HIV und Komorbidität

Antiretroviral therapy (ART) has improved quality of life and increased life expectancy of HIV-infected individuals. Opportunistic diseases are less common, and mortality has declined. Consequently, patterns of mortality and morbidity are changing among the HIV-positive population. The focus of care has shifted to ART-related problems and to various non-AIDS diseases. Such comorbidities, often occurring sequentially or concurrently, may be the consequences of long term ART toxicity, a state of chronic inflammation due to HIV infection, lifestyle-related risks for disease, and aging. The emergence of non-AIDS related conditions highlights the important role of primary care physicians, especially of those with extensive experience in HIV management.

Antiretrovirale Therapie

Antiretroviral therapy to treat HIV, as we know it today, is nothing less than a huge success story in modern medical history. What used to be an almost certain death-sentence was transformed into a very manageable chronic disease by means of highly efficient und mostly well tolerated drugs. Today, HIV-infected patients treated according to international recommendations have a very good chance to outgo the negative effects of HIV-1 and are therefore able to reach an almost normal life expectancy. Furthermore, patients successfully treated with antiretroviral drugs are no longer infectious, which is an essential aspect of global strategies to overcome the pandemic. Nevertheless, due to the complexity of HIV, physicians treating patients with antiretroviral therapy require profound knowledge of aspects such as viral resistance mechanisms and immune reconstitution, as well as drug-toxicity und drug-drug-interactions. Many other aspects such as long-term side-effects of antiretroviral drugs are still unknown. Strict adherence to treatment is of utmost importance.

The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients.

BACKGROUND Cytomegalovirus (CMV) retinitis is a major cause of visual impairment and blindness among patients with uncontrolled HIV infections. Whereas polymorphisms in interferon-lambda 3 (IFNL3, previously named IL28B) strongly influence the clinical course of hepatitis C, few studies examined the role of such polymorphisms in infections due to viruses other than hepatitis C virus. OBJECTIVES To analyze the association of newly identified IFNL3/4 variant rs368234815 with susceptibility to CMV-associated retinitis in a cohort of HIV-infected patients. DESIGN AND METHODS This retrospective longitudinal study included 4884 white patients from the Swiss HIV Cohort Study, among whom 1134 were at risk to develop CMV retinitis (CD4 nadir <100 /μl and positive CMV serology). The association of CMV-associated retinitis with rs368234815 was assessed by cumulative incidence curves and multivariate Cox regression models, using the estimated date of HIV infection as a starting point, with censoring at death and/or lost follow-up. RESULTS A total of 40 individuals among 1134 patients at risk developed CMV retinitis. The minor allele of rs368234815 was associated with a higher risk of CMV retinitis (log-rank test P = 0.007, recessive mode of inheritance). The association was still significant in a multivariate Cox regression model (hazard ratio 2.31, 95% confidence interval 1.09-4.92, P = 0.03), after adjustment for CD4 nadir and slope, HAART and HIV-risk groups. CONCLUSION We reported for the first time an association between an IFNL3/4 polymorphism and susceptibility to AIDS-related CMV retinitis. IFNL3/4 may influence immunity against viruses other than HCV.

Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance

Abstract Alteration of the surface glycosylation pattern on malignant cells potentially affects tumor immunity by directly influencing interactions with glycan-binding proteins (lectins) on the surface of immunomodulatory cells. The sialic acid-binding Ig-like lectins Siglec-7 and -9 are MHC class I-independent inhibitory receptors on human NK cells that recognize sialic acid-containing carbohydrates. Here, we found that the presence of Siglec-9 defined a subset of cytotoxic NK cells with a mature phenotype and enhanced chemotactic potential. Interestingly, this Siglec-9+ NK cell population was reduced in the peripheral blood of cancer patients. Broad analysis of primary tumor samples revealed that ligands of Siglec-7 and -9 were expressed on human cancer cells of different histological types. Expression of Siglec-7 and -9 ligands was associated with susceptibility of NK cell-sensitive tumor cells and, unexpectedly, of presumably NK cell-resistant tumor cells to NK cell-mediated cytotoxicity. Together, these observations have direct implications for NK cell-based therapies and highlight the requirement to consider both MHC class I haplotype and tumor-specific glycosylation.

Disentangling human tolerance and resistance against HIV.

In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.

AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be.

INTRODUCTION According to reports from observational databases, classic AIDS-defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART. MATERIALS AND METHODS In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non-immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in-depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune-compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation. RESULTS More than 13,000 participants were followed in SHCS in the period of interest. Twenty-four (48%) of the chart-reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune-compromising conditions such as immunosuppressive drugs in 14 (34%). CONCLUSIONS In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno-compromising conditions are more likely explanations in one-third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.

Loss to follow-up of HIV-infected women after delivery: The Swiss HIV Cohort Study and the Swiss Mother and Child HIV Cohort Study.

INTRODUCTION HIV-infected pregnant women are very likely to engage in HIV medical care to prevent transmission of HIV to their newborn. After delivery, however, childcare and competing commitments might lead to disengagement from HIV care. The aim of this study was to quantify loss to follow-up (LTFU) from HIV care after delivery and to identify risk factors for LTFU. METHODS We used data on 719 pregnancies within the Swiss HIV Cohort Study from 1996 to 2012 and with information on follow-up visits available. Two LTFU events were defined: no clinical visit for >180 days and no visit for >360 days in the year after delivery. Logistic regression analysis was used to identify risk factors for a LTFU event after delivery. RESULTS Median maternal age at delivery was 32 years (IQR 28-36), 357 (49%) women were black, 280 (39%) white, 56 (8%) Asian and 4% other ethnicities. One hundred and seven (15%) women reported any history of IDU. The majority (524, 73%) of women received their HIV diagnosis before pregnancy, most of those (413, 79%) had lived with diagnosed HIV longer than three years and two-thirds (342, 65%) were already on antiretroviral therapy (ART) at time of conception. Of the 181 women diagnosed during pregnancy by a screening test, 80 (44%) were diagnosed in the first trimester, 67 (37%) in the second and 34 (19%) in the third trimester. Of 357 (69%) women who had been seen in HIV medical care during three months before conception, 93% achieved an undetectable HIV viral load (VL) at delivery. Of 62 (12%) women with the last medical visit more than six months before conception, only 72% achieved an undetectable VL (p=0.001). Overall, 247 (34%) women were LTFU over 180 days in the year after delivery and 86 (12%) women were LTFU over 360 days with 43 (50%) of those women returning. Being LTFU for 180 days was significantly associated with history of intravenous drug use (aOR 1.73, 95% CI 1.09-2.77, p=0.021) and not achieving an undetectable VL at delivery (aOR 1.79, 95% CI 1.03-3.11, p=0.040) after adjusting for maternal age, ethnicity, time of HIV diagnosis and being on ART at conception. CONCLUSIONS Women with a history of IDU and women with a detectable VL at delivery were more likely to be LTFU after delivery. This is of concern regarding their own health, as well as risk for sexual partners and subsequent pregnancies. Further strategies should be developed to enhance retention in medical care beyond pregnancy.

Estrogen induces nitric oxide production via nitric oxide synthase activation in endothelial cells.

INTRODUCTION 17β-estradiol (E2) has been found to induce vasodilation in the cardiovascular system and at physiological levels, resulting in prevention of cerebral vasospasm following subarachnoid hemorrhage (SAH) in animal models. The goal of this study was to analyze the cellular mechanism of nitric oxide (NO) production and its relation to E2, in vitro in brain and peripheral endothelial cells. METHODS Human umbilical endothelial cells (HUVEC) and brain endothelial cells (bEnd.3) were treated with estradiol (E2, 0.1, 10, 100, and 1,000 nM), and supernatant was collected at 0, 5, 15, 30, 60, and 120 min for nitric oxide metabolome (nitrite, NO₂) measurements. Cells were also treated with E2 in the presence of 1400W, a potent eNOS inhibitor, and ICI, an antagonist of estradiol receptors (ERs). Effects of E2 on eNOS protein expression were assessed with Western blot analysis. RESULTS E2 significantly increased NO2 levels irrespective of its concentration in both cell lines by 35 % and 42 % (p < 0.05). The addition of an E2 antagonist, ICI (10 μM), prevented the E2-induced increases in NO2 levels (11 % p > 0.05). The combination of E2 (10 nM) and a NOS inhibitor (1400W, 5 μM) inhibited NO2 increases in addition (4 %, p > 0.05). E2 induced increases in eNOS protein levels and phosphorylated eNOS (eNOS(p)). CONCLUSIONS This study indicates that E2 induces NO level increases in cerebral and peripheral endothelial cells in vitro via eNOS activation and through E2 receptor-mediated mechanisms. Further in vivo studies are warranted to evaluate the therapeutic value of estrogen for the treatment of SAH-induced vasospasm.

Assessing the paradox between transmitted and acquired HIV-1 drug resistance in the Swiss HIV Cohort Study from 1998 to 2012.

BACKGROUND  Transmitted HIV-1 drug-resistance mutations(TDR) are transmitted from treatment-failing or treatment-naïve patients. Although prevalence of drug-resistance in treatment-failing patients has declined in developed countries, TDR prevalence has not. Mechanisms causing this paradox are poorly explored. METHODS  We included recently-infected, treatment-naïve patients with genotypic-resistance-tests performed ≤1year post-infection and <2013. Potential risk factors for TDR were analyzed using logistic regression. Association of TDR prevalences with population viral load(PVL) from treatment-patients during 1997-2011 was estimated with Poisson regression for all TDR and individually for most frequent resistance-mutations against each drug class(M184V/L90M/K103N). RESULTS  We included 2421 recently-infected, treatment-naïve patients and 5399 treatment-failing patients. TDR prevalence fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in TDR(Odds Ratio[OR]=1.13,p=0.010), punctuated by sharp decreases when new drug-classes were introduced. Overall, TDR prevalence increased with decreasing PVL(Rate Ratio[RR]=0.91/1000Log10-PVL,p=0.033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with PVL of treatment-failing patients carrying M184V(RR=1.50/100Log10-PVL,p<0.001). Such association was absent and negative for K103N(RR-K103N=1.00/100Log10-PVL,p=0.99) and L90M(RR-L90M=0.75/100Log10-PVL,p=0.022), respectively. CONCLUSIONS  Transmission of antiretroviral drug-resistance is temporarily reduced by the introduction of new drug classes and driven by treatment-failing and treatment-naïve patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1-infection.

A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation (DWLM).

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.

Increased mortality after a first myocardial infarction in human immunodeficiency virus-infected patients; a nested cohort study.

AIMS HIV infection may be associated with an increased recurrence rate of myocardial infarction. Our aim was to determine whether HIV infection is a risk factor for worse outcomes in patients with coronaray artery disease. METHODS We compared data aggregated from two ongoing cohorts: (i) the Acute Myocardial Infarction in Switzerland (AMIS) registry, which includes patients with acute myocardial infarction (AMI), and (ii) the Swiss HIV Cohort Study (SHCS), a prospective registry of HIV-positive (HIV+) patients. We included all patients who survived an incident AMI occurring on or after 1st January 2005. Our primary outcome measure was all-cause mortality at one year; secondary outcomes included AMI recurrence and cardiovascular-related hospitalisations. Comparisons used Cox and logistic regression analyses, respectively. RESULTS There were 133 HIV+, (SHCS) and 5,328 HIV-negative [HIV-] (AMIS) individuals with incident AMI. In the SHCS and AMIS registries, patients were predominantly male (72% and 85% male, respectively), with a median age of 51 years (interquartile range [IQR] 46-57) and 64 years (IQR 55-74), respectively. Nearly all (90%) of HIV+ individuals were on successful antiretroviral therapy. During the first year of follow-up, 5 (3.6%) HIV+ and 135 (2.5%) HIV- individuals died. At one year, HIV+ status after adjustment for age, sex, calendar year of AMI, smoking status, hypertension and diabetes was associated with a higher risk of death (HR 4.42, 95% CI 1.73-11.27). There were no significant differences in recurrent AMIs (4 [3.0%] HIV+ and 146 [3.0%] HIV- individuals, OR 1.16, 95% CI 0.41-3.27) or in hospitalization rates (OR 0.68 [95% CI 0.42-1.11]). CONCLUSIONS HIV infection was associated with a significantly increased risk of all-cause mortality one year after incident AMI.

The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals.

Systemic immune activation, a major determinant of HIV disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune system, and microbial translocation due to gut mucosal damage. While human genetic variants influencing HIV viral load have been identified, it is unknown to what extent the host genetic background contributes to inter-individual differences in other determinants of HIV pathogenesis like gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty-acid binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble sCD14 (sCD14), a marker of LPS bioactivity and microbial translocation. We also assessed the correlations between HIV viral load, sCD14 and I-FABP. While we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV viral load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection.

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.

The effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study.

BACKGROUND Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channelling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient years). In a conventional Cox model, recent - but not cumulative - exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past four years increased the risk of a CVD event (hazard ratio 2.06, 95% confidence interval 1.43-2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6 to 36 months caused the greatest increase in risk. CONCLUSIONS Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

High Hepatic and Extrahepatic Mortality and Low Treatment Uptake in HCV-coinfected Persons in the Swiss HIV Cohort Study between 2001 and 2013

BACKGROUND & AIMS The landscape of HCV treatments is changing dramatically. At the beginning of this new era, we highlight the challenges for HCV-therapy by assessing the long-term epidemiological trends in treatment uptake, efficacy and mortality among HIV/HCV-coinfected people since the availability of HCV therapy. METHODS We included all SHCS participants with detectable HCV RNA between 2001 and 2013. To identify predictors for treatment uptake uni- and multivariable Poisson regression models were applied. We further used survival analyses with Kaplan-Meier curves and Cox regression with drop-out as competing risk. RESULTS Of 12,401 participants 2107 (17%) were HCV RNA positive. Of those, 636 (30%) started treatment with an incidence of 5.8/100 person years (PY) (95% CI 5.3-6.2). Sustained virological response (SVR) with pegylated interferon/ribavirin was achieved in 50% of treated patients, representing 15% of all participants with replicating HCV infection. 344 of 2107 (16%) HCV RNA positive persons died, 59% from extrahepatic causes. Mortality/100 PY was 2.9 (95% CI 2.6-3.2) in untreated patients, 1.3 (1.0-1.8) in those treated with failure, and 0.6 (0.4-1.0) in patients with SVR. In 2013, 869/2107 (41%) participants remained HCV RNA positive. CONCLUSIONS Over the last 13 years HCV treatment uptake was low and by the end of 2013, a large number of persons remain to be treated. Mortality was high, particularly in untreated patients, and mainly due to non-liver related causes. Accordingly, in HIV/HCV-coinfected patients, integrative care including the diagnosis and therapy of somatic and psychiatric disorders is important to achieve mortality rates similar to HIV-monoinfected patients.