High prevalence of recreational and illicit drug use in German people living with HIV with a potential for drug-drug interactions with antiretroviral therapy.

Recreational drug use is higher in people living with HIV (PLHIV) than in the general population in Europe. This use increases the risk for drug-drug interactions (DDIs) and adverse events. We assessed the prevalence and clinical consequences of substance abuse among PLHIV. BESIDE was a cross-sectional, multi-center study in 2016/18, evaluating comorbidities, polypharmacy and recreational/illicit drug use in PLHIV on antiretroviral therapy (ART) in Germany. Legal and illicit drug use was recorded using two anonymous patient questionnaires one year apart (Q1 and Q2). The BESIDE study population consisted of 453 PLHIV (22% female, median age 46 years). Recreational drug use was reported by the majority (Q1: ever used 73%, within previous 6 months 56%): nitrite inhalants ("poppers"), cannabis and PDE-5 inhibitors were common across all age groups; ecstasy, (meth-)amphetamine and gamma-hydroxybutyrate/gamma-butyrolactone were predominantly reported by younger PLHIV. Based on Q2, two-thirds of PLHIV (67%) had been informed about potential risks of drug abuse by their doctors, whereas one-third (33%) had talked to their doctors on their own initiative with only 7% considering drug use in combination with ART a problem. Strikingly, 44% and 42% had undergone medical treatment or had been hospitalized due to drug use. These data emphasize the high clinical relevance of recreational drug use in PLHIV and the need for treating physicians to pro-actively communicate the potential risks.

PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis.

OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.

[Complications of knee arthroscopy]. / Komplikationen arthroskopischer Eingriffe am Kniegelenk.

BACKGROUND: Today, knee arthroscopy is one of the standard interventions performed by an orthopaedist and usually has a low potential for complications. PURPOSE: The surgeon should still be aware of possible problems, and be able to control and explain them to the patient in detail before surgery. MATERIALS AND METHODS: The possible relevant peri-, intra- and postoperative complications of knee arthroscopy are discussed. RESULTS: Evaluation of the patient's medical history and comorbidities is crucial to successful treatment, in addition to a correct diagnosis and indications with the assistance of appropriate imaging procedures. Nervous and vascular injuries, malplacement of arthroscopy portals, thrombosis, air embolism, material breakage and a possible compartment syndrome constitute the peri-and intraoperative complications. Postoperatively, the most frequent negative events are haemarthrosis, thrombosis, embolism and infection, and the appearance of synovial fistulas. In the case of a joint infection, consistent and immediate diagnosis and therapy are vital for joint preservation. Late complications after arthroscopic interventions include Ahlback's disease, arthrofibrosis and complex regional pain syndrome (CRPS). DISCUSSION: Nowadays, the systematic education of arthroscopic surgeons using simulators, models, and cadavers, in addition to shadowing experienced arthroscopists, is required to offer patients the best therapeutic options.

Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study.

OBJECTIVES: The incidence of HIV-related non-Hodgkin lymphoma (NHL) but not that of Hodgkin lymphoma (HL) has been declining. The aim of the study was to compare HIV-infected patients with NHL and HL with respect to antiretroviral therapy (ART) exposure at the time of lymphoma diagnosis. METHODS: HIV-infected patients with NHL and HL included in a prospective multicentre cohort study since January 2005 were compared with respect to ART exposure and viral load at the time of lymphoma diagnosis. RESULTS: As of 31 December 2012, data for 329 patients with NHL and 86 patients with HL from 31 participating centres were available. Patients with HL were more likely to be on ART (73.5% vs. 39.1%, respectively; P < 0.001) and more frequently had a viral load below the detection limit (57.3% vs. 27.9%, respectively; P < 0.001) than patients with NHL. The proportion of patients with HL was 8.0% in ART-naïve patients, 34.8% in patients with current HIV RNA < 50 HIV-1 RNA copies/mL, and 50.0% in patients with both HIV RNA < 50 copies/mL for > 12 months and a CD4 cell count of > 200 cells/µL. Of note, 45.8% of all patients with NHL were not currently on ART and had a CD4 count of < 350 cells/µL. CONCLUSIONS: This prospective cohort study shows that HL was as common as NHL in patients with sustained viral suppression and limited immune deficiency. In contrast to NHL, the majority of patients with HL were on effective ART, suggesting that ART provides insufficient protection from developing HL. The high proportion of untreated patients with NHL suggests missed opportunities for earlier initiation of ART.

Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066).

INTRODUCTION: There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions. MATERIALS AND METHODS: The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies). CONCLUSION: The review presented here is a translation of a short version of the German-Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.

Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial.

OBJECTIVE: This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1-infected adults. METHODS: ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. RESULTS: Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. CONCLUSION: Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients.

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.

Effective treatment of patients in a deep salvage situation with "non-active HAART": experiences with the expert advice system RADATA.

BACKGROUND: Clinical studies suggest expert recommendations as a possibility to optimize highly active antiretroviral therapy (HAART) in patients with multi-drug resistant virus strains. An online system (RADATA) has been developed to provide expert advice for the drug therapy of HIV-infected patients. OBJECTIVE: To evaluate the efficacy of expert-advice-guided HAART switches in patients with triple-class failure. METHODS: Virological and immunological outcome of patients having undergone at least three prior ART regimens, including nucleoside inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) use, were analyzed. Changes in HIV-RNA and CD4-cell count were evaluated every 3 months. RESULTS: 183 patients with a median baseline viral load of 3.90 log copies/ml (1.88-6.54 log) and a CD4-cell count of 298 c/ll (5-910 c/ll) were eligible for analysis. The patients had a median of seven prior ART regimens and a treatment duration of 83 months. A median of three (range 0-8) NRTI-, two (0-7) thymidine-associated (TA), one (0-4) NNRTI-, and three (0-13) PI-associated resistance mutations were present at baseline. Despite available resistance analyses and expert recommendations, 66% (n = 119) of the patients started a new ART regimen without any active drugs according to the resistance analysis. The HIV-RNA declined by a median of 0.61 log and 0.92 log after 12 and 24 months, respectively, while the CD4-cell count rose by a median of +9 c/microl and +25 c/microl during this period. No significant differences related to number of prior regimens or number of active substances used could be found. CONCLUSION: Despite extensive pre-treatment and multiple resistances against prescribed HAART, our patients demonstrated a decline in viral load and a stable CD4-cell count over the observation period. We conclude that the activity of antiretroviral regimens is not exclusively explained by the current algorithms used for estimating antiretroviral drug activity.

Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses.

Toxoplasmic encephalitis (TE) is the most important opportunistic infection of the central nervous system in patients infected with human immunodeficiency virus (HIV)-1. This study evaluated the effect of highly active anti-retroviral therapy (HAART) and Toxoplasma gondii-specific immune responses on the occurrence of TE. The clinical characteristics of all patients diagnosed with TE in two centres since 1990 (n = 140) were analysed. Patients were grouped according to the date of diagnosis (period 1, 1990-1993; period 2, 1994-1996; period 3, 1997 onwards). Immune responses to T. gondii were evaluated in a subgroup (n = 12) by interferon (IFN)-gamma-specific ELISPOT tests. There were marked differences in the estimated Kaplan-Meier overall survival (OS), with a 1-year OS (5-year OS) of 41% (7%) in period 1, 56% (29%) in period 2, and 90% (78%) in period 3 (p <0.0001). In period 3, TE was found to be the first AIDS-defining illness more frequently than in earlier periods (74% vs. 38%, p 0.0002). Persistent neurological deficits caused by TE were present in 37% of the patients. Patients with an acute episode of TE or a TE relapse had significantly lower responses in the T. gondii-specific ELISPOT than patients who discontinued maintenance therapy and were relapse-free (p 0.0044). Survival of HIV patients with TE has improved markedly since the introduction of HAART, but persistent neurological deficits are often present in surviving patients. While preventive therapy remains essential, evaluation of T. gondii-specific immune responses may be an important step in improving estimates of the individual risk of TE and TE relapses.

Radata - implementation of resistance analysis and expert advice for optimized HAART switches in general practice of HIV-infected individuals via a compiling internet presence.

BACKGROUND: HIV-infected patients fail viral load suppression, because resistance against antiretroviral drugs arises or for other reasons. HIV-resistance analyses can aid to achieve effective HAART regimen. Furthermore, clinical benefits from genotyping in study settings are significantly higher for treating physicians, who can include external advice from HIV-experts into HAART switch. OBJECTIVE: To develop a compiling internet presence to provide expert advice for HAART switch in general practice of HIV-infected individuals after therapy failure. - DESIGN: A multifactorial (genotyping, drug monitoring, adherence, expert advice) interdisciplinary internet service (www.radata.de) with an associated server hosted database. PATIENTS AND METHODS: HIV-infected patients after failure to HAART are eligible for registration to the Radata project. Genotyping is performed according to protocols specific for each participating institution. Therapeutic drug monitoring (NNRTIs, PIs) follows setting for drug level detection by mass spectrometry. An adherence self-report is completed by every patient. Clinical documentation is provided by the treating Primary Care Physician. Clinical expert advice for implementation into HAART switch in daily clinical practice for treating physicians is provided by HIV-experts according to data obtained. Clinical and laboratory follow-up visits are scheduled firstly 4 weeks after HAART switch and three monthly afterwards, over a period of one year. RESULTS: Technical resources and a compiling internet presence for generation of resistance analysis based expert advice were developed. Initially, 7 HIV-treatment centres, 7 laboratories and 17 HIV advisors contribute to Radata database project. 15 patients were enrolled during test period. 30 expert advices were generated during the test phase. Expert advice was provided in 6 weeks median for implementation into HAART switch. 13 out of 15 expert advices were implemented into HAART switch by treating Primary Care Physicians. CONCLUSIONS: Radata is a novel database concept with features to generate expert advice for implementation into HAART switch of HIV-infected subjects. A test period has shown, that the concept is technically approved to fit all requirements with regard to data collection, evaluation and to generate expert advice for therapy switch in daily clinical practice.

HHV-8 DNA in blood and the development of HIV-associated Kaposi's sarcoma in the era of HAART--a prospective evaluation.

OBJECTIVE: To explore the significance of HHV-8 viremia in HIV-positive individuals for the risk of developing Kaposi's sarcoma (KS) in the era of highly active antiretroviral therapy. METHODS: 237 HIV-positive patients were included in this prospective evaluation and followed over an average duration of 34 months. HHV-8 DNA in peripheral blood mononuclear cells (PBMCs) and CD4-lymphocytes were determined. In addition AIDS-defining conditions and antiretroviral therapy were documented of all participating subjects. RESULTS: HHV-8 DNA was detectable in PBMCs of 12.6% out of all individuals. 53.3% of these patients initially complained about KS, although 9.2% of patients without HHV-8 DNA in PBMCs were found on KS as well. Furthermore, four patients in total were observed with newly developed KS during follow up visits. None of these patients were noted with detectable HHV-8 DNA at their initial evaluation. CONCLUSIONS: Prevalence of HHV-8 DNA in PBMCs of subjects in this investigation was quite similar to former investigations. However, new diagnosed KS occurred less frequently than demonstrated in previous studies. All of those observed patients with new KS manifestations were negative for HHV-8 DNA in PBMCs at study entry. This observation differs from earlier studies which have postulated the detection of HHV-8 DNA in PBMCs as a predictive value for development of KS. Due to results as presented, a single HHV-8 DNA test in blood has no predictive value in support of predictability of KS development. With respect toto costs and to a less complicated performance antibody assays should be preferred.

Remission of cutaneous Mycobacterium haemophilum infection as a result of antiretroviral therapy in a Human Immunodeficiency Virus--infected patient.

We describe the first Mycobacterium haemophilum infection that occurred in a patient with human immunodeficiency virus in Germany and report 7 newly diagnosed cases of M. haemophilum infection. In the former case, a local M. haemophilum skin infection resolved as a result of successful antiretroviral therapy only; however, that clinical outcome may not be possible for more invasive forms of the disease.

Monitoring of endogenous interferon-alpha and human herpesvirus 8 in HIV-infected patients with Kaposi's sarcoma.

The incidence of AIDS-associated Kaposi's sarcoma has declined since the mid-nineties due to the availability of potent antiretroviral therapy including protease inhibitors. However, Kaposi's sarcoma is still the most common neoplasia in HIV-infected patients. In the pathogenesis of the HIV-associated as well as other forms of this disease an infectious agent seems to play a role, namely the human herpesvirus 8. Even before the discovery of the HIV virus, high levels of an unusual acid-labile form of endogenous interferon alpha were found in patients with AIDS-associated KS. The administration of recombinant interferon alpha evolved as standard therapy for Kaposi's sarcoma in HIV-infected patients with a moderate immunodeficiency in addition to antiretroviral therapy. This investigation monitored the levels of HHV 8 and endogenous interferon in 4 patients with and without Kaposi's sarcoma during the course of HIV-disease. The results of our experiments lead us to two hypotheses: First of all, the pre-therapeutic level of endogenous interferon may be a predictor of the response to an interferon-alpha therapy for HIV-associated Kaposi's sarcoma. Secondly, the determination of HHV 8 DNA in blood of HIV-positive patients may allow conclusions about the risk for the development of Kaposi's sarcoma. However these hypotheses should be tested by monitoring the levels of endogenous interferon and HHV 8 DNA in clinical studies of a greater number of HIV-infected patients.

Remission of a cutaneous Mycosis fungoides after topical 5-ALA sensitisation and photodynamic therapy in a patient with advanced HIV-infection.

BACKGROUND: Treatment of Mycosis fungoides (MF) in HIV-infected patients is controversially discoursed. Photodynamic therapy (PDT) after topical sensitization with 5-aminolevulinic acid (5-ALA) is a new and effective modality for treatment of skin malignancies. OBJECTIVE: In this report we describe, what is, to our knowledge, the first case of a patient with MF through advanced HIV-infection, successfully experiencing topical 5-ALA sensitization and PDT. METHODS: 5-ALA ointment was applied to plaques and held in occlusion for 4 hours. PDT was applied using the PDT 1200 irradiation source (Waldmann Medizintechnik System) with 180 J/cm superset 2. RESULTS: Complete remission of MF was achieved, after two completed cycles of photodynamic therapy. CONCLUSION: MF lesions in the presended case showed a high response to 5-ALA sensitization and PDT. This modality appeared to be very effective in treatment of MF in a HIV-infected patient and could be a valuable treatment option for cutaneous T-cell lymphoma in HIV-infected patients.

Resistance analyses in HIV infected patients with a history of multiple antiretroviral treatment regimens.

OBJECTIVE: To assess HIV-1 isolate based resistance profiles from extensively pretreated patients and effects of a resistance guided switch of antiretroviral therapy. METHODS: In a prospective study phenotypic and genotypic resistance analyses were performed on HIV infected individuals with failure of the current therapy and history of at least three antiretroviral regimens. Antiretroviral therapy was changed according to the results. Viral load and CD4 lymphocyte counts were measured at baseline, after 10 (SD 2), and 24 (2) weeks. RESULTS: All patients (n=52) failed their actual regimen. Currently versus ever previously taking the specific drug, resistance associated mutations and phenotypic resistance to AZT and 3TC were found in over 80% of individuals; resistance to DDI and D4T was detected in less than 10% of cases. A resistance guided switch of therapy was followed by a median decrease of viral load of 0.5 log10 units after 24 weeks. Individuals resistant to two or more drugs compared with patients with resistance to less than two drugs of ongoing treatment, were switched to a regimen containing DDI, D4T, and a PI or NNRTI. After 10 (SD 2) weeks viral load decrease was pronounced in patients with resistance to at least two drugs in the previous regimen. CONCLUSIONS: Among different RTI, the profile of clinically relevant resistance indicates pronounced differences when looking at separate drugs. Regarding virological response, in the context of available drugs, resistance tested with currently used methods is of limited value in extensively pretreated patients and seems to have its value primarily in first or second switch of therapy.

Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery.

OBJECTIVE: To evaluate the impact of immune recovery induced by highly active antiretroviral therapy (HAART) on the survival of AIDS patients with primary central nervous system lymphoma (PCNSL). METHODS: In a multicentric retrospective analysis, 29 HIV-infected patients with histologically confirmed PCNSL were identified. To evaluate median survival, Kaplan-Meier statistics were used. To explore the effects of different variables on survival, a Weibull accelerated failure time regression analysis was performed. RESULTS: Median age at manifestation of PCNSL was 39.1 years and median CD4 cell count was 11 x 10(6) cells/l. Seventy per cent of the patients had had a prior AIDS-defining illness. Cranial radiation (CR) was given to 12 out of 29 patients. Six patients were treated with HAART. Survival time of these patients and of the patients treated with CR alone differed significantly from those receiving neither CR nor HAART (median Kaplan-Meier survival estimate: 1093, 132, and 33 days, respectively). In the multivariate regression model, HAART and CR were identified as the only variables independently associated with prolonged survival. HAART versus no HAART and CR versus no CR increased the time to event by a factor of 6.1 (95% confidence interval, 2.4-16.0; P = 0.0002) and 3.1 (95% confidence interval, 1.5-6.3; P = 0.002), respectively. Four out of six patients on HAART showed a marked immune recovery and survived for more than 1.5 years, with two patients still alive. CONCLUSION: Data from this cohort indicate that immune recovery induced by HAART leads to dramatic improvement in survival of patients with AIDS-associated PCNSL. These findings may have important implications for future treatment strategies.

In vivo dynamics and pathogenicity of wild-type and resistant Hepatitis B virus during long-term lamivudine monotherapy - a clinical note.

BACKGROUND: Genotypic resistance of Hepatitis B virus (HBV) against lamivudine evolves within months after onset of therapy. OBJECTIVES: To determine the longitudinal order in which resistance mutations appear and to compare the kinetics and pathogenicity of wild-type and resistant HBV. STUDY DESIGN: In a longitudinal study, consecutive samples were drawn over a period of 28 months from a patient with chronic hepatitis B, and resistance mutations were followed by sequencing a part of the polymerase region of HBV. These data were compared with HBV copy numbers, HBsAg and ALT levels, and results of consecutive liver biopsies. RESULTS: After 21 weeks of treatment, a silent mutation at codon 528 (CTG to TTG) occurred. Significant genotypic resistance was detectable after 68 weeks, indicated by a substitution of isoleucine for methionine at residue 552 (M552I). Nineteen weeks later, the virus exhibited additional resistance-associated mutations (L528M and I552V). The resulting high-level resistance was reflected by an increase of serum HBV copies of 4.7 log(10). The turnover of wild-type and resistant HBV was 2.6x10(6) and 1.8x10(6) virions/day, respectively. HBsAg and ALT levels were lower within the period when resistant HBV was detectable. During treatment the progress of liver fibrosis was arrested. CONCLUSIONS: The in vivo replicative capacities and dynamics of wild-type and resistant HBV were similar. However, resistant HBV seemed to exhibit reduced pathogenicity.