become the most frequent cause of non-AIDS related death in this population. Therefore every HIV/HCV co-infected patient should be evaluated for possible anti-HCV therapy with the goal of reaching a sustained virological response and thus cure of hepatitis C infection. The standard of care for the treatment of chronic HCV infection in HIV-infected remains a pegylated interferon in combination with weight-adapted ribavirin. - HAART should not be withheld from HCV co-infected patients due to concerns of drug related hepatotoxicity and in patients with reduced CD4-cell counts HAART should be started first. Under pegylated interferon and ribavirin combination therapy drug to drug interactions and cumulated toxicity between nucleoside analogues and anti-HCV therapy may be observed and concomitant didanosine use is contraindicated and zidovudine and stavudine should be avoided if possible. - The development of new drugs for the treatment of chronic hepatitis C represents a promising perspective also for HIV positive patients. However, these substances will probably reach clinical routine for HIV patients later than HCV monoinfected patients. Therefore at present waiting for new drugs is not an alternative to a modern pegylated interferon/ribavirin therapy.

Background: In HIV patients, disorders in glucose metabolism seem to be side effects of highly active antiretroviral therapy (HAART) which may be favoured by obesity, abdominal fat accumulation and familial disposition for diabetes mellitus (DM). The aim of our study was to identify patients at high risk for abnormalities in glucose metabolism taking into account HAART, familial disposition for DM and anthropometric parameters., Methods: Plasma glucose, insulin, c-peptide and insulin resistance (homeostasis model assessment, HOMA) were determined in 44 HIV patients [16 without HAART, 19 with protease inhibitors (PI), 9 without PI (non-PI)] and in 11 healthy subjects. Glucose tolerance was determined by standard procedures. Body mass index (BMI), triceps skin fold thickness and waist circumference were measured and the waist-to-hip-ratio was calculated. Familial disposition for DM was assessed by questionnaire., Results: Impaired fasting glucose was observed in 28% of HAART-treated patients (21% with PI, 7% non-PI), in 13% of HAART-naive but none in healthy controls. 58% of PI, 44% of non-PI, 38% of HAART-naive and none of healthy controls had a HOMA-index > 2.5 which indicates insulin resistance. HAART-treated patients had significantly higher fasting glucose levels (PI: 97 +/- 11 mg/dL, p = 0.048; non-PI: 109 +/- 58 mg/dL, p = 0.009) compared to healthy controls (72 +/- 8 mg/dL). HOMA-Index was higher in PI treated patients (3.74 +/- 3.08) than in HIV negative controls (0.95 +/- 0.28, p = 0.018). The duration of HAART (p = 0.045), overweight and familial disposition for DM (p = 0.017) significantly affected fasting glucose among PI users. Waist circumference affected c-peptide (p = 0.046) concentration in these patients., Conclusion: HIV patients on long-term PI therapy with overweight and familial disposition for DM are at high risk to develop abnormalities of glucose metabolism. Thus, measurements of HOMA-Index, BMI and waist circumference should be routinely done especially in PI medicated patients.

In the context of emerging resistance to antiretroviral agents in HIV medicine, the development of new drugs classes with a novel mechanism of action remains essential. The CCR5 co-receptor antagonists inhibit fusion of HIV with the host cell by blocking the interaction between the gp-120 viral glycoprotein and the CCR5 chemokine receptor. So far, four CCR5 antagonists have entered clinical evaluation, of which three are currently still in different stages of clinical assessment. In this review we compare the clinical efficacy in phase I and II as well as the long-term tolerability, pharmacokinetics and interactions of these new antiretroviral drugs entering HIV practice. Being the first CCR5 antagonist to be investigated in clinical trials, aplaviroc showed initial potent antiviral activity. However, after the occurrence of severe hepatotoxicity in several patients, its development had to be stopped in October 2005. The second CCR5 antagonist, maraviroc, has displayed promising results in phase I, II and III studies, showing a significantly greater decline in HIV RNA and CD4 cell increase compared to placebo, with no clinically relevant differences in safety profile and tolerability. The expanded access program for maraviroc was opened in June 2007 in several European countries. The FDA approved the use of maraviroc for antiretroviral therapy of HIV on the 7th of august, 2007. Finally, the third CCR5 antagonist vicriviroc also showed long-term potent viral activity in phase II studies as long as it was boosted with low-dose ritonavir, with no significant differences in grade 3 and grade 4 adverse effects compared to placebo. The phase II clinical trial amongst ART experienced individuals who received Ritonavir-boosted vicriviroc 10-15 mg qd was unblinded early because of the unexpected occurrence of malignant lymphoma and adenoma. However, no further malignancies occurred in the extended follow-up evaluation of this drug until today. Vicriviroc is currently entering phase III evaluation. Pharmacokinetics of maraviroc and vicriviroc may be influenced by coadministration of CYP3A4-inhibitors and -inducers, since both substances are metabolised primarily by the CYP3A4 system. This requires dose adjustments when combined with for instance protease inhibitors (with the exception of tipranavir/r), efavirenz, ketoconazole or rifampin. Concerns have risen about possible class-specific long-term adverse effects of CCR5 antagonists, particularly with regard to hepatotoxicity or malignancy. The pooled data from phase II and III however, so far show no new or added toxicity risk for maraviroc or vicriviroc compared to the respective placebo arms of the trials. Extended follow-up of the vicriviroc trials showed no further case of malignancy, reassuring the overall good tolerability profile of the drug so far.

Objective: To compare two reduced dose indinavir (IDV) + ritonavir (RTV) combinations guided by therapeutic drug monitoring (TDM) in treatment-naive HIV1-infected patients., Methods: HIV1-infected treatment naive patients were prospectively randomized to treatment with IDV 600 mg or 400 mg BID each in combination with RTV 100 mg BID. Boosted IDV was combined with 2 NRTI, and patients were followed for 48 weeks. IDV-trough levels and initially also peak levels (C2h) were performed to allow dose modification of IDV following a specified protocol., Results: 14 patients were randomized (age 38 +/- 10.4 years; mean +/- SD; 3 female, 11 male). 8 were treated with 600 mg (group 1), 6 with 400 mg IDV BID (group 2). Efficacy of treatment was good: CD4-cell count increased from 198/microl (14-523; median, range) to 371/microl (214-927) after 48 weeks (p<0.01). All but one patient with adherence problems achieved a viral load below the limit of detection. At the beginning two patients had plasma levels below 0.1 mg/l, most likely due to adherence problems. However, in the course of the observation period all patients had adequate plasma levels. 3 patients in group 1 could further reduce their IDV dose to 400 mg BID due to high plasma (peak and trough) levels. Rate of discontinuation was high (1: 4 pat., 2: 2 pat.), but only one discontinuation was possibly associated with IDV (alopecia; group 2). There were no significant changes in laboratory parameters (bilirubin, triglycerides, cholesterol) or suspicious urine results. Incidence and severity of adverse events was lower than in previous studies., Conclusion: Despite the low number of patients it seems reasonable to state, that boosted IDV may be used in significantly reduced dose. Efficacy seemed not to be altered, whereas tolerability was improved.

Background: The immunological and clinical benefits of structured treatment interruptions (STIs) during primary HIV-1 infection remain largely unclear., Patients and Methods: Eight patients identified during primary HIV-1 infection were immediately treated with HAART and underwent subsequent STIs after reaching complete viral suppression of HIV-RNA in peripheral plasma. HAART was re-initiated if either HIV-1 RNA >5000 copies/ml, CD4-cells <200 cells/microl or symptomatic HIV-1 disease was observed., Results: After treatment discontinuation, four of eight patients were able to persistently control HIV-1 viremia below 5000 copies/ml until the last time point of follow-up (median 3 years). CD4-cell counts were within the interquartile range of untreated individuals compared to historical reference data from the MACS cohort. In the remaining study subjects persistent virological control was not reached despite repeated STIs. Moreover, compared to the MACS cohort repetitive virological failures during STIs appeared to induce an accelerated decline of CD4-cells., Conclusion: Spontaneous HIV-1 control after treated primary HIV-1 infection was possible in four out of eight individuals, however, if STIs after treated primary infection ameliorate the overall HIV-1 disease progression remains unknown. In the absence of viral control, repetitive viral exposure during STIs might be associated with accelerated decline of CD4-cell counts.

One third of all European and American HIV-patients are coinfected with hepatitis C. HIV accelerates hepatitis C virus liver disease especially when HIV-associated immune deficiency progresses. Indeed, liver cirrhosis rate is five times higher in HIV/HCV-coinfected patients than in HCV-monoinfected patients. With the introduction of pegylated interferon and ribavirin combination therapy sustained virological response rates of up to 40 % could be obtained in HIV/HCV-coinfected individuals. Moreover, cohort analyses could demonstrate that with the use of highly active antiretroviral therapy (HAART) an improved course of hepatitis C and a reduction in liver disease-associated mortality can be achieved. Under consideration of the increased rate of hepatotoxicity due to the presently available antiretroviral treatment regimens in HIV/HCV coinfected patients, however, the development of treatment strategies and guidelines for management of hepatitis coinfection in HIV remains of great clinical significance.

Background: Resistance against antiretroviral drugs in previously untreated HIV-infected persons is of growing relevance. The aim of the study is to determine the prevalence of resistance-associated mutations in this patient group., Methods: In a prospective multicenter-study in Nordrhein-Westfalen, Germany, genotypic resistance testing was performed in untreated HIV-positive patients before administration of first-line highly active antiretroviral therapy (HAART)., Results: Between January 2001 and August 2002 resistance testing was performed in 184 therapy-naive individuals. HAART was initiated in 143 patients, who were included into the study. 70.6 % were males, mean age was 39 years, mean duration of diagnosis of HIV-infection was 1.5 years. The proportion of cases at CDC stage C was 45.4%, mean CD4-cell count was 199 /ml, mean viral load was 206,855 copies/ml. Resistance-associated mutations were detected in 20 patients (14.0%). 10.5% showed mutations indicating nucleoside reverse transcriptase inhibitor- (NRTI) resistance (M41L, E44D, D67N, T69D/N, L74V, V118I, M184V, L210W, K219Q), 2.8% showed non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (K103N, V108I, Y181C), and 2.1% showed protease-inhibitor- (PI) associated resistance (V82A, L90M), respectively. Multi-class-resistance was found in 2.1%, mutations indicating revertant variants of resistant strains were found in 4.2% (T215C/E/L/S). 86.7% of the isolates showed secondary mutations in the protease gene. No significant difference in the distribution of the parameters age, sex, duration of HIV diagnosis, CDC stage, CD4-cell count, and viral load, between groups with and without resistance was identified., Conclusion: The prevalence of primary resistant virus strains can be estimated at 14% in chronically infected HAART-naive HIV-patients in Germany. The majority of these cases show NRTI-associated resistance. Resistance against NNRTI or PI as well as multi-class-resistance is of low prevalence. No risk factor of predictive value can be identified for the diagnosis of resistance mutations in the individual. In conclusion, routine genotypic resistance testing in untreated HIV-positive patients should be performed before administration of first-line HAART in this region.

Low dose-ritonavir boosted protease inhibitors are increasingly being used for the first-line antiretroviral treatment, though their virological efficacy has just poorly been compared to alternative antiretroviral therapies. Here, we retrospectively investigated the virological responses of 316 protease inhibitor-naive HIV patients receiving highly active antiretroviral treatment based on a single (n = 256) or a ritonavir-boosted protease inhibitor (n = 60), both in the background of two nucleoside analogues. - By intent-to-treat analysis, a complete initial virological response was achieved in 71.8% of all patients in the single protease inhibitor group (indinavir: 76%, ritonavir: 67.5%, nelfinavir: 70.6%) and in 88.3% (p = 0.008) of patients treated with a boosted protease inhibitor (saquinavir/r: 71.4%, indinavir/r: 92.1%, lopinavir/r: 86.6%). The multivariate risk analysis identified boosted PI treatment as an independent predictor of a complete virological response (OR = 2.8, p=0.02). Viral rebound after an initial complete virological response was observed in 28% and 17% (p = 0.06) of patients receiving a single or a dual protease inhibitor, respectively. The rate of durable viral suppression over 12 months was 44.5% and 56.7% (p = 0.09) in the respective study cohorts. Ritonavir-boosted protease inhibitors therefore seem to induce a superior virological response rate and a higher degree of sustained virological suppression.

Background: It is unclear whether enteric dysfunction and protein losses contribute to hypoproteinemia, which heralds poor survival in HIV infection., Methods: We investigated alpha-1-antitrypsin-clearance (AAT-CL), D-xylose resorption and total gut transition time in 14 HIV+ patients with hypoproteinemia (serum protein < 6 g/dl, albumin < 3 g/dl, median CD4-cell count 58/microl; (group I)), in 10 asymptomatic HIV+ patients (median CD4-cell count 290/microl, (group II)) and in 15 healthy volunteers (group III)., Results: AAT-CL in group I (16.5 (2.9 278.2) ml/d; median (range)) was higher than in groups II (9.5 (1.7 23.1) ml/d) and III (10.6 (0.8 19.5) ml/d; p = 0.0114). Likewise, D-xylose recovery was on average threefold lower in group I than in groups II (p = 0.0009) and III ( p < 0.0001), whereas total gut transition time was significantly shorter in both HIV-infected groups (group I: 49.8 h (23.5-72.7), p=0.0431; group II: 32.6 h (23-54.6), p=0.0104) than in the healthy controls (group III 61.6 h (39.1-87.7))., Conclusions: Thus, impaired intestinal resorption and enteral protein losses may contribute to hypoproteinemia in advanced HIV infection, whereas accelerated intestinal motility may be present already in asymptomatic stages of HIV infection.

Despite of changes in the use of antiviral or chemotherapy regimens, the median survival of patients with AIDS-related lymphoma has not significantly changed until recently. However, partly due to prolonged survival with the introduction of highly active antiretroviral therapy (HAART) prognosis in AIDS patients with lymphoma seems to improve. Recently, several new treatment options have been explored in patients with lymphoma. It is hoped that novel strategies will lead to a survival benefit in these patients. In this review, we discuss the current strategies for the treatment of AIDS-related lymphoma.

A therapeutic dilemma arises once HIV-infected patients develop a break-through of HIV-replication under potent antiretroviral therapy. Therefore, we studied whether patients (n = 12) who failed double nucleoside reverse transcriptase (NRTI) plus indinavir or ritonavir triple therapy can be rescued when therapy is switched to double protease inhibitor (PI) treatment (nelfinavir and hard gel saquinavir) and stavudine. With the rescue regimen HIV-RNA levels initially dropped from 148,571 +/- 45,258 copies/ml to 9,310 +/- 6, 965 copies/ml at week 4 (p = 0.0117). However, virus load subsequently increased to almost baseline levels (131,230 +/- 37,743 copies/ml) at week 12. Likewise, CD4-cell counts could only be stabilized initially (baseline 267 +/- 51; week 4 296 +/- 65 cells/microl), but gradually declined thereafter (216 +/- 34 cells/microl week 12). Before therapy was switched, the viral protease gene from 5 analyzed patients showed 3-5 amino acid substitutions. Moreover, 4 of these patients had one amino acid substitution associated with resistance to nelfinavir. Our data suggest that HIV-infected patients resistant to indinavir or ritonavir and double NRTI combination therapy respond to double PI nelfinavir/saquinavir and D4T rescue therapy only initially but have no sustained benefit.

Background: Pneumocystis carinii pneumonia (PCP) is one of the most common AIDS defining diagnoses., Methods: In a prospective observational trial all cases of Pneumocystis carinii pneumonia (PCP) were evaluated. Patients with and without PCP-prophylaxis were compared for symptoms, efficacy, side effects and mortality at week 4 and 26., Results: 293 patients developed a PCP episode. Patients with no prophylaxis had a significant lower CD4 cell count and a more severe clinical status at time of diagnosis. This was pronounced in the group with first positive HIV test at time of diagnosis. There was no difference in the rate of successful treatment between both groups. At week four a tendency to a better survival in the group with prophylaxis was observed, however this changed to a trend to a better survival at week 26 for the group without prophylaxis., Conclusion: Even in the era of highly active antiretroviral treatment many patients present with PCP. Nearly 60% of patients presented without antiretroviral treatment or PCP-prophylaxis. Nearly 25% of all patients had their first HIV-test at time of PCP diagnosis.

Kaposi's sarcoma (KS) is the most frequent neoplastic complication observed in HIV-infected patients. Cutaneous KS is the most common manifestation but visceral and lymph node involvement may occur. HIV-infection does not only lead to a decrease of certain cell types (CD4 T-lymphocytes), but also modifies the function of non-infected cells such as B-lymphocytes and NK-cells by upregulating cytokine release of IL-1, IL-6, GM-CSF, IFN-gamma and TNF-alpha. These multifunctional mediators show both autocrine and paracrine proliferative effects on normal endothelial cells and AIDS-related KS-cells. Using ELISA-, RIA- and IRMA-techniques we analysed the influence of seven cytokines (IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-alpha, IFN-beta, IFN-gamma) and the soluble IL-2 receptor (sIL-2R) on the growth of eight different KS-derived cell lines compared with eight fibroblast cell lines, established from skin biopsies of HIV-positive individuals. Furthermore, we analysed the dose-dependent effect of the above mentioned cytokines on KS-derived cells in vitro. The KS-derived cell culture medium demonstrated significantly higher concentrations than the fibroblast cell lines in view of the following cytokines: sIL-2R, IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-gamma (p<0.05). The most pronounced differences between KS-cells and fibroblasts were observed for IL-1beta and IFN-gamma. The antiproliferative effect of IFN-beta and IFN-gamma began at a concentration of 20 and 50 IU/ml, respectively, whereas for IFN-alpha an antiproliferative effect was observed at a concentration of 100 U/ml. Furthermore we observed a proliferative effect in low concentrations (2-5 IU/ml) of IFN-gamma in our in vitro model

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same parenteral, sexual and vertical routes of transmission (McNair et al. 1992). This common epidemiology explains the high frequency of combined infections by hepatotropic viruses in HIV-infected patients. The aim of the present review is to clarify some important issues dealing with the reciprocal interactions between HIV and hepatitis C virus infections. The main topics include epidemiology, virological markers of HIV-infection, histopathology, natural course and treatment of hepatitis C in HIV-infected individuals.

In addition to quantification of viral load the graded cytopathogenicity of the human immunodeficiency virus may provide prognostic information for the course of HIV infection. However, the prognostic value of graded cytopathogenicity in addition to the CD4 count has not been evaluated in a large longitudinal study. Therefore a total of 216 HIV-seropositive hemophiliacs have been followed up from 1985 to 1998 (mean follow-up 70.4 +/- SD 26 months, median 72, range: 12 to 120 months). In vitro virulence was determined according to cytopathic effects on freshly isolated PBMC of healthy donors and graded from A (strongest cytopathogenic effect) to D (no cytopathic isolate effect). Survival was analyzed among patients with different virus isolates by Kaplan-Meier statistics (log rank) and factors independently associated with decreased survival were analyzed by Cox hazard regression analysis. - A virus isolate A was found in 22 (10.2%) patients, a virus isolate B was found in 21 (9.3%) patients, a virus isolate C was found in 9 (4.2%) and a virus isolate D was found in 10 (4.2%) patients. Mean survival times were 48 months (95% Confidence Interval (CI) = 36 - 60) in patients with isolate A, 72 months (CI = 36 - 108) with isolate B, 84 months (CI = 48-120) with isolate C, 72 months (60 - 96) with isolate D and 96 months (CI = 96 - 108) in patients with a negative virus culture (p < 0.001). Cox regression analysis indicated significant associations with outcome for young age (p <0.001), positive virus culture (p < 0.0001) and CD4 count (p < 0.0001) as independent predictors of survival. The presence of an isolate A revealed the strongest odds ratio (6.3, 95% CI 2.9-13.2). Our data indicate that the presence of a virus isolate A represents a strong risk factor for mortality in the course of HIV infection. Besides quantification of viral load and CD4 count, the graded cytopathogenicity may provide additional information for early and aggressive antiretroviral treatment, since the mean survival in patients with cytopathogenic virus isolates is reduced significantly.