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The unprecedented global scale of COVID‐19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarize the evidence for antiretrovirals to treat COVID‐19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the paper is to present the outcomes of the HepHIV 2019 conference, held in Bucharest under the Romanian EU Presidency and focusing on challenges of timely and integrated testing and care. Methods: The conference programme was put together by the organizing committee. It consisted of invited talks and peer‐reviewed abstracts. Results: In all, 65 abstracts from 20 countries were presented during the conference, which had nearly 250 delegates, including high‐profile political representation. The conference highlighted the need to shift towards further disease integration because of the epidemiological characteristics of the hepatitis B (HBV), hepatitis C (HCV), HIV, sexually transmitted infection (STIs) and tuberculosis (TB) epidemics in the WHO European region. Integration should be a priority in the response to the epidemics to better reach key populations and to ensure better testing coverage. This relates to both the integration of services in shared care models and the integration of different settings and stakeholders in national strategies. Conclusions: The conference demonstrated the need for greater political support for the policy changes required to implement integration. Testing normalization efforts are key to maximizing the impact of integration efforts. The conference call to action can help to guide developments in testing and linkage‐to‐care interventions across the European region. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Studies have shown that hepatitis C virus ( HCV) RNA levels remain stable over time in HIV/ HCV-coinfected individuals taking combination antiretroviral therapy (c ART), while spontaneous clearance of HCV RNA during the persistent infection phase has been documented only rarely among those with the CC interleukin ( IL)-28B genotype. This study describes HCV RNA profiles and factors associated with changes over time in HCV RNA levels in the ESPRIT study. Methods HIV/ HCV-coinfected individuals positive for HCV RNA were included in the study. Follow-up was counted from the first HCV RNA positive test and censored at the initiation of interferon-based treatment. HCV RNA and IL-28B measurements were performed in the same reference laboratory. Random effects mixed models were used to analyse changes over time in HCV RNA. Results A total of 312 ESPRIT patients were included in the study (151 in the arm receiving subcutaneous recombinant IL-2 and 161 in the control arm). Most of the patients were white (89%) and male (76%), and they had a median of 5 HCV RNA measurements per person [interquartile range ( IQR) 3-6; range 1-9]. Median follow-up was 5 years ( IQR: 2−6 years). At baseline, 96% of patients were taking cART and 93% had undetectable HIV RNA. Mean HCV RNA levels decreased by 13% per year over the study period [95% confidence interval ( CI) 8-18%; P < 0.0001]. Baseline HCV RNA levels and the change over time in HCV RNA did not differ by randomization arm ( P = 0.16 and P = 0.56, respectively). Nine individuals spontaneously cleared HCV RNA during follow-up [ IL-28B genotypes: CC, five patients (56%); CT, four patients (44%)]. Conclusions HCV RNA levels decreased over time in this population with well-controlled HIV infection. Spontaneous clearance of HCV RNA was documented in five individuals with IL-28B genotype CC and four with the CT genotype. [ABSTRACT FROM AUTHOR]

Background The European AIDS Clinical Society ( EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. Guideline highlights The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment ( ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment ( START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (Pr EP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug−drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus ( HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. Conclusions The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy ( ART) on liver fibrosis progression. Methods Sites in the Strategic Timing of AntiRetroviral Treatment ( START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline. Results A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography ( TE) result. The median TE score was 4.9 kPa [interquartile range ( IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval ( CI) 5.1-12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase ( ALT) per 10 U/ L ( P = 0.045), higher log10 HIV RNA ( P < 0.001) and Hispanic/ Latino ethnicity ( P = 0.01). TE correlated weakly with noninvasive markers. Conclusions At baseline, significant liver fibrosis was observed in approximately 8% of participants, with higher ALT and HIV RNA the only clinical factors associated with increasing TE score. TE will be used annually to monitor fibrosis and evaluate the role of ART in further fibrosis progression. [ABSTRACT FROM AUTHOR]

Objectives Following resolution of hepatitis C virus ( HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. Methods All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. Results Of 191 eligible patients, 35 [18.3%; 95% confidence interval ( CI) 12.8-23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users ( IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0-5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio ( OR) 0.44; 95% CI 0.20-0.99; P = 0.046] and older persons ( OR 0.51 per 10 years older; 95% CI 0.28-0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non- IDUs ( OR 6.58; 95% CI 1.48-29.28; P = 0.013). Conclusions Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early. [ABSTRACT FROM AUTHOR]

Objectives The incidence of sexually transmitted hepatitis C virus ( HCV) reinfection is on the rise in HIV-infected men who have sex with men ( MSM). Data on natural history of acute hepatitis C and possible factors associated with spontaneous clearance are limited. The aim of this study was to analyse the outcome of HCV reinfections in HIV-positive MSM. Methods A retrospective analysis was carried out on patients with more than one sexually acquired HCV infection who were diagnosed at four major German HIV and hepatitis care centres. Reinfection was defined by genotype or phylogenetic clade switch, detectable HCV RNA after a sustained virological response ( SVR) or after spontaneous clearance ( SC). Results In total, 48 HIV-positive MSM were identified with HCV reinfection, among them 11 with a third episode and one patient with four episodes. At the first episode, 43 and five patients had an SVR and SC, respectively. The second episode was accompanied by a genotype switch in 29 patients (60%). Whereas 30 and nine patients showed an SVR and SC, respectively, eight patients developed chronic hepatitis. Neither HCV genotype switch nor interleukin-28 B genotype was associated with SC. However, SC rates at the second episode were higher for patients with SC at the first episode compared with patients without SC (60 vs. 14%, respectively; P = 0.03). Two patients with SC at the first episode were reinfected with the same genotype. Conclusions Multiple reinfections in HIV-infected MSM do occur, with or without genotype switch, and with prior SC of previous episodes. In this large case series, except for SC at the first episode, no factor was of value in clinical decision-making for early therapeutic intervention in acute HCV reinfection. [ABSTRACT FROM AUTHOR]

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 χ2 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. [ABSTRACT FROM AUTHOR]

Objectives All HIV/hepatitis C virus ( HCV)-coinfected patients with chronic HCV infection and ≥ F2 fibrosis should be considered for HCV therapy. This study aimed to determine the rate of HCV treatment uptake among coinfected patients in Europe. Methods EuroSIDA patients with viraemic HCV infection were included in the study. Poisson regression was used to identify temporal changes and regional differences in HCV treatment uptake. Results A total of 1984 patients were included in the study, with a median follow-up time of 168 months [interquartile range ( IQR) 121-204 months]. To date, 501 (25.3%) HIV/ HCV-coinfected patients have received HCV therapy. Treatment incidence rose from 0.33 [95% confidence interval ( CI) 0.16-0.50] per 100 person-years of follow-up ( PYFU) in 1998 to 5.93 (95% CI 4.49-7.38) in 2007, falling to 3.78 (95% CI 2.50-5.07) in 2009. After adjustment, CD4 cell count > 350 cells/μL [incidence rate ratio ( IRR) 1.33 (95% CI 1.06-1.67) vs. CD4 count 200−350 cells/μL] and ≥ F2 liver fibrosis [ IRR 1.60 (95% CI 1.14-2.25; P = 0.0065) vs. < F2 fibrosis] were predictors of anti- HCV treatment initiation. However, 22% of patients who remain untreated for HCV, with fibrosis data available, had ≥ F2 fibrosis and should have been considered for treatment, while only 36% of treated patients had ≥ F2 fibrosis. Conclusions Although treatment incidence for HCV has increased, there remain a large proportion of patients indicated for treatment who have yet to be treated. [ABSTRACT FROM AUTHOR]

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 ( Cmin) 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. [ABSTRACT FROM AUTHOR]

Objectives Infection with hepatitis C virus ( HCV) is a major cause of chronic liver disease. High HCV RNA levels have been associated with poor treatment response. This study aimed to examine the natural history of HCV RNA in chronically HCV/ HIV-coinfected individuals. Methods Mixed models were used to analyse the natural history of HCV RNA changes over time in HIV-positive patients with chronic HCV infection. Results A total of 1541 individuals, predominantly White (91%), male (73%), from southern (35%) and western central Europe (23%) and with HCV genotype 1 (58%), were included in the analysis. The median follow-up time was 5.0 years [interquartile range ( IQR) 2.8 to 8.3 years]. Among patients not on combination antiretroviral therapy ( cART), HCV RNA levels increased by a mean 27.6% per year [95% confidence interval ( CI) 6.1−53.5%; P = 0.0098]. Among patients receiving cART, HCV RNA levels were stable, increasing by a mean 2.6% per year (95% CI −1.1 to 6.5%; P = 0.17). Baseline HCV RNA levels were 25.5% higher (95% CI 8.8 to 39.1%; P = 0.0044) in individuals with HCV genotype 1 compared with HCV genotypes 2, 3 and 4. A 1 log HIV-1 RNA copies/mL increase in HIV RNA was associated with a 10.9% increase (95% CI 2.3 to 20.2%; P = 0.012) in HCV RNA. Conclusions While HCV RNA levels increased significantly in patients prior to receiving cART, among those treated with cART HCV RNA levels remained stable over time. [ABSTRACT FROM AUTHOR]

GB virus C (GBV-C) is a member of the Flaviviridae family and the most closely related human virus to HCV. However, GBV-C does not replicate in hepatocytes, but rather in lymphocytes. GBV-C has a worldwide distribution and is transmitted sexually, parenterally and through mother-to-child transmission. Thus, co-infection with HCV and HIV is common. Until now, no human disease has been associated with GBV-C infection. However, there are several reports of a beneficial effect of GBV-C on HIV disease progression in vivo. Different mechanisms to explain these observations have been proposed, including modification of antiviral cytokine production, HIV co-receptor expression, direct inhibition of HIV-1 entry, T-cell activation and Fas-mediated apoptosis. Further understanding of these mechanisms may open new strategies for the treatment of HIV/AIDS. [ABSTRACT FROM AUTHOR]

Objective The aim was to examine the long-term safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double-blind, randomized, controlled Phase III studies. Methods In STARTMRK, treatment-naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK-1 and -2, highly treatment-experienced patients with multi-drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK. Results Hepatitis coinfection was present in 6% (34 of 563) of treatment-naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment-experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug-related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2-4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV-1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK). Conclusion Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV-infected patients with HBV/HCV coinfection. [ABSTRACT FROM AUTHOR]

Recently, we showed chronic hepatitis C to be associated with increased expression of HLA-E and identified peptide hepatitis C virus (HCV) core amino acids 35-44 as a ligand for HLA-E that stabilizes HLA-E expression, favoring inhibition of natural killer cell cytotoxicity. Here we describe HLA-E-restricted recognition of peptide HCV core amino acids 35-44 by CD8(+) T cells. Frequency of HLA-E-restricted responses was significantly higher in patients homozygous for the HLA-E(R) allele (60% vs 38%; [Formula: see text]). Moreover, we found that the HLA-E(R) allelic variant confers protection against chronic infection with HCV genotypes 2 and 3. Taken together, our data indicate an important immunomodulating function of HLA-E in hepatitis C. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of < 500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). RESULTS: HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a > or = 50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a > or = 50 cells/microL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. CONCLUSIONS: HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

BACKGROUND: The combination of highly active antiretroviral therapy (HAART) and liposomal doxorubicin is a promising approach for the treatment of progressive HIV-related Kaposi's sarcoma (KS). Here, we determined the safety, tolerability, and efficacy of liposomal doxorubicin and HAART as a combined treatment approach for advanced KS, and assessed the impact of liposomal doxorubicin on HAART-mediated immune reconstitution and viral suppression. PATIENTS AND METHODS: In an uncontrolled observational trial, KS treatment responses were assessed in 54 HIV-1-infected patients with advanced KS according to ACTG criteria. Immunological and virological treatment responses were compared to 54 non-KS-affected HIV-1 patients who were individually matched to the study participants according to sex, age (+/- 5 years), CD4+ T cell count (+/- 25%), HIV RNA load (+/- 25%) and previous antiretroviral therapy exposure. RESULTS: In 81.5% of the study patients, complete or partial responses were observed within a median of 8 weeks. Treatment-related side effects were predominantly confined to leukopenia (44.4% of patients) and mild-to-moderate liver enzyme elevation (22.3% of patients). Relative CD4+ T cell counts increased to a similar degree both in study patients and matched pairs (7% vs 6%, respectively), yet, absolute CD4+ T cell counts augmented considerably stronger in chemotherapy-naive matched pairs than in the study patients. CONCLUSION: The simultaneous administration of HAART and liposomal doxorubicin is a safe and effective treatment approach for advanced KS and HAART-mediated recovery of relative CD4+ T cell counts does not seem to be impaired by concomitant treatment with liposomal doxorubicin. [ABSTRACT FROM AUTHOR]

Objective To assess the effect of highly active antiretroviral therapy (HAART) on surrogate markers of lymphocyte apoptosis in HIV 1-infected individuals. Methods Ex vivo apoptosis was studied prospectively in 26 antiretroviral naive HIV-positive patients up to 12 weeks after sequential initiation of HAART [phase I: nucleoside reverse transcriptase inhibitor (NRTI), phase II: NRTI + protease inhibitor (PI)]. Apoptosis was assessed via CD95-, Apo2.7-expression and annexin-V-binding in peripheral CD4, CD8, B and NK-cells, and compared to changes in activation markers (HLA-DR, CD38) and viral loads. Results After introduction of HAART CD4-counts rose significantly mainly through cell redistribution, while activation markers decreased. Although Apo2.7 expression decreased throughout the study period, it was not possible to establish a correlation to the rise in CD4 cells. Unexpectedly, CD95 expression and annexin V binding were elevated during phase I of treatment without PI and began to decline only after the addition of a PI in phase II. Poor responders to antiretroviral therapy had significantly higher CD95 expression and annexin V binding in the initial phase of antiretroviral regimen. Conclusion These data show divergent effects of HAART on surrogate markers of apoptosis, when treatment is initiated sequentially with NRTIs first. Partial suppression of HIV replication during treatment without PI may be associated with increased rates of apoptosis. [ABSTRACT FROM AUTHOR]

Objectives To evaluate safety and efficacy of the protease inhibitor combination ritonavir/indinavir 100/800 mg twice daily plus 2–3 nucleoside reverse transcriptase inhibitors (NRTI) in antiretroviral-naive patients. Methods Within this open-label, uncontrolled multicentre trial, antiretroviral-naive patients (n = 57) with median baseline HIV-RNA of 308 000 copies/mL (range 170–3.01 million copies/mL) and median CD4 cell count of 50 cells/μL (range 0–853 cells/μL) were started on 2–3 NRTIs plus ritonavir/indinavir 100/800 mg twice daily. CD4 cell counts and HIV-RNA were determined at weeks 0, 4, 8, 12, 16, 20, 24 and 48. Statistical analysis was performed on treatment as well as intent-to-treat. Results Viral load decreased by a median of 3.79 log10 copies/mL (range 2.0–4.60 log10 copies/mL) until week 48. At week 48, 23/57 (40%, intent-to-treat) patients showed a viral load ≤ 80 copies/mL. In parallel, median CD4 cell counts increased by a median of 149 cells/μL (range -60–420 cells/μL). Median triglycerides and cholesterol increased from baseline 160 mg/dL (range 33–364 mg/dL) to 218 mg/dL (range 110–527 mg/dL) at week 48 and from 166 mg/dL (range 63–262 mg/dL) to 233 mg/dL (range 95–359 mg/dL), respectively. Twenty-seven of fifty-seven patients (47%) discontinued study medication, 19 (33%) due to nephrolithiasis. Two patients changed their antiretroviral regimen after failing virologically. Conclusion Ritonavir/indinavir 100/800 mg twice daily appears to be effective up to 48 weeks despite high baseline viraemia and low CD4 cell count in antiretroviral-naive patients. However, discontinuation due to adverse events, especially nephrotoxicity, is frequent and limits treatment duration. Therefore, extra hydration appears inevitable with this combination. [ABSTRACT FROM AUTHOR]

In a controlled, prospective study, the efficacy of ritonavir 200 mg twice daily (bid) in inhibiting the decrease of amprenavir plasma concentrations caused by co-administration of lopinavir was assessed. Twelve HIV-seropositive patients were enrolled, and nine patients completed the 28-day study. At day 14, plasma concentrations of amprenavir 600 mg bid and ritonavir 200 mg bid were determined over 12 h. At day 15, lopinavir 400 mg bid was added. At day 28, plasma concentrations of amprenavir, ritonavir and lopinavir were assessed. Co-administration of lopinavir was found to decrease the amprenavir concentration, determined as the median area under the curve over 12 h (AUC12), by 25% (AUC12 24.9 microg/h/mL vs. 18.5 microg/h/mL; P<0.01), despite the presence of ritonavir 200 mg bid. Eight participants discontinued the study regimen during the first 6 weeks because of adverse gastrointestinal events. In conclusion, gastrointestinal tolerance of a regimen containing an increased dose of ritonavir 200 mg bid was low, while the regimen did not prevent a decrease of amprenavir and possibly lopinavir plasma concentrations. [ABSTRACT FROM AUTHOR]

Objective To determine the long-term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs). Design and methods In an open-label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients (n = 93) with a high median baseline HIV-1 RNA level of 210 000 copies/mL (range 17 000–2 943 000) and a median CD4 cell count of 195 copies/µL (range 4–656 copies/µL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4-week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures. Results HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks. Conclusions Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load. [ABSTRACT FROM AUTHOR]