Efficacy and safety of dolutegravir/lamivudine in virologically suppressed female participants: week 48 data from the pooled TANGO and SALSA studies.

OBJECTIVES: Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV-1 without prior virological failure in a pooled analysis of two randomized controlled trials. METHODS: This analysis included 48-week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV-1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. RESULTS: Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV-1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV-1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40-3.75]). CONCLUSIONS: Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV-1, with outcomes similar to those in males.

Medium-grade proteinuria is a risk factor for incident markers of chronic kidney disease.

OBJECTIVE: Medium-grade proteinuria (100-500 mg/g creatinine) is common among people living with HIV/AIDS (PLWHA) but is often undetected or ignored. This prospective, observational cohort study examined medium-grade proteinuria as a risk factor for markers of chronic kidney disease (CKD). METHODS: Quantitative urine samples were collected from 241 PLWHA without known renal disease at baseline between January 2009 and February 2011 and at follow-up 240 weeks later. Multivariate analysis was performed to assess medium-grade proteinuria as a risk factor for incident markers of CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 , albuminuria, phosphaturia). RESULTS: Incident markers of CKD were identified in 33 patients (14%), of whom 24 (74%) had medium-grade proteinuria at baseline. Of these, 22 even had proteinuria of < 200 mg/g creatinine. Multivariate analysis showed an adjusted relative risk (aRR) of 2.4 for patients with baseline medium-grade proteinuria to develop signs of CKD. Age was identified as an additional independent predictor. By testing for interaction, tenofovir disoproxil fumarate (TDF)-independent proteinuria was strongly associated with incident CKD markers (aRR = 12.1). CONCLUSION: Medium-grade proteinuria of 100-500 mg/g creatinine is both frequent in PLWHA and a significant risk factor for developing markers of CKD, especially in the absence of TDF. Relevant risk seems to be associated with proteinuria levels as low as 100-200 mg/g creatinine. Current guidelines recommend specific action for proteinuria exceeding 135-200 mg/g but still will miss a relevant number of PLWHA potentially at risk for CKD. An even lower cut-off to trigger nephrological work-up and potentially renoprotective interventions appears to be indicated.

Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe.

OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

Measles, mumps, rubella and VZV: importance of serological testing of vaccine-preventable diseases in young adults living with HIV in Germany.

Measles, mumps, rubella (MMR) and varicella zoster virus (VZV) infection can cause serious diseases and complications in the HIV-positive population. Due to successful vaccination programmes measles, mumps and congenital rubella syndrome has become neglected in Germany. However, recent outbreaks of measles have occurred from import-associated cases. In this cross-sectional study the serostatus for MMR and VZV in 2013 HIV-positive adults from three different university outpatient clinics in Bonn (n = 544), Cologne (n = 995) and Munich (n = 474) was analysed. Sera were tested for MMR- and VZV-specific immunglobulin G antibodies using commercial immunoassays. Seronegativity was found in 3% for measles, 26% for mumps, 11% for rubella and 2% for VZV. Regarding MMR, 35% of patients lacked seropositivity against at least one infectious agent. In multivariable analysis younger age was strongly associated with seronegativity against all four viruses, measles, mumps, rubella (P < 0·001, P < 0·001 and P = 0·001, respectively) and VZV (P = 0·001). In conclusion, there is high need for MMR and VZV vaccination in people living with HIV in Germany born in 1970 or later. Thus, systematic MMR and VZV antibody screening and vaccination should be implemented in the HIV-positive population to prevent serious disease and complications of vaccine-preventable diseases.

Medium-grade tubular proteinuria is common in HIV-positive patients and specifically associated with exposure to tenofovir disoproxil Fumarate.

OBJECTIVES: The aim of this cross-sectional study was to evaluate the prevalence and risk factors of medium-grade proteinuria (100-500 mg/g creatinine) among HIV-positive adults. METHODS: Spot urine samples of HIV-positive adults without known renal disease were analyzed quantitatively between January 2009 and February 2011. Demographic and medical data were collected. Multivariate regression models for different patterns of proteinuria were constructed. RESULTS: Among 411 patients, 18 (4.4 %) presented albuminuria >300 mg/g creatinine and/or proteinuria >500 mg/g creatinine and were excluded from further analyses. Among the study population of 393 patients, 181 (46.1 %) had no significant proteinuria or albuminuria (<100 and <30 mg/g creatinine, respectively), 60 (15.3 %) had moderate albuminuria, while 152 (38.7 %) had proteinuria without albuminuria, suggesting tubular proteinuria. Independent predictors for medium-grade tubular proteinuria in multivariate analysis were exposure to tenofovir (DF), a CD4 nadir <500/µl, older age, and anti-HCV-antibodies. There was no association with classic renal risk factors like diabetes mellitus and arterial hypertension, or with estimated glomerular filtration rate (eGFR). CONCLUSIONS: We detected significant proteinuria in 230 (56.0 %) of 411 HIV-positive patients. Among this group, 152 (66.1 %) had medium-grade proteinuria without albuminuria, which was significantly associated with exposure to tenofovir, older age, a lower CD4 nadir and Hepatitis C. Nephrologic or HIV treatment guidelines fail to detect most of these patients but rather identify patients with high cardiovascular risk. In the absence of an association with eGFR the role of medium-grade tubular proteinuria as a potential early marker of chronic kidney disease remains unclear. Prospective studies are needed.

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.

Transmission risk behaviour at enrolment in participants in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: A proportion of HIV-positive people have condomless sex. Antiretroviral treatment (ART) reduces infectiousness, but a substantial proportion of HIV-diagnosed people are not yet on ART. We describe baseline self-reported risk behaviours in ART-naïve Strategic Timing of AntiRetroviral Treatment (START) trial participants. METHODS: All START participants completed a risk behaviour questionnaire. Data were collected on sociodemographics, lifestyle factors, health and wellbeing status and clinical status. Recent sexual behaviour and HIV transmission beliefs in the context of ART were also assessed. The primary interest was in condomless sex with serodifferent partners (CLS-D) in the past two months. RESULTS: A total of 4601 of 4685 HIV-positive participants (98%) completed the questionnaire [2559 men who have sex with men (MSM), 803 heterosexual men and 1239 women]. Region of recruitment was Europe/Israel, 33%; South America/Mexico, 25%; Africa, 22%; other, 21%. Median age was 36 years [interquartile range (IQR) 29, 44 years]. Forty-five per cent reported white ethnicity and 31% black ethnicity. Two per cent had HIV viral load < 50 HIV-1 RNA copies/mL. Seventeen per cent (767 of 4601) reported CLS-D; 20% of MSM compared with 10% of heterosexual men and 14% of women. MSM were also more likely to report multiple CLS-D partners. Possible risk limitation measures (reported by more than half of those who had CLS-D) were seropositioning (receptive anal CLS-D only) or withdrawal (insertive anal CLS-D always without ejaculation). CLS-D was more commonly reported by participants from South America/Mexico and North America compared with Europe; among heterosexual men and women CLS-D was also more commonly reported among participants from Africa compared with Europe. Knowledge of ART impact on transmission risk was low. CONCLUSIONS: A substantial minority recruited to the START study reported CLS-D at baseline. CLS-D reporting was higher in MSM than heterosexuals and varied significantly according to region of recruitment. A substantial proportion of MSM reporting CLS-D appear to take transmission risk limitation measures.

Novel antibiotics: are we still in the pre-post-antibiotic era?

PURPOSE: Therapeutic efficacy and safety in infections due to multidrug-resistant bacteria can be improved by the clinical development of new compounds and devising new derivatives of already useful antibiotics. Due to a striking global increase in multidrug-resistant Gram-positive but even more Gram-negative organisms, new antibiotics are urgently needed. METHODS: This paper provides a review of novel antibiotic compounds which are already in clinical development, mainly in phase III clinical trials. CONCLUSION: Each of these new trials increases the possibility of new antibiotics receiving approval.

[Cost of Illness of HIV Patients under Anteretroviral Therapy in Germany - Results of the 48-Week Interim Analysis of the Prospective Multicentre Observational Study 'CORSAR']. / Krankheitskosten von HIV-Patienten unter antiretroviraler Therapie in Deutschland - Ergebnisse einer 48-Wochen-Interimsanalyse im Rahmen der prospektiven multizentrischen Kohortenstudie "CORSAR".

BACKGROUND: With the introduction of highly active combined antiretroviral therapy (c-ART) mortality and morbidity of HIV patients declined substantially. Earlier studies reported that c-ART was able to save health-care costs due to a reduction of other direct medical costs, particularly for inpatient treatments and concomitant medication. To date, analyses of costs and health-related quality of life (HRQOL) of patients under c-ART are lacking in Germany. Hence, this study aims to estimate the current cost of illness and HRQOL of HIV-patients under c-ART in different treatment lines. METHODS: A multicenter, prospective observational study was carried out in 12 specialised German centres for infectious diseases: 8 private practices/outpatient centres and 4 specialised hospitals offering both inpatient and outpatient services. Demographic, clinical and medication data were derived from patient records. Resource utilisation, information on productivity, out of pocket costs and HRQOL (EQ-5D) were collected every 12 weeks via a patient questionnaire. All costs were calculated based on price information from publicly accessible databases. RESULTS: N=1,154 patients were included in the analysis. Mean direct disease-related costs of -patients under c-ART amounted to 22,563 Euro/year. Patients beyond the 3(rd) line of treatment -incurred considerably higher costs 24,654 Euro/year. In the 1(st) treatment line, c-ART accounted for 83.2% of the total direct costs, in the 2(nd)/3(rd) line for 80.8% and in >3(rd) line for 83.4%, respectively. Indirect costs due to impaired productivity were higher in the 2(nd)/3(rd) treatment line (2,843 Euro) compared to the 1(st) (1,604 Euro) and >3(rd) (1,752 Euro) treatment lines, respectively. The average HRQOL (EQ-5D) varied between 0.77 (self-assessment via visual analogue scale) and 0.91 (utility score based on the German time trade-off tariff). CONCLUSIONS: Over the last decade, cost of illness of HIV patients under c-ART decreased slightly with average costs per year still being substantial. Main cost driver of overall costs is c-ART. There have been, however, noticeable shifts between different cost domains.

[New antibiotics prior to approval: is this the end of the innovative stagnation?]. / Neue Antibiotika vor Zulassung: Ende des Innovationsstaus?

BACKGROUND: Therapeutic efficacy and safety in infections due to multiresistant bacteria can be improved by the clinical development of new compounds and devising new derivatives of already useful antibiotics. Due to a striking global increase of multiresistant gram-negative and gram-positive organisms, new antibiotics are urgently needed. This paper provides a review of new pharmaceuticals which are already in clinical development, mainly in phase III trials. CONCLUSION: Each of these new trials increases the possibility of new antibiotics receiving approval.

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.

Sexual and reproductive health services for people living with HIV/AIDS in Germany: are we up to the challenge?

PURPOSE: Germany is witnessing an increase in the number of new infections with human immunodeficiency virus (HIV). Enabling persons living with HIV (PLHIV) to adopt safer sex practices might contribute towards reducing the incidence of HIV infections. The aim of this study was to identify gaps in the sexual and reproductive health (SRH) services provided to PLHIV in Germany. METHODS: Within the framework of the European public health project Eurosupport 5, self-reported questionnaires were distributed to PLHIV and a survey of SRH-service providers was carried out. The completed questionnaires and survey results were analysed. RESULTS: Of the questionnaires distributed, 218 PLHIV (90 % men, 10 % women) returned a completed questionnaire. Of these, 74 % self-identified as men having sex with men (MSM) and 13 % as heterosexual men. MSM reported a median number of ten casual partners in the previous 6 months and unprotected sex in one-third of anal intercourses with casual partners, demonstrating that this group adopted more risky sexual behaviours than heterosexual PLHIV. Even though all PLHIV stated they would appreciate more support and service providers indicated that they provided a wide range of SRH services, SRH-relevant topics were rarely discussed between PLHIV and service providers. According to the patients' perception, shortage of time, lack of initiative by service providers and their own difficulty to address SRH-related topics were the most relevant obstacles to receiving satisfactory support. CONCLUSION: Many PLHIV consult their HIV-physician regularly for medical follow-up and also indicate that HIV-physicians should be the source of information concerning SRH counselling. HIV-physicians should take advantage of their key role in HIV care and strengthen their efforts to integrate SRH services in routine HIV care.

Is there a benefit to a routine preoperative screening of infectivity for HIV, hepatitis B and C virus before elective orthopaedic operations?

PURPOSE: Before elective operations, particularly orthopaedic surgery, national guidelines in Germany recommend testing for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) to reduce the risk of transmission of the virus through a needlestick or cutting injury. Such testing is expensive. The number of new and unknown diagnoses of viral infections that can be detected by routine screening has not yet been evaluated. METHODS: The aim of our department of orthopaedic surgery is to screen every adult patient listed for an operation for HBV, HCV and HIV. We retrospectively analysed the number of operations in this single centre from 2001 to 2010, correlated this number with the total number of screens and calculated the number of newly diagnosed infections. An additional cost:benefit ratio was calculated. RESULTS: A total of 20,869 operations were performed by the department between 2001 and 2010. After exclusion of all interventions in children and all patients who had multiple operations, 15,482 patients remained. Test results were found for 10,011 of these patients during this period (screening rate 65 %). Of those screened, in only four cases (0.4 ‰) was a previously unknown infection detected. CONCLUSIONS: Two-thirds of the patients included in our study actually underwent screening; this rate was lower than expected. The incidence of newly detected infections was low, putting the benefit of a routine preoperative screening for HBV, HCV and HIV into question. From an economic point of view the low detection rate is a strong argument in favour of omitting routine preoperative screening. Screening only those patients with risk factors may be as safe as screening every patient and would help reduce costs.

[HIV infection : chronic disease with comorbidities]. / HIV-Infektion : Chronische Krankheit mit Komorbiditäten.

While HIV therapy is highly efficient comorbidities come into the focus of HIV long-term treatment and prognosis. The pathogenesis of many comorbid diseases is determined not only by the biological effects of the HIV infection itself but also by lifestyle and long-term adverse reactions of antiviral treatment. The HIV specialist should nowadays be an all-round internist or needs a good infrastructure of cooperation. Cardiovascular risk factors in HIV infection include serum lipids, especially high LDL levels under antiviral treatment. They can be managed either by a switch of HIV therapy of by the addition of lipid-lowering agents. However, smoking habits and normalization of high blood pressure are also of importance. Further important comorbidities present in patients are viral hepatitis B or C, nephropathy (HIV or secondary) and changes of bone turnover resulting in lower bone mass and stability. Other aspects include vaccination status and prevention also for non-HIV associated carcinomas.

Infections are a global issue: infection addresses global issues.

Infections are of unifying global concern, despite regional differences in disease epidemiology, clinical appearance and the instruments to tackle them. The primary aim of Infection is "to be a forum for the presentation and discussion of clinically relevant information on infectious diseases… from all over the world". To that end, and as a reflection of the global burden of infectious diseases, we intend to increase the number of high-quality contributions from authors addressing the aetiology, pathogenesis, diagnosis and treatment of infectious diseases from outside Europe and the affluent North (Chang et al. Infection 40:359-365, 2012; Misra et al. Infection 40:125-130, 2012). The Editorial Board of Infection envisages the journal as an interface between where infectious diseases meet and mix between "North and South"--i.e., the field of travel medicine--frequently functioning as a sentinel for altered/novel disease activities that are encountered as imported conditions. With the change in generation on the Editorial Board, Infection aims to expand the areas of tropical medicine, travel medicine and global health with its own section editors (GC and MPG). Contributions from outside Europe are actively encouraged.