Andreas Plettenberg

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10–15 d, with a mean reduction of ≥1.6 log10 copies/ml at all twice daily doses ≥100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy.

Objective:To evaluate the impact of different antiretroviral therapies on the prognosis of AIDS patients affected by progressive multifocal leukoencephalopathy (PML). Methods:A retrospective analysis of all HIV-infected patients admitted to hospital between 1988 and 1996 found 29 patients (25 men) with histologically or PCR- confirmed PML. Their mean age was 39.3 years. The median CD4 cell count was 40 × 106/l (mean, 106 × 106/l). Six patients had CD4 cell counts > 200 × 106/l. Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients started highly active antiretroviral therapy (HAART) including protease inhibitors (group C). Results:The median survival following the onset of symptoms was 131 days, but differed significantly between the three groups: group A, 127 days; group B, 123 days; group C, > 500 days (P < 0.0002 for the difference between group C versus group A and B, stratified log-rank test). As of July 1997, four out of five patients on HAART were still alive 391, 500, 543, and 589 days after diagnosis of PML and have either experienced a resolution of the symptoms (three patients) or had progressed very slowly (one patient). A multivariate analysis using Cox regression found younger age at diagnosis to be the only other variable associated with improved survival (P < 0.02). CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or interferon-α did not affect survival in this cohort (P > 0.1). Conclusion:This study of a large cohort of patients with confirmed PML indicates that AIDS patients with PML may benefit significantly from HAART. All patients with PML should be offered optimal antiretroviral combination therapy.

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

ObjectiveTo 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). MethodsIn 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. ResultsMedian age at manifestation of PCNSL was 39.1 years and median CD4 cell count was 11 × 106 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. ConclusionData 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.

Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin's disease

Hodgkins disease (HD) is the most common non‐acquired immunodeficiency syndrome (AIDS)‐defining malignancy in human immunodeficiency virus (HIV)‐infected patients. We analysed the outcome of patients with HIV‐associated HD (HIV‐HD) with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and other prognostic factors. To evaluate the effects of several variables on overall survival (OS), Kaplan–Meier statistics and extended Cox regression analysis were performed. Response to HAART was used as a time‐dependent variable and was defined as an increase of >0·1 × 109 CD4 cells/l and/or at least one viral load <500 copies/ml during the first 2 years following diagnosis of HIV‐HD. Fifty‐seven patients with HIV‐HD diagnosed between 1990 and 2002 were included in the study. In the Cox model, the only factors independently associated with OS were HAART response [relative hazard (RH) 0·19; 95% confidence interval (CI) 0·06–0·60], complete remission (RH 0·30, 95% CI 0·13–0·72), and age 45 years (RH 0·23; 95% CI 0·09–0·60). Median survival time in patients without HAART response was 18·6 months, whereas the median survival time in patients with HAART response was not reached (89% OS at 24 months). In this cohort, a significant improvement in survival was found in patients with HIV‐HD who responded to HAART.

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BACKGROUND Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.

The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial.

ObjectiveTo compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA ⩽ 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. DesignOne-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts ⩾ 100 × 106/l and plasma HIV-1 RNA of 400–50 000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. MethodsAntiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. ResultsAt week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA ⩽ 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%;P  < 0.001). A similar response was observed in both the lamivudine naïve and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a ⩾ 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of ⩽ 400 copies/ml by week 16. ConclusionsABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.

Bacillary Angiomatosis in HIV-Infected Patients – An Epidemiological and Clinical Study

Background: No data were available on the epidemiological and clinical characteristics of bacillary angiomatosis (BA) in Germany. Objective: To determine epidemiological and clinical data on HIV-associated BA. Methods: A chart review of all BA cases between 1990 and 1998 was performed in 23 German AIDS treatment units. Results: A total of 21 cases of BA was diagnosed. During this period, the participating HIV centers treated about 17,000 HIV-infected patients. As a result, a BA prevalence of 1.2 cases/1,000 patients can be assumed. 19 BA were localized in the skin; in 5 cases bones and in 4 cases the liver were involved. Out of 20 patients who received antibiotic therapy, 13 had complete remission. The median time of duration up to complete remission was 32 days (9–82). During the follow-up of the 20 patients, 7 relapses were observed. Conclusion: BA is a rare HIV-associated disease with a prevalence of 1,2 cases/1,000 patients in the presented study.

Repeated detection of lymphogranuloma venereum caused by Chlamydia trachomatis L2 in homosexual men in Hamburg

Bacteria of the species Chlamydia trachomatis are divided into serovars that are associated with different disease manifestations. Serovars A-C cause trachoma, which occurs mainly in undeveloped countries. Serovars D-K are responsible for oculogenital infections, and serovars L1, L2, and L3 cause lymphogranuloma venereum (LGV). Infections of serovars A-K are usually confined to the mucosal epithelia of the eyes and the anogenital tract. In contrast, the L-serovars are more invasive and may induce genital ulcer or inguinal lymphadenopathy after passing the epithelial surface.1 While serovars D-K are distributed worldwide and represent the most frequent bacterial sexually transmitted disease in Europe and North America, LGV caused by the L-serovars is a very rare …

AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping.

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.

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

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