Multicentric performance analysis of HCV quantification assays and its potential relevance for HCV treatment.

An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1-47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1-21.0 % and CTM v2: 15.0-32.3 %; CVs at 25 IU/ml: RealTime 17.6-34.9 % and CTM v2 28.2-54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.

Variation analysis of six HCV viral load assays using low viremic HCV samples in the range of the clinical decision points for HCV protease inhibitors.

In the range of clinical decision points for response-guided therapy of HCV, there is still insufficient data concerning the conformity of quantification results obtained by different assays and their correlation with the HPS/CTM v2 assay which was used for initial clinical studies. In a head-to-head comparison, assay accuracy and detection rates of six quantitative assays [artus HCV QS-RGQ, COBAS Ampliprep/COBAS TaqMan HCV v1/v2, High Pure System/COBAS TaqMan (HPS), RealTime HCV, and Versant HCV1.0] were assessed by measuring WHO and PEI standards at dilution steps near clinical decision points. Detection rates and mean differences between assays were evaluated by analyzing twenty clinical samples at 10, 100, and 1,000 IU/mL. Ten replicates from specimens with different HCV genotypes were used to analyze pan-genotypic intra-assay variation. At ≤ 25 IU/mL, RealTime demonstrated the highest detection rates. With 0.1 log difference when testing clinical samples, results obtained from the Versant and RealTime assays matched best with results from HPS. Mean difference analysis across all assay results revealed wide differences between 0.01 and 0.75 log IU/mL. RealTime showed the lowest intra-assay variation across genotypes 1-4 (25, 100, 1,000 IU/mL). There are substantial analytical differences between viral load assays clinicians should be aware of. These variations may have impact on clinical decisions for patients on HCV triple therapy and may argue for assay-specific decision points equivalent to reference values established in studies using HPS. A comparison of quantification is recommended prior to a switch of assays during ongoing therapy.

The rainbow cohort: 96 week follow-up of saquinavir-containing regimens in previously antiretroviral therapy (ART)-naive and pre-treated but protease inhibitor (PI)-naive HIV-infected patients.

OBJECTIVE: We have previously reported data from the German cohort of the multinational observational prospective RAINBOW survey which assessed the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r)-containing regimens over 48 weeks in routine clinical practice. This analysis presents data from antiretroviral (ART)-naive and pretreated but protease inhibitor (PI)-naive patients treated in a long-term one line (96 weeks) follow-up of the initial study. METHODS: All ART- and PI-naive patients from the initial RAINBOW cohort who had recorded data to one line 96 weeks of treatment were eligible for inclusion in the current analysis. Efficacy assessments included the proportion of patients with HIV-1 RNA <50 and <400 copies/mL and changes in CD4 cell count from baseline to week 96. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 96. For evaluation of efficacy, intent-to-treat analysis, in which missing values were recorded as failure (ITT), and last-observation-carried-forward (LOCF) analysis were used. Metabolic parameters were assessed using LOCF analysis. RESULTS: The analysis included 175 ART-naive and 109 pretreated but PI-naive patients. After 96 weeks, a similar proportion of patients in the ART-naive and in the pretreated but PI-naive group had HIV-1 RNA levels <400 copies/mL (68.0% and 70.6% [ITT], respectively; 96.6% and 90.8% [LOCF], respectively). The proportion of patients with HIV RNA <50 copies/mL was higher in the ART-naive group compared with the pretreated but PI-naive group (61.1% and 56.9% [ITT], respectively; 84.0% and 75.2% [LOCF], respectively). Median change in CD4 cell count from baseline to week 96 was +263 cells/mm3 (IQR 170; 384. LOCF; p<0.0001) in the ART-naive group, and one line +181 cells/mm3 (IQR 60; 309. LOCF; p<0.0001) in the pretreated but PI-naive group. Treatment was well tolerated, with only 2.5% of patients withdrawing from treatment due to side effects. There were no clinically relevant changes in liver enzyme levels. Overall total cholesterol, triglyceride, and low- and high-density lipoprotein levels increased to week 96, although levels remained within normal ranges in the majority of ART-naive and pretreated patients. CONCLUSIONS: This follow-up analysis confirms the long term efficacy and tolerability of SQV/r in ART-naive and pretreated but PI- naive patients in the real-life clinical setting.

Safety and efficacy after switch to a saquinavir-containing antiretroviral regimen in protease inhibitor pretreated HIV-positive patients.

OBJECTIVE: the RAINBOW survey is a multinational observational study assessing the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r), using the 500 mg film-coated SQV formulation, in routine clinical practice. This analysis presents data from the German subgroup of protease inhibitor (PI)-pretreated, but SQV-naive patients. METHODS: multicenter, prospective, open-label, 48 week cohort study. Efficacy assessments included the proportion of patients with HIV-1 RNA <50 and <400 copies/mL and changes in CD4 cell count from baseline to week 48. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 48. RESULTS: a total of 426 patients were included in the analysis. The proportion of patients with HIV RNA levels <50 copies/mL at week 48 was 60.3 % (compared with 31.7% at switch to SQV/r) (intent-to-treat, last observation carried forward analysis). After 48 weeks, median CD4 count increased by +61 cells/mm3 from baseline (p<0.01) and 60.3% of patients achieved HIV-1 RNA <50 copies/mL. Median changes in fasting triglyceride levels (stratified according to baseline level) at week 48 were: +14 mg/dL (IQR -8; 57) for patients with baseline triglyceride <200 mg/dL; -50 mg/dL (IQR -139; 0) for baseline triglyceride 200-750 mg/dL, and -656 mg/dL (IQR -1024; 0) for baseline triglyceride >750 mg/dL (p<0.01 for all). Median changes in fasting total cholesterol (TC) levels (stratified according to baseline) were +16 mg/dL (IQR -3; 43) for patients with baseline TC <200 mg/dL (p<0.01), -3 mg/dL (IQR -25; 25) for baseline TC 200-300 mg/dL (p = 0.4), and -47 mg/dL (IQR -87; -4) for baseline TC >300 mg/dL (p<0.01). No significant changes in liver enzymes or bilirubin were observed. SQV treatment was discontinued in 22% of patients, 6% due to side effects. CONCLUSIONS: these data confirm the efficacy and tolerability of SQV/r in PI-experienced, SQV-naive patients treated in a real-life clinical setting. Of particular relevance are the improvements in triglycerides and TC levels observed in patients with baseline grade III-IV elevations.

Safety and efficacy of a saquinavir-containing antiretroviral regimen in previously ART-naïve or pretreated but protease inhibitor-naïve HIV-positive patients.

BACKGROUND: The RAINBOW survey is a multinational observational study assessing the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r), using the 500-mg film-coated SQV formulation, in routine clinical practice. This analysis presents data from the German subgroup of antiretroviral therapy (ART)-naïve and pretreated but protease inhibitor (PI)-naïve patients. METHODS: This was a multicenter, prospective, open-label, 48-week observational cohort study. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 48. Efficacy assessments included changes in the proportion of patients with HIV-1 RNA <50 and <400 copies/ml, and changes in CD4 cell count from baseline to week 48. RESULTS: The analysis included 275 ART-naïve and 179 pretreated but PI-naïve patients. The proportion of ART-naïve patients achieving <50 copies/ml by 48 weeks was 53.1% by intent-to-treat (ITT) analysis and 67.3% using last observation carried forward (LOCF) analysis. In pretreated but PI-naïve patients, the proportions achieving <50 copies/ml by 48 weeks were 53.1% (ITT) and 70.4% (LOCF). The median increase in CD4 count at week 48 was +174 cells/mm3 (interquartile range [IQR] 86, 265) in the ART-naïve group and +100 cells/mm3 (IQR 0, 209) in the pretreated but PI-naïve group (p < 0.01 for both; LOCF). Drug-related adverse events were reported in 7.6% of ART-naïve and 2.8% of pretreated but PI-naïve patients. Treatment with SQV/r was stopped in 21.5% of ART-naïve and 17.9% of pretreated but PI-naïve patients (due to side effects in 3.3% and 2.8%, respectively). There were no clinically relevant changes in liver enzyme levels. Overall, the total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein levels increased to week 48, although the levels remained within normal ranges in the majority of patients. CONCLUSIONS: The results of this observational cohort study of treatment with the 500-mg tablet formulation of SQV are consistent with high efficacy and tolerability results seen in controlled studies of SQV/r. This analysis confirms that SQV/r is effective and well tolerated in ART-naïve and pretreated but PI-naïve patients in 'real-world' clinical settings.

[Pre-exposure prophylaxis in HIV--a vision or soon a reality?]. / Präexpositionsprophylaxe bei HIV - Vision oder bald Realität?

Condom use is propagated as the most efficient measure to prevent HIV-transmission. For several reasons, condoms are NOT ALWAYS used or misapplied during sexual intercourse. Therefore, alternative preventive measures through intake of antiretroviral drugs before sexual intercourse with a (presumably) HIV-positive person are being considered, so called Pre-Exposure Prophylaxis (PrEP). In animal models the efficacy of HIV-PrEP was shown for Tenofovir alone or in combination with Emtricitabine). Several clinical studies are currently being conducted in different HIV-risk groups on various continents. First results from these studies are anticipated for the year 2010. In case of proven efficacy for HIV-PrEP, our health system would face a large interdisciplinary challenge. It would be a difficult task to define the appropriate recipients. Measures would have to be taken to limit possible misuse of antiretroviral drugs, due to the negative consequences with development of resistance, adverse events and illegal trading. It is already evident that HIV-PrEP will not provide absolute protection, nor will it replace other preventive strategies. However, if used cautiously, HIV-PrEP might be established as a useful supplement in the prevention of HIV. Paramount questions from the fields of epidemiology, behavioural science, logistics, health politics and ethics should be answered in advance.

Treatment during primary HIV infection does not lower viral set point but improves CD4 lymphocytes in an observational cohort.

OBJECTIVE: To investigate if early treatment of primary HIV-1 infection (PHI) reduces viral set point and/or increases CD4 lymphocytes. METHODS: Analysis of two prospective multi-centre PHI cohorts. HIV-1 RNA and CD4 lymphocytes in patients with transient treatment were compared to those in untreated patients. Time to CD4 lymphocyte decrease below 350/ microl after treatment stop or seroconversion was calculated using Kaplan-Meier and Cox-PH-regression analyses. RESULTS: 156 cases of PHI were included, of which 100 had received transient HAART (median treatment time 9.5 months) and 56 remained untreated. Median viral load (563000 cop/ml vs 240000 cop/ml; p<0.001) and median CD4 lymphocyte (449/ microl vs. 613/ microl; p<0.01) differed significantly between treated and untreated patients. Median viral load was 38056 copies/ml in treated patients (12 months after treatment stop) and 52880 copies/ml in untreated patients (12 months after seroconversion; ns). Median CD4 lymphocyte change was +60/ microl vs. -86/ microl (p = 0.01). Median time until CD4 lymphocytes decreased to <350/ microl (including all patients with CD4 lymphocytes <500/ microl during seroconversion) was 20.7 months in treated patients after treatment stop and 8.3 months in untreated patents after seroconversion (p<0.01). Cox-PH analyses adjusting for baseline VL, CD4 lymphocytes, stage of early infection and symptoms confirmed these differences. CONCLUSIONS: Treatment during PHI did not lower viral set point. However, patients treated during seroconversion had an increase in CD4 lymphocytes, whereas untreated patients experienced a decrease in CD4 lymphocytes. Time until reaching CD4 lymphocytes <350/ microl was significantly shorter in untreated than in treated patients including patients with CD4 lymphocytes <500/ microl during seroconversion.

Differences of nine drug resistance interpretation systems in predicting short-term therapy outcomes of treatment-experienced HIV-1 infected patients: a retrospective observational cohort study.

OBJECTIVE: Drug resistance interpretation systems are used to select the optimal antiretroviral therapy in HIV-infected patients. It is unclear how the systems perform in predicting therapy success and failure and in how far the interpretations are affected by insufficient drug levels. METHODS: The accuracy of nine different interpretation systems in predicting therapy outcomes was evaluated using virological, immunological, pharmacological, and clinical data of 130 patients treated at 13 outpatient centers. Individual susceptibility scores of the interpretation systems were converted into active drug scores (ADS) and correlated with therapy success and failure, defined as viral load reduction of equal to or more (n=66) and less than 1 log10 copies/ml (n=64) at three months after drug resistance testing. RESULTS: Three interpretation systems considered the respective therapies as more active compared to the other interpretation systems (p<0.01). These systems predicted therapy success better than the other systems, while the others performed better in predicting therapy failure. Thus, the overall rate of correctly predicted treatment outcomes was comparable between the different systems (73.1-80.0 %). Univariate and multivariate regression analysis revealed significant correlations between the ADS of all interpretation systems and virological therapy outcomes (p<0.0001). In contrast, only three interpretation systems were significantly correlated with immunological therapy outcomes in univariate and just one in multivariate models (p<0.05). Among 128 determinations of drug levels in 64 patient samples, 19.4 % revealed no detectable drug levels. The consideration of insufficient drug levels significantly improved the prediction accuracy of all interpretation systems (p<0.005). CONCLUSION: Differences between interpretation systems in predicting therapy failures and success need to be considered for future consensus algorithms. The prediction accuracy of interpretation systems can be improved by consideration of plasma drug levels.

Consensus recommendation from a group of German experts for the use of enfuvirtide in heavily pretreated HIV patients.

BACKGROUND: The EU approval of enfuvirtide (Fuzeon) was granted in May 2003 on the basis of the 48-week data from the TORO 1 and TORO 2 studies. Enfuvirtide is licensed for use in pretreated HIV patients experienced with three classes of drugs who exhibited treatment failure or who have shown intolerance to previous antiretroviral treatment regimens. Recent studies with the new protease inhibitors tipranavir and darunavir (RESIST and POWER studies) showed that a high proportion of heavily pretreated HIV patients achieve a viral load reduction to below the limit of detection when treated with enfuvirtide plus one of these new ritonavir-boosted protease inhibitors and an optimised background treatment regimen. The International AIDS Society (IAS-USA Panel) has recently updated its treatment guidelines in view of these new data and recommends the use of an antiretroviral treatment regimen containing at least two active drugs, one of which that has a new mechanism of action, for HIV patients who have been heavily pretreated. A new treatment goal has also emerged for heavily pretreated patients with advanced HIV disease: reduction of the viral load to below the detection limit of 50 copies/ml. The IAS concluded that the likelihood of achieving this treatment goal is higher when enfuvirtide is selected as one of the two active drugs. OBJECTIVE: A panel of German experts convened to discuss the currently available data and to incorporate them into the updated German consensus recommendations for the use of enfuvirtide when switching treatment in heavily pretreated HIV patients. METHODS: The consensus recommendations are based on published data from controlled, randomised clinical studies and on the expert opinions of the discussants. RESULTS AND CONCLUSIONS: The consensus recommendations were developed to provide practice-relevant standardised recommendations for selecting suitable candidates for enfuvirtide therapy and for their management. Aspects including predictive prognostic factors, disease stage, selection of the optimised background regimen, early indicators of a response to enfuvirtide, as well as accompanying educational measures treatment were considered. New protease inhibitors or other remaining active drugs should be used together with enfuvirtide in heavily pretreated patients in order to enable at least two active drugs to be included in such a salvage regimen.

[Epidemiology of primary drug resistance in chronically HIV-infected patients in Nordrhein-Westfalen, Germany, 2001-2005]. / Epidemiologie der primären Medikamentenresistenz bei chronisch HIV-Infizierten in Nordrhein-Westfalen 2001-2005.

BACKGROUND AND OBJECTIVE: Primary HIV drug resistance, characterized by mutant virus strains in untreated HIV-infected persons, is of significant epidemiological significance. Primary resistance is associated with reduced efficacy of antiretroviral therapy (ART). We determined the prevalence of primary resistance in Nordrhein-Westfalen, Germany. PATIENTS AND METHODS: Genotypic resistance testing was performed in a prospective multicenter study in chronically infected previously untreated HIV-positive patients before administration of first-line ART. Mutations were classified according to the International AIDS Society USA guidelines and the geno2pheno interpretation tool. RESULTS: Between January 2001 and December 2005, resistance testing was performed in 831 patients. 77.4% were males, the mean age was 39 years (SD: 10.5). The mean duration of diagnosis of HIV infection was 1.6 years (SD: 3.4). 32.4% of patients were at CDC stage C, mean CD4 cell count was 236 /microl (SD: 205), and mean viral load was 206,855 copies/ml (SD: 450,610). In total, resistance-associated mutations were detected in 75 patients (9.0%; 95%CI, 7.1-11.0). After inclusion of mutations E44D and V118I, resistance was identified in 99 patients (11.9%; 95%CI, 9.7-14.1). 5.4% had mutations indicating nucleoside reverse transcriptase inhibitor (NRTI) resistance (95%CI, 3.9-7.0), 3.0% had non-NRTI resistance (95%CI, 1.8-4.2), and 2.4% had protease inhibitor resistance (95%CI, 1.4-3.4), respectively. Two-class resistance was detected in 0.8% (95%CI, 0.2-1.5), three-class resistance in 0.5% (95%CI, 0.01-1.0). Mutations indicating revertant variants of resistant strains were found in 3.9% (95%CI, 2.5-5.2). Considering the variables age, gender, time since diagnosis, CDC stage, CD4 cell count, viral load, HIV subtype, ethnic origin, and HIV transmission group, no significant risk factor for the presence of primary resistance was demonstrated in univariate and mutlivariate analyses. CONCLUSION: The prevalence of primary resistant virus strains was about 10% in chronically infected ART-naive HIV-patients in the largest federal state of Germany. The majority of these patients had NRTI-associated resistance. No risk factor for the presence of primary drug resistance was identified. Because of the high prevalence and the possible impact on efficacy of drug treatment, routine genotypic resistance testing should be performed in untreated HIV-positive patients before administration of first-line ART.

[High incidence of non-AIDS-defined cancers among HIV-infected patients in Germany. A 3-year nationwide review]. / Hohe Inzidenz nicht AIDS-definierender Neoplasien bei HIV-infizierten Patienten in Deutschland. Ein 3-jähriger bundesweiter Uberblick.

OBJECTIVE: It was the main aim of this study to obtain data on the epidemiology of AIDS- and not AIDS-defined malignancies in HIV-positive persons, the results to provide an epidemiological overview and to be the basis for further research initiatives. Additionally it sought to gain an impression of the realities of treatment of patients with HIV-associated malignant tumors in Germany. PATIENTS AND METHODS: Over a period of 3 years (from the beginning of 2000 to the end of 2002) data were retrospectively collected on the incidence of malignant tumors in HIV-positive patients. A questionnaire was sent to all members of the German Working Party of Physicians in Private Practice Treating HIV-Infected Patients, all members of the Association of Haematologists and Oncologists in Private Practice, and all out-patient HIV clinics in Germany. The questionnaires were sent to a total of 949 practices/clinics. The data were collected on all AIDS- and not-AIDS-defined haematological malignancies and all AIDS- and not-AIDS-defined solid malignant tumors in HIV-positive patients, as well as on time of diagnosis of the malignancy, tumor stage, tumor treatment and response to treatment. RESULTS: 380 data sets on 376 patients of 50 practices/clinics were included in the analysis (four patients had two malignant tumors). 180 malignant neoplasms (47%) were AIDS-defined: 89 Kaposi's sarcomas, 82 aggressive B-cell lymphomas and 9 invasive cervical carcinomas. The aggressive B-cell lymphomas consisted of 19 cases of Burkitt's lymphoma, 8 of Castleman's disease and 12 of primary cerebral malignant lymphoma. Of the 200 (52.6%) not-AIDS-defined malignant tumors 133 were 133 solid tumors, 40 of them anal carcinoma (20% of all not-AIDS-defined malignancies) and 67 haematological malignancies, 22 of these Hodgkin's lymphoma (11.0% of all not-AIDS-defined malignancies). The incidence of anal carcinoma is estimated to be 34 (95% CI 24-470) per 100 000 patient-years, that of Hodgkin's lymphoma 19 (95% CI 12-28) per 100 000 patient-years. CONCLUSIONS: This study indicates that over a period of 3 years there was a very high incidence of not-AIDS-defined malignancies. Of special note is the high incidence of anal carcinoma and Hodgkin's lymphoma, compared with their incidence among the entire German population.

Long-term efficacy and safety of ritonavir/indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy.

OBJECTIVE: To determine the long-term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs). DESIGN AND METHODS: In an open-label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients (n = 93) with a high median baseline HIV-1 RNA level of 210 000 copies/mL (range 17 000-2 943 000) and a median CD4 cell count of 195 copies/microL (range 4-656 copies/microL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4-week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures. RESULTS: HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks. CONCLUSIONS: Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load.

Risk factors for the HIV-associated lipodystrophy syndrome in a closed cohort of patients after 3 years of antiretroviral treatment.

OBJECTIVE: To identify prevalence and risk factors associated with the HIV-associated lipodystrophy syndrome (HIVLD) after 3 years of antiretroviral therapy, to investigate the diagnostic value of anthropometric measures and to assess the impact of HIVLD on quality of life. DESIGN AND METHODS: A prospective, cross-sectional, multicentre, observational, cohort study was performed in 27 German teaching hospitals, nonacademic hospitals and private practices. A total of 221 HIV-positive patients commencing antiretroviral therapy between July and September 1996 were studied. The main outcome measure was lipodystrophy, defined as otherwise unexplained truncal fat accumulation and/or fat loss in face or extremities. The analysis consisted of multiple logistic regression models, receiver operating characteristics (ROC) curves for anthropometric measures and visual analogue scales for quality of life. RESULTS: The prevalence of HIVLD after 3 years was 34%. The following variables were independently associated with HIV-LS: stavudine use > 12 months [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-3.9], CD4 count nadir < 200 cells/microL (OR 2.2, CI 1.1-4.6), hypertriglyceridaemia (OR 2.3, CI 1.3-4.2) and nonnucleoside reverse transcriptase inhibitor (NNRTI) intake > 12 months (OR 0.2, CI 0.04-0.87). No cut-off point was found for anthropometric indices with a sensitivity and specificity of > or = 0.8. The mean visual analogue ratings for impaired quality of life, on a scale of 0-10, were: 5.2 (self-esteem), 2.9 (social contacts), 4.2 (sexuality) and 3.5 (daily activities). CONCLUSIONS: These findings suggest a multifactorial aetiology for HIVLD. Stavudine use and a CD4 count below 200 cells/microL may be associated with an increased risk for the development of HIVLD. In contrast, NNRTI treatment may be associated with a reduced risk. Anthropometric indices were found to be insufficient as a diagnostic tool. Quality of life was severely affected by HIVLD.

Treatment of HIV-associated wasting with recombinant human growth hormone: monitoring of body composition changes by bioelectrical impedance analysis (BIA).

INTRODUCTION: Recombinant human growth hormone (r-hGH) has demonstrated efficacy in treating HIV-associated wasting (HAW), however, HAW has become less prominent since the introduction of highly active antiretroviral therapy (HAART). Recent studies suggest that patients receiving HAART may still experience HAW. We investigated the nature of HAW and the efficacy of r-hGH in these patients. METHODS: We treated 27 HIV-positive patients receiving HAART who had either recent loss of >5% body weight or weight <90% lower limit of normal with 12 weeks of r-hGH (6 mg given either daily or every other day). Body composition changes were monitored using bioelectrical impedance analysis (BIA). RESULTS were assessed for all patients and for a subgroup meeting more stringent definitions of wasting (BIA phase angle a<5.6 degrees, n = 14). - RESULTS: Significant increases from baseline in weight and body cell mass (BCM) occurred in the full population (medians: 2.0 kg weight, 1.5 kg BCM). Patients with phase angle alpha<5.6 degrees also showed increases in weight and BCM (medians: 2.5 kg weight, 1.95 kg BCM), and 10 of 14 showed improvements in the ratio of extracellular mass (ECM) to BCM. At follow-up there was a trend towards loss of the weight and BCM gained on treatment. Treatment was well tolerated. CONCLUSION: Patients receiving HAART continue to experience wasting, and respond well to r-hGH therapy as monitored by BIA.

Switch to efavirenz in a protease inhibitor-containing regimen.

PURPOSE: This report evaluated the efficacy and safety of switching from a protease inhibitor (PI)-containing HIV treatment regimen to an efavirenz (EFV)-containing regimen. METHOD: We retrospectively analyzed data from 64 patients, with a plasma viral load (VL) less than 50 copies/mL and CD4+ counts >200 cells/mL at baseline, who had been taking a regimen consisting of a PI and two nucleoside reverse transcriptase inhibitors (NRTIs; d4T/3TC [n = 45]; AZT/3TC [n = 19]) for a median of 27.5 months (range, 6-41 months) and who chose to substitute EFV for the PIs in the regimens. Statistical analyses were performed by Wilcoxon test. Fat atrophy was evaluated by physician's assessment and patients' subjective self-estimation with the criteria of well being and body state. RESULTS: 57 patients completed 36 weeks on the EFV regimen; 4 patients changed therapy but continued EFV, 2 moved to another area, and 1 discontinued EFV. During the first weeks of therapy, 56.3% of patients suffered from moderate nervous system symptoms. The plasma VL of 63 patients remained at <50 copies/mL at final analysis. Compared with time of switching to EFV, analysis at 36 weeks showed no statistically significant change from 626+/-283 to 643+/-296 cells/mL in mean absolute CD4+ cells and a statistically significant increase from 26.8+/-9.6% to 28.0+/-9.1% in relative CD4+ cells. There was a statistically significant reduction in relative CD8+CD38+ from 62.2+/-16.3% at time of switching to EFV to 55.1+/-15.0% at week 36. At baseline, 27 patients suffered from lipodystrophy, including fat atrophy and fat accumulation. After 36 weeks, nine patients showed intensified fat atrophy. In contrast, five patients improved their state concerning fat redistribution and 13 patients showed no alterations. CONCLUSION: The switch to a non-PI-containing regimen with EFV offers a good drug alternative for patients with suppressed viral load, problems of adherence, and/or adverse events due to PIs but not for patients suffering from lipoatrophy caused by nucleoside reverse transcriptase inhibitors. The intention of such a switch aims at the avoidance of fatal mutations in HIV.

Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. German Ritonavir/Indinavir Study Group.

OBJECTIVE: To evaluate the virological efficacy and safety of quadruple therapy with two nucleoside analogues and ritonavir (400 mg twice daily) plus indinavir (400 mg twice daily) combination in antiretroviral therapy-naive patients. DESIGN AND METHODS: An open-label, uncontrolled multicentre trial. Antiretroviral therapy-naive patients (n = 90) with high median baseline HIV RNA levels of 220,000 copies/ml (range, 36,000-2,943,000 copies/ml) and median CD4 cell count of 189 x 10(6)/l (range, 4-656 x 10(6)/l) were started on a twice daily regimen of either zidovudine/lamivudine (49%), stavudine/lamivudine (38%) or stavudine/didanosine (13%) plus ritonavir 400 mg twice daily and indinavir 400 mg twice daily combination therapy. CD4 cell counts and HIV RNA were determined at weeks 0, 4, 8, 12, 16, 20, and 24. Statistical analysis was performed on treatment as well as intent-to-treat, where missing values were accounted for as failure. RESULTS: In the intent-to-treat analysis at week 24, the proportion of patients with HIV RNA of < 500 copies/ml, and < 80 copies/ml was 86.7% and 71.1%, respectively. In the on-treatment analysis at week 24, 80.0% of patients had undetectable viral load in the ultrasensitive assay (< 80 copies/ml; n = 80). The quadruple therapy was well tolerated except for mild diarrhoea, initial nausea and increased triglyceride levels. Treatment was stopped in seven (7.7%) patients because of adverse events and three (3.3%) were lost to follow-up. CONCLUSIONS: Our preliminary data suggest that the protease inhibitor combination ritonavir/indinavir plus double nucleoside therapy appears to be effective and safe in short-term treatment (up to 24 weeks).

[Evaluation of HIV-related continuing education programs for established physicians]. / Evaluation von HIV-bezogenen Fortbildungsveranstaltungen für niedergelassene Arzte.

Neither the HIV-specialists, the cooperating specialists, nor the family physicians are required to have special qualifications to treat HIV-infected patients. CME-courses don't consider the very different fields of interest of the participants or that the transfer of knowledge is quite important to ensure the quality of medical care. Questionnaires regarding HIV related topics were distributed in nine HIV-CME courses (9/93-5/94) of the DAGNA (German association of panel physicians treating HIV-infected patients) in cooperation with the society of physicians of Germany and the association of public health insurances. The satisfaction of the participants, the topics with regard to their relevance for the task group, the importance for the daily routine, and didactic manners were investigated. Feed-back: 41%. Although the general impression of most participants was "quite satisfying" (87%) there was some critic regarding special aspects. The rating of the courses depended on the level of qualification. Specialists in internal medicine rated the relevance for their medical practice, the topics and the possibility of contribution more positive than other specialists or general practitioners (GP). In general, there was a great difference regarding the rating of the courses among the participants because of their individual level of qualification and knowledge. In order to take the different levels of qualification and demands for topics into account there must be graduated courses: specialists, experts, elementary and beginner courses. The basic courses should contain not only the lectures but also the possibility of an active contribution of the participants. Adequate guidelines have to be developed.