Christian Kollan

Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma.

BACKGROUND AIDS-related lymphoma contributes to significant morbidity and mortality among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART). We assessed the predictive role of cumulative HIV viremia and other risk factors in the development of AIDS-related non-Hodgkin lymphoma. METHODS Data from the Clinical Surveillance of HIV Disease (ClinSurv) study, an ongoing, observational, open cohort study of HIV-infected patients from different urban areas in Germany, were analyzed using a Cox proportional hazards model. RESULTS In the Cox model, which comprised 6022 patients and 27,812 patient-years of follow-up while patients were receiving HAART from 1999 through 2006, cumulative HIV viremia was found to be independently associated with the risk of lymphoma (hazard ratio, [HR], 1.67 [95% confidence interval {CI}, 1.27-2.20]) (P < .001]). This association differed markedly between lymphoma subtypes. Although the association was more pronounced for Burkitt-type lymphoma (HR, 3.45 [95% CI, 1.52-7.85]) (P = .003), there was no association between cumulative HIV viremia and the incidence of primary central nervous system lymphoma (HR, 1.00 [95% CI, 0.39-2.57]) (P = .997). Other risk factors associated with an increased risk in a multivariable analysis included the latest CD4 T cell count as well as age per 10-year increment. CONCLUSIONS Cumulative HIV viremia is an independent and strong predictor of AIDS-related lymphoma among patients receiving HAART. The influence of cumulative HIV viremia may differ between lymphoma subtypes.

Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort.

Background The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. Methods Genotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008). A genotypic resistance result was obtained for 1,276/1,312 (97.3%). The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml. Results Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N = 158/1,276; 12.4%; CIwilson 10.7–14.3; p for trend = 0.25). NRTI resistance was predominant (7.5%) but decreased significantly over time (CIWilson: 6.2–9.1, p for trend = 0.02). NNRTI resistance tended to increase over time (NNRTI: 3.5%; CIWilson: 2.6–4.6; p for trend  = 0.07), whereas PI resistance remained stable (PI: 3.0%; CIWilson: 2.1–4.0; p for trend  = 0.24). Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%). The majority of NRTI-resistant strains (79.8%) carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61). The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%). Conclusion Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected with HIV might be related to the introduction of novel antiretroviral drugs and a wider use of genotypic resistance analysis prior to treatment initiation.

Clinical Outcome of HIV-Infected Patients with Discordant Virological and Immunological Response to Antiretroviral Therapy

BACKGROUND A subgroup of human immunodeficiency virus type 1 (HIV-1)-infected patients with severe immunodeficiency show persistently low CD4+ cell counts despite sustained viral suppression. It is unclear whether this immuno-virological discordance translates into an increased risk for clinical events. METHODS Data analysis from a large multicenter cohort incorporating 14,433 HIV-1-infected patients in Germany. Treatment-naive patients beginning antiretroviral therapy (ART) with CD4+ cell counts <200 cells/μL who achieved complete and sustained viral suppression <50 copies/mL (n = 1318) were stratified according to the duration of immuno-virological discordance (failure to achieve a CD4+ cell count ≥200 cells/μL). Groups were compared by descriptive and Poisson statistics. The time-varying discordance status was analyzed in a multivariable Cox model. RESULTS During a total of 5038 person years of follow-up, 42 new AIDS events occurred. The incidence rate of new AIDS events was highest in the initial 6 months of complete viral suppression (immuno-virological discordance group, 55.06; 95% confidence interval [CI], 30.82-90.82; and immune responder group, 24.54; 95% CI, 10.59-48.35) and decreased significantly by 65% per year in patients with immuno-virological discordance (incidence risk ratio, 0.35; 95% CI, 0.14-0.92; P = .03). Immuno-virological discordance and prior AIDS diagnosis were independently associated with new AIDS events (hazard ratio, 3.10; 95% CI, 1.09-8.82; P = .03). CONCLUSION Compared with immune responders, patients with immuno-virological discordance seem to remain at increased risk for AIDS. Absolute risk is greatly reduced after the first 6 months of complete viral suppression.

Relation between the HIV and the re-emerging syphilis epidemic among MSM in Germany: an analysis based on anonymous surveillance data

In 2003, for the first time since the introduction of highly active antiretroviral therapy (HAART), the number of newly diagnosed HIV infections in Germany increased considerably compared to the previous year. The increase was largely restricted to men who have sex with men (MSM) from larger cities. In this group the number of newly diagnosed HIV infections increased about 30% compared to 2002. Since the late 1990s syphilis infections among MSM also increased in Germany, concentrated in larger cities.

Tuberculosis among people living with HIV/AIDS in the German ClinSurv HIV Cohort: long-term incidence and risk factors

BackgroundTuberculosis (TB) still presents a leading cause of morbidity and mortality among people living with HIV/AIDS (PLWHA), including those on antiretroviral therapy. In this study, we aimed to determine the long-term incidence density rate (IDR) of TB and risk factors among PLWHA in relation to combination antiretroviral therapy (cART)-status.MethodsData of PLWHA enrolled from 2001 through 2011 in the German ClinSurv HIV Cohort were investigated using survival analysis and Cox regression.ResultsTB was diagnosed in 233/11,693 PLWHA either at enrollment (N = 62) or during follow-up (N = 171). The TB IDR during follow-up was 0.37 cases per 100 person-years (PY) overall [95% CI, 0.32-0.43], and was higher among patients who never started cART and among patients originating from Sub-Saharan Africa (1.23 and 1.20 per 100PY, respectively). In two multivariable analyses, both patients (I) who never started cART and (II) those on cART shared the same risk factors for TB, namely: originating from Sub-Saharan Africa compared to Germany (I, hazard ratio (HR); [95% CI]) 4.05; [1.87-8.78] and II, HR 5.15 [2.76-9.60], CD4+ cell count <200 cells/μl (I, HR 8.22 [4.36-15.51] and II, HR 1.90 [1.14-3.15]) and viral load >5 log10 copies/ml (I, HR 2.51 [1.33-4.75] and II, HR 1.77 [1.11-2.82]). Gender, age or HIV-transmission risk group were not independently associated with TB.ConclusionIn the German ClinSurv HIV cohort, patients originating from Sub-Saharan Africa, with low CD4+ cell count or high viral load at enrollment were at increased risk of TB even after cART initiation. As patients might be latently infected with Mycobacterium tuberculosis complex, early screening for latent TB infection and implementing isoniazid preventive therapy in line with available recommendations is crucial.

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.

The denominator problem: Estimating MSM-specific incidence of sexually transmitted infections and prevalence of HIV using population sizes of MSM derived from Internet surveys

BackgroundMeasuring prevalence and incidence of sexually transmitted infections in hard to reach populations like men who have sex with men (MSM) is hampered by unknown size and regional distribution of this population. Community sample – and study-based measurements are often fraught with participation biases and do not allow generalization of the results for other regions or the whole population group of MSM.MethodsWe used the proportional regional distribution of participants of large internet-based surveys among MSM from Germany together with a general population survey-derived estimate of the MSM population to estimate regional population sizes. Based on transmission group category from surveillance data and regional MSM population size we calculated regional population-specific incidence rates of newly diagnosed HIV infection and syphilis. For HIV prevalence we compared estimates of prevalent HIV infections in MSM from a surveillance data-based model with a mixed model in which we used the proportional regional distribution of HIV positive participants from surveys and the estimated total number of prevalent HIV infections from the surveillance based model.ResultsAssuming a similar regional distribution of survey participants and the MSM population as a whole, the regional proportion of MSM in the general population can be estimated. Regional incidence calculated with the estimated MSM population as denominator and national surveillance data as numerator results in regional peak incidence rates of 7–8 per 1,000 MSM for newly diagnosed HIV infection and syphilis. The gradient between metropolitan and rural areas narrows considerably compared with calculations which use the total (male) population as denominator. Regional HIV prevalence estimates are comparable in the two models.ConclusionConsidering the difficulties to obtain regionally representative data by other sampling methods for MSM, in Western post-industrialized countries internet-based surveys may provide an easy and low cost tool to estimate regional population distributions. With national surveillance data, which categorize transmission groups, regional population-specific incidence rates for reportable sexually transmitted infections can be estimated. HIV prevalence estimates for regional MSM populations show differences related to the level of urbanization, MSM concentration, and starting points of the HIV epidemic in western and eastern Germany.

Cohort profile: the German ClinSurv HIV project--a multicentre open clinical cohort study supplementing national HIV surveillance.

New forms of HIV/AIDS therapy require new surveillance instruments to meet shifting public health demands. The Clinical Surveillance of HIV Disease (ClinSurv HIV) project was established in 1999 as a collaboration between major HIV treatment centres in Germany and the Robert Koch Institute (RKI). The project contributes to national HIV surveillance and focuses on the changing epidemiology of HIV/AIDS after the introduction of new therapies in 1995.

Estimating Trends in the Proportion of Transmitted and Acquired HIV Drug Resistance in a Long Term Observational Cohort in Germany

Objective We assessed trends in the proportion of transmitted (TDR) and acquired (ADR) HIV drug resistance and associated mutations between 2001 and 2011 in the German ClinSurv-HIV Drug Resistance Study. Method The German ClinSurv-HIV Drug Resistance Study is a subset of the German ClinSurv-HIV Cohort. For the ClinSurv-HIV Drug Resistance Study all available sequences isolated from patients in five study centres of the long term observational ClinSurv-HIV Cohort were included. TDR was estimated using the first viral sequence of antiretroviral treatment (ART) naïve patients. One HIV sequence/patient/year of ART experienced patients was considered to estimate the proportion of ADR. Trends in the proportion of HIV drug resistance were calculated by logistic regression. Results 9,528 patients were included into the analysis. HIV-sequences of antiretroviral naïve and treatment experienced patients were available from 34% (3,267/9,528) of patients. The proportion of TDR over time was stable at 10.4% (95% CI 9.1–11.8; p for trend = 0.6; 2001–2011). The proportion of ADR among all treated patients was 16%, whereas it was high among those with available HIV genotypic resistance test (64%; 1,310/2,049 sequences; 95% CI 62–66) but declined significantly over time (OR 0.8; 95% CI 0.77–0.83; p for trend<0.001; 2001–2011). Viral load monitoring subsequent to resistance testing was performed in the majority of treated patients (96%) and most of them (67%) were treated successfully. Conclusions The proportion of TDR was stable in this study population. ADR declined significantly over time. This decline might have been influenced by broader resistance testing, resistance test guided therapy and the availability of more therapeutic options and not by a decline in the proportion of TDR within the study population.

Verlauf der HIV-Epidemie in Deutschland

ZusammenfassungZwischen dem Zeitpunkt der Infektion und dem Zeitpunkt der Diagnose der HIV-Infektion vergeht in aller Regel ein individuell unterschiedlich langer Zeitraum von oftmals mehreren Jahren. Die Meldedaten über HIV-Neudiagnosen erlauben daher keinen direkten Rückschluss auf den Infektionszeitpunkt. Die tatsächliche Zahl der HIV-Neuinfektionen (HIV-Inzidenz) und der zurückliegende Verlauf der HIV-Epidemie in Deutschland können bis zum Zeitraum der frühen 1990er-Jahre mit Hilfe von Rückrechnungsmodellen beschrieben werden. Zur Beschreibung des aktuellen Verlaufes der HIV-Epidemie muss man sich unter Berücksichtigung anderer Datenquellen überwiegend auf die Meldungen der HIV-Neudiagnosen stützen. Auf dieser Grundlage kann davon ausgegangen werden, dass die Zahl der jährlichen HIV-Neuinfektionen in Deutschland ihren Höhepunkt in den frühen 1980er-Jahren erreicht hat und seit Anfang der 1990er-Jahre relativ stabil zwischen 2000 und 2500 pro Jahr lag. Größte Betroffenengruppe sind nach wie vor Männer, die Sex mit Männern haben, gefolgt von heterosexuell Infizierten und Migranten aus Hochprävalenzregionen. I.v.-Drogengebraucher haben zahlenmäßig über die Jahre abgenommen und belegen den vierten Rang. Aktuell gibt es Anzeichen dafür, dass eine Zunahme von Risikoverhalten sowie die Zunahme anderer sexuell übertragbarer Infektionen in Verbindung mit Veränderungen in Bezug auf den Zeitpunkt des Therapiebeginns zu einem Anstieg der HIV-Neuinfektionen geführt haben. Zur frühzeitigen Erfassung einer Änderung des Risikoverhaltens wäre eine Verbesserung der epidemiologischen Erfassung weiterer sexuell übertragbarer Infektionen in Verbindung mit Erhebungen zum Verhalten im Sinne einer „Second Generation Surveillance“ wünschenswert.AbstractThe course of the HIV epidemic in Germany can be modelled by back calculation until the beginning of the nineties. The recent course of the epidemic can only be derived from surveillance data of newly diagnosed HIV infections in conjunction with other data sources. Based on these surveillance data HIV incidence in Germany can be estimated to have been stable with 2000 to 2500 new infections per year since the early nineties, after having peaked in the early eighties. The most affected group are men who have sex with men followed by persons infected by heterosexual contact and migrants from high prevalence countries. The number of intravenous drug users has declined over the years and is now in fourth place. There are indications that increased risk behaviour and rising numbers of other sexually transmitted infections together with a change towards later initiation of antiretroviral therapy has led to an increase in new HIV infections in Germany in recent years. An improvement of the epidemiological surveillance for “indicator” STIs in combination with the assessment of risk behaviours in high risk groups would be desirable steps towards a second generation surveillance in Germany.