Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: DNA methylation-based estimators of biological age are reliable biomarkers of the ageing process. We aimed to investigate a range of epigenetic ageing biomarkers in a substudy of the NEAT001/ANRS143 clinical trial, which compared ritonavir-boosted darunavir with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in antiretroviral therapy (ART)-naive adults. METHODS: We analysed frozen whole blood samples from 168 ART-naive participants with HIV from the NEAT001/ANRS143 trial, before ART initiation and after 2 years of ART (84 participants on ritonavir-boosted darunavir with raltegravir and 84 participants on ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine). We also included 44 participants without HIV with a similar age and sex distribution. We analysed DNA methylation. Epigenetic age estimators (Horvath's clock, Hannum's clock, GrimAge, and PhenoAge) and estimated leucocyte compositions were generated using Horvath's New Online Methylation Age Calculator and Houseman's method. We calculated epigenetic age acceleration measures for each estimator of epigenetic age. The NEAT001/ANRS143 trial is registered with ClinicalTrials.gov, NCT01066962. FINDINGS: Compared with the HIV-uninfected group, ART-naive participants with HIV showed higher epigenetic age acceleration (EAA) according to all EAA estimators (mean 2·5 years, 95% CI 1·89-3·22 for Horvath-EAA; 1·4 years, 0·74-1·99 for Hannum-EAA; 2·8 years, 1·97-3·68 for GrimAge-EAA; and 7·3 years, 6·40-8·13 for PhenoAge-EAA), with all differences being statistically significant except for Hannum-EAA (Horvath-EAA p=0·0008; Hannum-EAA p=0·059; GrimAge-EAA p=0·0021; and PhenoAge-EAA p<0·0001). Epigenetic ageing was more pronounced in participants who had CD4 counts less than 200 cells per µL (significant for PhenoAge and Hannum's clock, p=0·0015 and p=0·034, respectively) or viral loads over 100 000 copies per mL at baseline (significant for PhenoAge, p=0·017). After 2 years of ART, epigenetic age acceleration was reduced, although PhenoAge and GrimAge remained significantly higher in participants with HIV compared with participants without HIV (mean difference 3·69 years, 95% CI 1·77-5·61; p=0·0002 and 2·2 years, 0·47-3·99; p=0·013, respectively). There were no significant differences in the ART effect on epigenetic ageing between treatment regimens. At baseline, participants with HIV showed dysregulation of DNA methylation-based estimated leucocyte subsets towards more differentiated T-cell phenotypes and proinflammatory leucocytes, which was also partly restored with ART. INTERPRETATION: ART initiation partly reversed epigenetic ageing associated with untreated HIV infection. Further studies are needed to understand the long-term dynamics and clinical relevance of epigenetic ageing biomarkers in people with HIV. FUNDING: NEAT-ID Foundation.

HIV care in Central and Eastern Europe: How close are we to the target?

OBJECTIVES: The aim of this survey was to describe the current status of HIV care in the countries of Central and Eastern Europe and to investigate how close the region is to achieving the UNAIDS 2020 target of 90-90-90. METHODS: In 2014, data were collected from 24 Central and Eastern European countries using a 38-item questionnaire. RESULTS: All countries reported mandatory screening of blood and organ donors for HIV. Other groups subjected to targeted screening included people who inject drugs (PWID) (15/24, 62.5%), men who have sex with men (MSM) (14/24, 58.3%), and sex workers (12/24, 50.0%). Only 14 of the 24 countries (58.3%) screened pregnant women. The percentages of late presentation and advanced disease were 40.3% (range 14-80%) and 25.4% (range 9-50%), respectively. There was no difference between countries categorized by income or by region in terms of the percentages of persons presenting late or with advanced disease. The availability of newer antiretroviral drugs (rilpivirine, etravirine, darunavir, maraviroc, raltegravir, dolutegravir) tended to be significantly better with a higher country income status. Ten countries reported initiating antiretroviral therapy (ART) regardless of CD4+ T cell count (41.7%), five countries (20.8%) used the threshold of <500 cells/µl, and nine countries (37.5%) used the threshold of <350cells/µl. Initiation of ART regardless of the CD4+ T cell count was significantly more common among high-income countries than among upper-middle-income and lower-middle-income countries (100% vs. 27.3% and 0%, respectively; p=0.001). Drugs were provided free of charge in all countries and mostly provided by governments. There were significant discrepancies between countries regarding the follow-up of people living with HIV. CONCLUSIONS: There are major disparities in the provision of HIV care among sub-regions in Europe, which should be addressed. More attention in terms of funding, knowledge and experience sharing, and capacity building is required for the resource-limited settings of Central and Eastern Europe. The exact needs should be defined and services scaled up in order to achieve a standard level of care and provide an adequate and sustainable response to the HIV epidemic in this region.

Prevalence of Anal Human Papillomavirus Infection in Hungarian Men Who Have Sex with Men.

Anal cancer is one of the leading causes of death in non-AIDS defining cancers. Most of these cancers are associated with high risk HPV infection. So far, the prevalence and the significance of anal HPV infection have not been studied in the Hungarian MSM population. The main objective of our study was to determine the prevalence and associated risk factors of HPV-infection in the Hungarian MSM community, particularly in HIV-infected MSM. Out of 109 examinations 92 samples (80 HIV-infected and 12 HIV-negative MSM) were evaluated for both cytological abnormalities and HPV genotyping PCR. Using a questionnaire all enrolled individuals were interviewed about their sexual behavior, socioeconomic factors, drug use and other known or suspected risk factors. In the HIV-infected cohort 97.5% of the examined individuals were positive for any HPV type. In this group we detected high risk (HR) HPV in 88.8%, low risk (LR) HPV in 75.0% and probably high risk (PHR) HPV in 47.5% and multiple HPV infection was absolutely common (82.5%). In the HIV-negative MSM group the incidence of HPV-infection was 58.3%. The respective rate of HR-HPV, LR-HPV and PHR-HPV genotypes were 33.3%, 58.4%, and 16.7%. In the HIV-negative group both HPV infection frequency and the prevalence of the pertinent genotypes were much lower. The Hungarian MSM population is severely infected with HPV and HR-HPV. High-risk sexual behaviors are strong predictors for acquiring HR-HPV co-infections. Our results underline the necessity of anal cancer screening and the introduction of the vaccination program in the high-risk population.

Telaprevir-based therapy for treatment of HIV-1 and hepatitis C virus co-infected patients: An early access programme.

OBJECTIVES: HPC3005 is a multicentre, open-label, telaprevir trial in HCV/HIV coinfected patients with severe fibrosis or compensated cirrhosis. METHODS: Patients were treated with telaprevir 750 mg every 8 h (1125 mg if on efavirenz) plus pegylated interferon-alpha (PEG-IFN, 180 µg once-weekly) and ribavirin (RBV, 800 mg/day) for 12 weeks, followed by 36 weeks of PEG-IFN/RBV. RESULTS: Mean age was 44 years, 97/118 patients were male and all were Caucasian, 68 had severe fibrosis and 50 had cirrhosis. Seventy-eight had HCV RNA levels ≥800 000 IU/mL, 72 had HCV genotype 1a, baseline HIV RNA was <50 copies/mL in 112 patients. Overall, 114/118 patients continued antiretroviral treatment, 4 were untreated. Seventy-five patients received tenofovir and 74 emtricitabine; in addition 53 received atazanavir/ritonavir, 43 raltegravir, and 24 efavirenz. By intention-to-treat, 78 (66%) patients achieved SVR24. Nineteen discontinued telaprevir, 8 for virological endpoint, 5 for adverse events (2 anaemia, 2 rash, 1 asthenia), 5 for non-compliance and 1 withdrew consent. The most common adverse events were anaemia (36 patients), thrombocytopaenia (33), rash (26), bilirubin increase (17), and neutropenia (16). CONCLUSIONS: In this early access programme in coinfected patients with severe fibrosis or cirrhosis, 66% of patients achieved SVR. The most common adverse events were haematological. CLINICAL TRIAL NUMBER: NCT01500616.

[Anal cytology]. / Anális citológia.

INTRODUCTION: The incidence of anal cancer has increased in recent decades, particularly among human immunodeficiency virus infected men who have sex with men. Anal intraepithelial neoplasia is a potential precursor lesion of anal cancer. Anal cytology is the primary screening test for anal intraeptithelial neoplasia. AIM: The authors aimed to analyze the results of anal cytology of patients with human immunodeficiency virus infection at the National Centre of STD, Department of Dermatology, Dermatooncology and Venereology, Semmelweis University. METHOD: 155 anal cytological examinations were performed in 140 patients between November 1, 2012 and August 31, 2014. RESULTS: 44% of patients were found to have anal dysplasia, and only 1.6% of patients had high-grade lesions. This rate is lower as compared to published studies including larger number of patients. CONCLUSIONS: The study underlines the necessity of screening for anal lesions in the population at-risk.

[Lymphogranuloma venereum: the first Hungarian cases]. / Lymphogranuloma venereum: elso hazai esetek.

Lymphogranuloma venereum is a sexually transmitted infection caused by the Chlamydia trachomatis serovars L1-3. It has been found to be endemic in tropical countries. In the last decades several cases have been reported in Western Europe, particularly in men who have sex with men population infected with human immunodeficiency virus. The authors present three cases of lymphogranuloma venereum infections, observed at their department in 2013 and 2014. The three human immunodeficiency virus infected patients who belonged to men who have sex with men population had casual sexual contacts in Western Europe. The symptoms included urethral discharge, discomfort and inguinal lymphadenomegaly in two patients, and rectal pain, discharge and perianal ulceration in one patient. The diagnosis was confirmed by nucleic acid amplification test performed in samples obtained from urethral discharge and exudate of perianal ulcer; lymphogranuloma venereum 2b serovars were demonstrated in two patients and serovar 2 in one patient. Doxycyclin (daily dose of two times 100 mg for 21 days) resolved the symptoms in all cases. The authors conclude that lymphogranuloma venereum is a diagnostic challenge in Hungary, too. It is important to be aware of the altered clinical features of this disease to prevent complications and spreading.

[Neurocognitive impairments of HIV infected individuals -- preliminary results of a national prevalence study in Hungary]. / HIV-fertozött személyek neurokognitív eltérései -- hazai prevalenciavizsgálat elozetes eredményei.

UNLABELLED: BACKGROUND and PURPOSE: The outcome of HIV infection has dramatically improved due to the widespread use of combined antiretroviral therapy (cART). Opportunistic infections faded and internal and hemato-oncological diseases along with neurological conditions came to the forth. Present study is to evaluate neurocognitive performance of the Hungarian HIV infected individuals, at first in this setting. PATIENTS and METHODS: We performed this cross-sectional pilot study within the frames of a national, single-center; prospective study on group of HIV infected patients, analyzing medical data and neurocognitive performance. Based on international recommendations visual memory, visuomotor coordination, non-verbal learning ability, executive functions and reaction time were tested by six domains of a computerized neuropsychological test battery (Vienna Test System). RESULTS: Data of 59 enrolled HIV individuals were analysed; nine of whom were women (15%), median age 42.6 (IQR: 32.4-48.1) years. In 32.2% (n=19) of patients neurocognitive impairment was detected. Duration of infection and cART treatment time tended to be longer in impaired group (not significant). Lower CD4 cell count at the time of examination (p=0.047), psychiatric diseases other than depression (p=0.005) were found significantly associated with impairment; tertiary education qualification were more common (p=0.033) among non-affected patients. By correlation analysis age, infected time and duration of cART were significantly associated with motor deficit. CONCLUSION: HAND was detected in almost one third part of examined patients, which largely corresponds that in developed countries were observed. Duration of infection and of cART therapy associated motor deficit was found to be the most common impairment. This finding might be interpreted by direct effect of HIV, neurotoxicity of antiretro virals and also by accelerated ageing of this population.

Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals.

BACKGROUND: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). METHODOLOGY/PRINCIPAL FINDINGS: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline. CONCLUSIONS/SIGNIFICANCE: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up. TRIAL REGISTRATION: ClinicalTrial.gov NCT00712530.

Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN.

Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96 efficacy and safety of darunavir/ritonavir (DRV/r) versus lopinavir/ritonavir (LPV/r). Treatment-experienced, LPV-naive, HIV-1-infected patients were randomised to DRV/r 600/100 mg bid or LPV/r 400/100 mg bid plus optimised background regimen (≥ 2 NRTIs/NNRTIs). 595 patients were enrolled (mean baseline HIV-1 RNA: 4.30 log10 copies/mL; median CD4 count: 232 cells/mm3). At Week 96, more DRV/r than LPV/r patients achieved HIV-1 RNA < 400 copies/mL (66.8% versus 58.9% [intent-to-treat (ITT)/time-to-loss of virological response (TLOVR)], estimated difference 8.7%, 95% confidence interval [CI]: 0.7-16.7), demonstrating the primary endpoint of non-inferiority of DRV/r (p < 0.001); the difference in response was statistically significant (p = 0.034). For the secondary efficacy parameter (HIV-1 RNA < 50 copies/mL) at Week 96, response to DRV/r was 60.4% versus 55.2% for LPV/r (ITT-TLOVR), estimated difference 5.8%, 95% CI: -2.3-13.9. Virological failure (VF; HIV-1 RNA > 400 copies/mL) with DRV/r (13.8%) was nearly half that with LPV/r (25.6%). Discontinuations due to adverse events were 8.1% for both DRV/r and LPV/r. Treatment-related grade 2-4 diarrhoea was 8.1% (DRV/r) versus 15.2% (LPV/r). Increases in triglycerides and total cholesterol were less pronounced with DRV/r. At 96 weeks, noninferiority (HIV-1 RNA < 400 copies/mL) of DRV/r over LPV/r was maintained; the difference in response was statistically significant. VF rate and treatment-related grade 2-4 diarrhoea were lower with DRV/r versus LPV/r.

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy.

BACKGROUND: The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. METHODS: The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. RESULTS: Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. CONCLUSIONS: The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline.

BACKGROUND: In virologically suppressed patients, switching to darunavir/ritonavir monotherapy could avoid resistance and adverse events from continuing nucleoside analogues. METHODS: Two hundred and fifty-six patients with HIV RNA <50 copies/mL on current antiretrovirals were switched to darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside analogues (n = 129). Treatment failure was defined as two consecutive HIV RNA levels at least 50 copies/mL by week 96, or discontinuation of study drugs. The trial had 80% power to show non-inferiority (δ = -12%) at week 48. Results Patients were 81% male, 91% Caucasian, and had a median baseline CD4 count of 575 cells/mm(3). There were more patients with hepatitis C co-infection at baseline in the monotherapy arm (18%) compared with the triple therapy arm (12%). In the efficacy analysis, HIV RNA <50 copies/mL by week 96 (per protocol, time to loss of virological response, switch equals failure) was 78% versus 82% in the monotherapy and triple therapy arms [difference -4.2%, 95% confidence interval (CI) -14.3% to +5.8%]; in a switch included analysis, HIV RNA <50 copies/mL was 93% versus 92% (difference +1.6%, 95% CI -5.0% to +8.1%). The percentage of patients with HIV RNA <5 copies/mL (optical density from the sample equal to the negative control) remained constant over time in both treatment arms. Conclusions In the week 96 analysis of the MONotherapy in Europe with TMC114 (MONET) trial, switching to darunavir/ritonavir monotherapy showed non-inferior efficacy to darunavir/ritonavir plus two nucleoside analogues in the switch included and observed failure analyses, but not in the main switch equals failure analysis.

A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population.

BACKGROUND: Although efavirenz is a universally recommended treatment for naive HIV-infected individuals, neuropsychiatric adverse events are common. METHODS: The Study of Efavirenz NeuropSychiatric Events versus Etravirine (SENSE) trial is a double-blind, placebo-controlled study in which 157 treatment-naive individuals with HIV-RNA higher than 5000 copies/ml were randomized to etravirine 400 mg once daily (n = 79) or to efavirenz 600 mg once daily (n = 78), with two investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs). The primary end point was the percentage of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric adverse events up to week 12. RESULTS: The study population were 81% men and 85% whites, with a median age of 36 years, baseline CD4 cell counts of 302 cells/µl and HIV-RNA of 4.8 log10 copies/ml. In the intent-to-treat analysis, 13 of 79 individuals (16.5%) in the etravirine arm and 36 of 78 individuals (46.2%) in the efavirenz arm showed at least one grade 1-4 drug-related treatment-emergent neuropsychiatric adverse event (P < 0.001). The number with at least one grade 2-4 drug-related treatment-emergent neuropsychiatric adverse event was four of 79 individuals (5.1%) in the etravirine arm and 13 of 78 individuals (16.7%) in the efavirenz arm (P = 0.019). The change in HIV-RNA to week 12 was -2.9 log10 in both treatment arms. The median rise in CD4 cell counts was 146 cells/µl in the etravirine arm and 121 cells/µl in the efavirenz arm. CONCLUSIONS: After 12 weeks, first-line treatment with etravirine 400 mg once daily with two NRTIs was associated with significantly fewer neuropsychiatric adverse events when compared with efavirenz with two NRTIs. The virological and immunological efficacy profile was similar between the two arms.

Incidence of abacavir hypersensitivity reactions in euroSIDA.

BACKGROUND: The aim of the study was to investigate the incidence of abacavir-related hypersensitivity reaction (HSR) and associated deaths in EuroSIDA HIV-1-infected patients. METHODS: Poisson regression models were developed to compare incidence of abacavir discontinuation according to the line of therapy within which abacavir was received, geographical regions, calendar time and drug formulation (abacavir/lamivudine combination tablet versus abacavir as a single drug or abacavir/zidovudine/lamivudine combination). RESULTS: Of 3,278 patients that started abacavir, 2,101 (64.1%) discontinued. Of these, 167 (5.1%) discontinued abacavir within 3 months due to HSR with an incidence of 22.1 (95% confidence interval [CI] 18.7-25.4) per 100 person-years of follow-up. After adjustment for gender, prior AIDS, hepatitis C serostatus, baseline CD4+ T-cell count, region and calendar time, HSR incidence was significantly higher in those starting abacavir in a first-line regimen compared with second-line (incidence rate ratio [IRR] 2.04 [95% CI 1.24-3.38]; P=0.005). There was no significant difference between regions. HSR incidence from 2005 onwards was significantly lower compared with 1999-2000 (IRR 0.54 [95% CI 0.32-0.92]; P=0.024). There was a lower observed incidence in patients starting abacavir/lamivudine compared with other formulations (IRR 0.33 [95% CI 0.13-0.88]; P=0.027), however, available data were limited. CONCLUSIONS: Incidence of abacavir-related HSR is higher in patients starting abacavir in first-line therapy, which could indicate increased over-diagnosis. HSR incidence has decreased in recent years, which might reflect the wider availability of genetic screening and improved awareness of symptoms. There were no reported deaths due to abacavir HSR.

[The first case of human alveolar Echinococcosis in Hungary]. / A humán Echinococcus multilocularis infectio elso hazai esete.

Infection caused by Echinococcus multilocularis is a rare helminthiasis, human cases have not been diagnosed in Hungary until now. The endemic region is Central Europe; the occurrence of this infection has been reported from most of the neighbouring countries; however, E. multilocularis has been found in the red fox population in Hungary. Summarizing the recent knowledge concerning epidemiological, clinical patterns and therapeutic options, the authors describe the first Hungarian case of alveolar echinococcosis. In the presence of appropriate clinical findings, the possibility of this rare infection has to be considered in the differential diagnosis of infiltrative hepatic lesions.

Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial.

BACKGROUND: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients. METHODS: Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS: Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients. INTERPRETATION: In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.

Development of a sensitive assay for the measurement of antibodies against heat shock protein binding protein 1 (HspBP1): increased levels of anti-HspBP1 IgG are prevalent in HIV infected subjects.

The 70 kDa heat shock protein (Hsp70) is generally considered to be an intracellular protein, however, there is evidence that Hsp70 can be found in the extracellular environment. Hsp70 and antibodies against Hsp70 have been reported in human serum. Recent evidence has shown that Hsp70 antibodies are elevated in HIV infected individuals. This study reports on the antibody levels against a co-chaperone, HspBP1, that regulates Hsp70 activity. We have developed a solid-phase enzyme linked assay for the determination of anti-HspBP1 IgG antibodies. We report here that HspBP1 antibodies are present in human serum and the levels are elevated approximately twofold in HIV infected patients. There was no correlation between HspBP1 antibody levels and clinical parameters nor was there a relation between anti-Hsp70 levels and anti-HspBP1 levels. The presence of HspBP1 antibodies in human serum suggests that the protein may also be present in the serum. The increased level of HspBP1 antibodies in HIV infected individuals suggests a relationship directly to the virus or indirectly to secondary consequences of HIV infection.

Decline in esophageal candidiasis and use of antimycotics in European patients with HIV.

BACKGROUND: Esophageal candidiasis (EC) remains one of the most common AIDS defining illnesses in patients with human immunodeficiency virus (HIV) in the era of highly active antiretroviral therapy (HAART), but little is known about factors associated with EC after starting HAART. OBJECTIVES: To describe changes in the use of antimycotic medication, the incidence of EC and factors associated with EC before and after starting HAART. METHODS: Patients from EuroSIDA, a pan-European longitudinal, prospective observational study. Generalized linear models and poisson regression models were used to investigate the relationships. RESULTS: A total of 9,873 patients did not have EC at recruitment, subsequently 537 (15.8%) developed EC. The proportion of patients taking any antimycotic dropped from 18% at January 1995 to 2% at January 2004 (p < 0.0001); the duration of treatment declined from 10 to 3 months over the same period (p < 0.0001). There was a 32% annual decline in the incidence of EC (95% CI 30-35%, p < 0.0001). There was a significant annual decline in the incidence of EC pre-HAART in time-updated, adjusted models, (incidence rate ratio (IRR) 0.80, 95% CI 0.76-0.85, p < 0.0001) but not post-HAART (IRR 0.97; 95% CI 0.90-1.06, p= 0.54). Older patients and those with low CD4 counts had the greatest incidence of EC in the post-HAART era. CONCLUSIONS: There has been a marked decline in the incidence of EC between 1994 and 2004. This was accompanied by a decline in markers associated with fungal disease, including use of antimycotics and a decline in duration of treatment.

Antibodies against heat shock proteins and cholesterol in HIV infection.

This review summarizes data on the presence and function of different heat shock proteins (Hsp) in the HIV virions and the infected cells. A 60 kD heat shock protein-like molecule is present in the envelope of the human immunodeficiency virus type 1 which can specifically interact with the transmembrane glycoprotein gp41. The role of cholesterol in the so-called cholesterol-rich lipid raft where HIV is budding from the infected cells as well as the consequential insertion of cholesterol into the envelope of HIV virion are also discussed. Natural antibodies against 60 kD (Hsp60) and 70 kD (Hsp70) families of Hsp and cholesterol can be detected in most healthy individuals. HIV infection results in a sharp increase in the serum concentration of anti-Hsp70 and cholesterol antibodies whereas no difference in the concentration of anti-Hsp60 antibodies can be detected. Highly active antiretroviral therapy leads to normalization of the levels of both anti-Hsp70 and anti-cholesterol antibodies.

Elevated levels of antibodies against 70 kDa heat shock proteins in the sera of patients with HIV infection.

Heat shock proteins (Hsp), especially 70 kDa heat shock protein (Hsp70) play an important role in the life cycle of HIV-1 virus. Hsp70 is overexpressed in HIV-infected cells and this is the most abundant Hsp associated with HIV virions. The aim of our study was to investigate whether HIV infection increases the extent of specific humoral immune response against Hsp70. The serum concentration of anti-Hsp70 IgG antibodies was measured in 47 HIV-infected patients, and 62 healthy, HIV-seronegative persons. Nineteen patients on highly active anti-retroviral therapy (HAART) were followed for 24 months in a longitudinal study. Anti-Hsp70 antibodies were measured by ELISA, using recombinant human Hsp70. Levels of anti-Hsp70 antibodies were significantly (P < 0.0001) higher in the HIV-infected patients (median: 1409 (25th-75th percentile: 1031-2214) AU/ml) than in healthy control subjects (626 (429-970) AU/ml). In 19 HIV patients, serum levels of anti-Hsp70 antibodies significantly (P < 0.001) decreased during 24 (11-41) months HAART (1309 (887-2213) AU/ml before and 640 (386-959) AU/ml during HAART), accompanied by viral load reduction and CD4+ count elevation. It is concluded that HIV-infection induces a marked increase in the anti-Hsp70 antibody levels, which is consistent with the enhanced expression of Hsp70 on the surface of HIV-infected cells and/or incorporation of the protein into the membrane of HIV virions.

Significant decrease of the enhancement/neutralization index in HIV patients during highly active antiretroviral therapy (HAART).

Authors studied the effect of highly active antiretroviral therapy (HAART) on balance of the antibodies that enhance or neutralize growth of HIV-1(IIIB) strain in MT-4 cells in the presence or absence of human complement. Sequential serum samples were collected from 28 patients in advanced stage of HIV disease before and during HAART. The balance of the enhancing and neutralizing antibodies was expressed by an index value (E/N I). Samples with an E/N I of <0.5 (twofold decrease in virus production) were considered as neutralizing, whereas samples with an E/N I>2.0 (twofold increase in virus production) were considered as enhancing. At the beginning of HAART serum samples from eight patients enhanced, and samples from only two patients neutralized the virus in the presence of complement, median (25th-75th percentile) value of E/N I was 1.32 (0.79-2.29). E/N I significantly (P<0.0001) dropped to 0.37 (0.19-0.57) during the follow-up period of 18.5 (10.5-23.5) months under HAART. Similar changes were detected when serum samples were tested with no complement added. The E/N I values were also markedly decreased when cultures inoculated with mixtures of HIV and purified IgG prepared from serum pools taken before and during HAART, respectively, were compared. In the last samples of 20/28 patients, neutralization was measured even in the presence of complement while enhancement was found with none of these samples. These findings suggest that HAART results in disappearance of enhancing antibodies and switches the E/N I toward neutralization.