Clinical characteristics of women with HIV in the RESPOND cohort: A descriptive analysis and comparison to men.

BACKGROUND: Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND. METHODS: RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM. RESULTS: Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/µl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/µL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001). CONCLUSION: RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV.

Predictors of serofast state after treatment for early syphilis in HIV-infected patients.

OBJECTIVES: Non-treponemal serological tests are used to monitor treatment response during syphilis infection. Syphilis- and HIV-coinfected patients may experience incomplete resolution in non-treponemal titres, which is referred to as the serofast state. The goal of this study was to evaluate risk factors for serofast state in HIV-infected patients. METHODS: From November 2015 to June 2018, 1530 HIV-positive patients were tested for syphilis using a Treponema pallidum particle agglutination (TPPA) assay. Among TPPA-positive patients, medical records were reviewed for early syphilis infection. Serofast state was defined as a less than four-fold decrease in non-treponemal antibody titres during a 6-month follow-up period in the absence of symptoms of syphilis. Baseline characteristics were tested as predictive factors of serological response. RESULTS: In all, 515 patients (33.7%) tested positive in TPPA assays, and in 163 patients at least one previous syphilis infection was documented. A total of 61 out of 163 patients (37.4%) were in a serofast state. A history of previous syphilis infection (61 vs. 43%; P = 0.04) was more common in serofast patients than in patients with serological cure after 6 months. Non-treponemal titres ≥ 1:32 before therapy (47 vs. 25%; P = 0.005) and adjunctive corticosteroids to prevent the Jarisch-Herxheimer reaction (35% vs 15%; P = 0.006) were associated with serological cure after 6 months, but corticosteroid therapy had no influence at 12 months. The intensity of syphilis treatment did not affect serological cure. CONCLUSION: Corticosteroids for prevention of the Jarisch-Herxheimer reaction were associated with earlier serological cure. Although serological response is the accredited surrogate method to monitor syphilis treatment, the biological significance of the serofast state remains unclear.

Rabies post-exposure prophylaxis in Germany - What are the challenges?

Rabies post-exposure prophylaxis (R-PEP) including wound treatment, vaccination and application of rabies immunoglobulin (RIG) is essential in preventing rabies mortality. Today, Germany is officially declared free from terrestrial rabies and rabies is only found in bats. However, physicians in A&E Departments are frequently consulted on the need for R-PEP. We retrospectively analysed patients who received R-PEP at the A&E Department of the University Hospital Bonn between 01.01.2013 and 30.06.2019. Demographic data, travel history, clinical and laboratory findings, previous rabies vaccinations and R-PEP vaccination regimen were recorded. During the study period, 90 patients received R-PEP at the University Hospital Bonn, in 10 cases without indication for R-PEP. Altogether, we found deviations from R-PEP guidelines in 51% (n = 41/80). Infiltration of RIG was missed in 12 patients and incorrectly administrated in 24 patients. Furthermore, vaccination scheme was incorrect in 11 patients. Correct wound washing and documentation of tetanus status was missing in 14% and 63% of patients, respectively. Despite rabies elimination in Germany patients frequently seek advice for R-PEP, the majority returning from foreign travel. Our data show that there is a high need for education on indication for R-PEP before and after travel and for implementation of precise R-PEP guidelines in daily clinical practice.

Switching tenofovir disoproxil fumarate to tenofovir alafenamide in a real life setting: what are the implications?

OBJECTIVES: Development of novel antiretrovirals aims at reducing long-term toxicities. Tenofovir disoproxil fumarate (TDF) has been associated with potential nephrotoxicity. The aim of our study was to assess the impact of switching from TDF to tenofovir alafenamide (TAF) on functional nephropathy and lipid parameters in a real-life setting. METHODS: We retrospectively analysed data from 347 HIV-infected patients switching from a TDF- to a TAF-containing regimen between April and December 2016. Sociodemographic, clinical and laboratory data were collected at TDF-to-TAF switch, and at 3 and 6 months thereafter. Proteinuria and albuminuria were classified according to Kidney Diseases Improving Global Outcomes (KDIGO) guidelines. RESULTS: At time of switch, moderately and severely increased proteinuria was detected in 32% and 8% of patients, respectively; however, urine dipstick analysis was negative in 84% and 42%, respectively. Moderately and severely increased albuminuria was found in 17% and 3% of patients, respectively. In patients with a urinary protein-to-creatinine ratio (UPCR) ≥ 150 mg/g, the mean value declined from 416 mg/g at baseline to 272 mg/g (P < 0.001) and 242 mg/g (P < 0.001) after 3 and 6 months, respectively. Patients with an albumin-to-creatinine ratio (UACR) ≥ 30 mg/g showed no significant decrease of albuminuria. Mean total cholesterol increased from 187 mg/dL at baseline to 202 (P < 0.001) and 208 mg/dL (P < 0.001) at 3 and 6 months, respectively, and mean low-density lipoprotein (LDL) cholesterol increased from 114 mg/dL at baseline to 124 (P < 0.001) and 128 mg/dL (P < 0.001), respectively. As mean high-density lipoprotein (HDL) cholesterol increased from 50 mg/dL at baseline to 54 (P < 0.001) and 57 mg/dL (P < 0.001) at 3 and 6 months, respectively, the LDL:HDL ratio remained stable. CONCLUSIONS: In an aging HIV-infected cohort, proteinuria and albuminuria were common findings and were underdiagnosed via urine dipstick. Our real-life data suggest that laboratory markers of moderately/severely increased proteinuria improved after TDF-to-TAF-switch. Lipid profiles were not aggravated. Long-term follow-up is needed to determine the clinical benefit of the TDF-to-TAF switch.

Treatment outcomes of integrase inhibitors, boosted protease inhibitors and nonnucleoside reverse transcriptase inhibitors in antiretroviral-naïve persons starting treatment.

OBJECTIVES: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. METHODS: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12 ± 3 months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL < 200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4 count > 750 cells/µL or a 33% increase where the baseline CD4 count was ≥ 500 cells/µL. Poisson regression compared clinical failures (AIDS/death ≥ 14 days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. RESULTS: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged > 50 years, 2539 (49.4%) had CD4 counts < 350 cells/µL and 1891 (36.8%) had VL > 100 000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40-50 and > 50 years), CD4 count categories (≤ 350 vs. > 350 cells/µL) and VL categories at ART initiation (≤ 100 000 vs. > 100 000 copies/mL), with all investigated interactions being nonsignificant (P > 0.05). CONCLUSIONS: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

Liver stiffness regression after successful Hepatitis C treatment is independent of HIV coinfection.

OBJECTIVES: The aim of the study was to assess the regression of liver stiffness after successful direct-acting antiviral (DAA) treatment in patients with hepatitis C virus (HCV) monoinfection and HCV/-HIV coinfection. In addition, we aimed to identify factors associated with liver stiffness regression. METHODS: We studied patients treated with interferon-free DAA regimens with a sustained virological response at week 12 (SVR12 ) or 24 (SVR24 ) post-treatment. Liver stiffness was assessed by transient elastography (TE) before the initiation and after the end of treatment (median 12 weeks). RESULTS: Of 214 enrolled patients, 85 (40%) were HCV monoinfected and 129 (60%) HCV/HIV coinfected. Baseline median TE values were 7.8 kPa [interquartile range (IQR) 5.9-12.0 kPa] in mono-infected patients and 10.7 kPa (IQR 7.8-17.0 kPa) in coinfected patients. Overall, the median TE value decreased from 10.1 to 6.8 kPa (n = 214; P < 0.0001). There was no difference between mono- and coinfected patients (-2.2 versus -3.3 kPa, respectively; P = 0.88), which was verified by an analysis of covariance (ANCOVA) adjusting for baseline TE values. Significant (≥ 30%) regression of liver stiffness was achieved by 45% of patients (54% with baseline TE ≥ 7.1 kPa). In multivariate analysis, a prior HCV treatment was a negative predictor of liver stiffness regression [odds ratio (OR) 0.31; P = 0.001]. A higher baseline TE value was positively associated with achieving a significant regression (OR 1.06; P = 0.02). HIV coinfection status, HCV genotype, age, sex, treatment duration, controlled attenuation parameter value, bilirubin concentration, platelet count and aspartate aminotransferase concentration were not associated with liver stiffness regression. CONCLUSIONS: Regression of liver stiffness after successful DAA treatment did not differ in patients with HCV monoinfection and those with HCV/HIV coinfection. Half of all patients achieved a significant (≥ 30%) regression. Prior treatment for HCV was a negative predictor for this endpoint, while a higher baseline TE value was positively associated with regression.

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.

[HIV infection : Test and treatment]. / HIV-Infektion : Test und Behandlung.

In Europe depending on the country 15-80 % of all individuals infected with human immunodeficiency virus (HIV) are either not aware of the diagnosis or are diagnosed later. An early HIV diagnosis could, however, considerably improve the prognosis of individuals infected with HIV and decrease the risk of new infections; therefore, in the presence of indicator diseases, such as sexually transmitted diseases, oral thrush, herpes zoster and lymphoma, the performance of a HIV test is of utmost importance. A newly diagnosed HIV infection represents an indication for starting antiretroviral combination therapy independent of the clinical stage or CD4 cell count. A decline of the viral burden to below the limit of detection and subsequent continuous suppression of viral replication can prevent transition from HIV to acquired immune deficiency syndrome (AIDS) and if started early enough a normal life expectancy can be achieved. Challenges which remain in HIV therapy are the lifelong daily intake of medication and the complex long-term adverse effects.

Pulmonary hypertension in HIV infection: a prospective echocardiographic study.

OBJECTIVES: While idiopathic pulmonary arterial hypertension (PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of pulmonary hypertension (PH) in patients with HIV infection by echocardiographic screening. METHODS: Echocardiography and N-terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV-positive patients (n = 374) during routine follow-up visits for HIV disease. RESULTS: In echocardiographic screening, PH was detected in a total of 23 of 374 HIV-infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure (sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high-prevalence countries (HPCs). CONCLUSIONS: Echocardiographic screening detected PH in a substantial proportion of HIV-positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV-associated PH. The relevance and long-term outcome of these findings need to be validated in follow-up studies, which are ongoing.

Screening colonoscopy in HIV-infected patients: high rates of mucosal abnormalities in a German HIV-infected cohort.

OBJECTIVES: Because of the improved life expectancy provided by successful antiretroviral combination therapy, preventive health measures in HIV-infected patients have assumed increasing importance. To date, no data exist on rates of mucosal abnormalities detected by screening colonoscopy in > 50-year-old HIV-infected patients in Germany. The aim of this study was to obtain such data. METHODS: A screening colonoscopy was offered to 159 HIV-infected patients (age > 50 years) who presented for HIV standard of care visits at the infectious diseases out-patient clinic at the university hospital in Bonn over a 1-year period from February 2010. Pearson's χ(2) test, Fisher's exact test and the Mann-Whitney U-test were used for statistical analysis. RESULTS: Fifty-one patients (32.1%) had undergone a screening colonoscopy in the past 10 years, and 45 patients (28.3%) were eventually screened in the observation period. The median age of the 96 screened patients (86% male and 14% female) was 58 years [interquartile range (IQR) 54-64 years]. Overall, endoscopic abnormalities were found in 61% of patients. Histological examination showed tubular adenomas in 21.9% of patients, tubulovillous adenomas in 3.1% and serrated adenomas in 1%. Hyperplastic polyps were found in 15.6% of patients, a nonspecific colitis in 16.7% and diverticulosis in 12.5%. In four cases there was even an early-stage carcinoma (two anal, one rectal and one colon cancer). In univariate analysis, no significant differences with regard to immune status, highly active antiretroviral therapy, family history, personal risk factors or comedication were found between patients with dysplastic and normal mucosas. CONCLUSIONS: The high acceptance rate of screening colonoscopy and the in comparison with the HIV-negative population comparably higher rate of abnormalities in this cohort of HIV-infected patients justify enhanced implementation of screening colonoscopy in clinical practice.

Peginterferon-alfa mono-therapy in the treatment of acute hepatitis C in HIV-infection.

The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co-infected individuals. Cohort study of 105 HIV-infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN-alfa alone (group 1; n = 36) or pegIFN-alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV-RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm(3) . Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5-36 weeks after diagnosis (P = 0.03). PegIFN-alfa alone or in combination with ribavirin results in similar response rates in HIV-infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono-therapy might be sufficient to allow for an optimal treatment response.

Causes of death in HIV-infected patients from the Cologne-Bonn cohort.

PURPOSE: Causes of death in human immunodeficiency virus (HIV)-infected subjects have changed in countries with high resources over the last several years. Acquired immunodeficiency syndrome (AIDS)-related diseases have become less prevalent, whereas deaths due to non-AIDS causes are increasing. The aim of the present study was to analyse causes of death in the Cologne-Bonn cohort. METHODS: Causes of death from the Cologne-Bonn cohort between 2004 and 2010 were systematically recorded using the CoDe algorithm (The Coding Causes of Death in HIV Project). RESULTS: In 3,165 patients followed from 2004 to 2010, 182 deaths occurred (5.7 %, 153 males, 29 females). The median age at the time of death was 47 years (range 24-85 years). The most frequent causes of death were AIDS-defining events (n = 60, 33 %), with non-Hodgkin lymphoma (NHL) (n = 29, 16 %) and infections (n = 20, 11 %) being the leading entities in this category. Non-AIDS malignancies accounted for 16 % (n = 29), non-HIV-related infections for 10 % (n = 18), cardiovascular diseases for 7 % (n = 14), suicide or accident for 4 % (n = 7) and liver diseases for 3 % (n = 5) of deaths (unknown n = 47, 26 %). Although the majority of patients (92.5 %) was on antiretroviral therapy (ART), only 50 % were virologically suppressed (HIV-RNA <50 copies/mL) and 44 % had a decreased CD4+ count (<200/µL) at their last visit before death. CONCLUSION: One-third of the causes of death in our cohort between 2004 and 2010 was AIDS-related. Since most of these deaths occur with severe immune suppression, they can possibly be prevented by the early diagnosis and treatment of HIV infection. Care providers must be aware of an increased risk for a broad range of diseases in HIV-infected patients and should apply appropriate preventive measures.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

Pharmacokinetics of the combination raltegravir/atazanavir in HIV-1-infected patients.

OBJECTIVES: To evaluate the use of raltegravir with unboosted atazanavir in combination with one nucleoside reverse transcriptase inhibitor (NRTI) (lamivudine or emtricitabine) as a potentially well-tolerated once-daily (qd) maintenance regimen. METHODS: We compared the pharmacokinetics of raltegravir 400 mg twice daily (bid) with raltegravir 800 mg qd in HIV-infected patients (n=17) on unboosted atazanavir (600 mg qd) in combination with lamivudine or emtricitabine. RESULTS: The area under the plasma concentration vs. time curve for a dose interval t (AUC0 -t ) of 800 mg qd divided by 2 was not significantly different from the AUC0 -t of 400 mg bid (P=0.664) but the minimum concentration (C min ) was 72% lower with the qd regimen (P=0.002). The regimen was well tolerated and the viral load remained undetectable in all patients during the 6 weeks of the study follow-up. CONCLUSIONS: A qd regimen of raltegravir 800 mg, atazanavir 600 mg and lamivudine or emtricitabine resulted in favourable pharmacokinetic profiles and good short-term safety and efficacy data. Larger phase IIb studies are needed to explore this novel regimen.

Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.

Hereditary hyperekplexia, or familial startle disease (STHE), is an autosomal dominant neurologic disorder characterized by marked muscle rigidity of central nervous system origin and an exaggerated startle response to unexpected acoustic or tactile stimuli. Linkage analyses in several large families provided evidence for locus homogeneity and showed the disease gene was linked to DNA markers on the long arm of chromosome 5. Here we describe the identification of point mutations in the gene encoding the alpha 1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families. All mutations occur in the same base pair of exon 6 and result in the substitution of an uncharged amino acid (leucine or glutamine) for Arg271 in the mature protein.

A novel cDNA detects homozygous microdeletions in greater than 50% of type I spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disease in Caucasians (after cystic fibrosis). Childhood SMAs are divided into three groups (type I, II and III), which are allelic variants of the same locus in a region of approximately 850 kb in chromosome 5q12-q13, containing multiple copies of a novel, chromosome 5-specific repeat as well as many atypical pseudogenes. This has hampered the identification of candidate genes. We have identified several coding sequences unique to the SMA region. A genomic fragment detected by one cDNA is homozygously deleted in 17/29 (58%) of type I SMA patients. Of 235 unaffected individuals examined, only two showed the deletion and both are carriers of SMA. Our results suggest that deletion of at least part of this novel gene is directly related to the phenotype of SMA.

A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse.

Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). Spasmodic (spd), a recessive neurologic mouse mutant, resembles hyperekplexia phenotypically, and the two disease loci map to homologous chromosomal regions. Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro. We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns.

Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.

Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. Mutations causing achondroplasia are in FGFR3, suggesting that mutations in this gene may cause TD. A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder.

Liver fibrosis progression after acute hepatitis C virus infection in HIV-positive individuals.

Fibrosis progression after acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients with follow-up >9 months became similar to reported rates from studies in chronic HIV/HCV coinfection, as measured with transient elastometry. The duration of follow-up and serum alanine transaminase correlated with liver stiffness, and short follow-up resulted in high fibrosis progression rates.

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.