bluuebunny/crossref_metadata_2025 huggingface dataset:
Pegylated Interferon-α2b plus Ribavirin: An Efficacious and well-Tolerated Treatment Regimen for Patients with Hepatitis C virus Related Histologically Proven Cirrhosis
Authors: Roff Luigi , Colloredo Guido , Pioltelli Pietro , Bellati Giorgio , Pozzi Massimo , Parravicini Pierpaolo , Bellia Valentina , Del Poggio Paolo , Fornaciari Giovanni , Ceriani Roberto , Ramella Giuliano , Corradi Chiara , Rossini Angelo , Bruno Savino
Published: April 2022

Background

Little is known about the efficacy, safety and tolerability of pegylated interferon plus ribavirin treatment in patients with chronic hepatitis C virus (HCV) infection and histologically proven fully established cirrhosis. We aimed here to evaluate the safety of this regimen in such patients and to identify baseline and on-treatment predictors of a sustained virological response (SVR).

Methods

Patients with histologically proven, HCV-induced cirrhosis were randomized to receive pegylated interferon-α2b (PEG-IFN-α2b; 1.0 μg/kg/week, n=56; group A) or recombinant interferon-α2b (IFN-α2b; 3 million IU three times/week, n=36; group B), each in combination with a weight-based dose of ribavirin (800–1,200 mg/day) for up to 48 weeks. The primary endpoint of the study was the assessment of SVR, defined as undetectable HCV RNA 24 weeks after treatment cessation.

Results

Overall, 40% (37/93) of patients attained SVR: 44% (25/57) in group A and 33% (12/36) in group B ( P=0.31). SVR rates were significantly higher in genotype 2/3 patients than in genotype 1 patients (69% versus 25%; P<0.0001). Platelet count at baseline, rapid virological response, and early virological response were predictors of SVR. Twelve patients discontinued treatment because of an adverse event and 20 patients required ribavirin dose reduction for the management of anaemia.

Conclusions

PEG-IFN-α2b plus ribavirin for 48 weeks is an efficacious and well-tolerated treatment regimen for patients with HCV-induced cirrhosis. Although SVR rates were more satisfactory in genotype 2/3 than in genotype 1 patients, our study identified additional predictors of response that could allow physicians to better manage treatment in this ‘difficult-to-cure’ subset of patients.
Incidence of abacavir hypersensitivity reactions in EuroSIDA
Authors: Bannister Wendy P , Friis-Møller Nina , Mocroft Amanda , Viard Jean-Paul , van Lunzen Jan , Kirk Ole , Gargalianos Panagiotis , Bánhegyi Dénes , Chiesi Antonio , Lundgren Jens D ,   the EuroSIDA study group
Published: April 2022

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.
Comparison of the antiviral activity of adefovir and tenofovir on hepatitis B virus in HIV–HBV-coinfected patients
Authors: Lacombe Karine , Gozlan Joël , Boyd Anders , Boelle Pierre-Yves , Bonnard Philippe , Molina Jean-Michel , Miailhes Patrick , Lascoux-Combe Caroline , Serfaty Lawrence , Zoulim Fabien , Girard Pierre-Marie
Published: April 2022

Background

Characteristics and factors influencing viral decay under tenofovir (TDF) and adefovir (ADV) need to be determined in HIV–HBV-coinfected patients.

Methods

This open-label study compared the HBV dynamics in 85 HIV–HBV-coinfected patients initiating an antiretroviral regimen, either including TDF or associated with ADV. The first 6-month change in viral load was analysed using mixed linear models. The adjusted hazards ratio, comparing the rates of undetectable HBV DNA between treatments, was calculated using a Cox proportional hazard model.

Results

The HBV DNA decay, adjusted for baseline HBV viral load was more pronounced in patients treated with TDF than with ADV at 12 months (66% versus 53%, P=0.0001). Patients in the TDF group presented a steeper slope of decline at 1.1 (95% confidence interval [CI] 0.9–1.3), compared with 0.8 (95% CI 0.6–1.0) in the ADV group ( P=0.036). The mean time to HBV DNA undetectability was 19.3 months (95% CI 16.7–22.0) with TDF and 25.9 months (95% CI 21.1–30.7) with ADV. When adjusted for hepatitis B virus e antigen, HBV DNA and alanine aminotransferase levels at baseline, the influence of treatment on time to HBV DNA undetectability remained in favour of TDF versus ADV (hazard ratio=2.79, 95% CI 1.05–7.40, P=0.039)

Conclusions

TDF influenced more strongly the early-phase HBV DNA kinetics than ADV. This is associated with a sustained antiviral activity in the TDF group, in which patients reached the threshold of HBV undetectability at a faster rate and in a larger proportion than those taking ADV.
Variability in the Plasma Concentration of Efavirenz and Nevirapine is Associated with Genotypic Resistance after Treatment Interruption
Authors: Darwich Laila , Esteve Anna , Ruiz Lidia , Bellido Rocio , Clotet Bonaventura , Martinez-Picado Javier
Published: April 2022

Background

Selection and persistence of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations during treatment interruptions (TIs) has been attributed to the long plasma half-life of these drugs. However, little is known about the contribution of variable NNRTI plasma levels before a TI. We evaluated the selection of NNRTI-related mutations and the coefficient of variation of NNRTI plasma concentrations during different TI periods.

Methods

The selection of NNRTI-related mutations was examined in 50 HIV type-1 (HIV-1)-infected patients on a virologically suppressive regimen who underwent TI guided by CD4+ T-cell counts and plasma viraemia. Population and clone-based sequencing of the reverse transcriptase coding region was performed using plasma HIV-1 RNA samples during TI and proviral DNA from peripheral blood mononuclear cells before TI. NNRTI plasma concentrations were determined by HPLC.

Results

In 7/50 treated patients, de novo and transient NNRTI-related mutations appeared when treatment was interrupted. Emergence of resistant variants (including K103N, Y181C or G190S) after interruption was associated with a higher coefficient of variation in NNRTI plasma concentrations during the treatment period. Moreover, minority HIV-1 variants containing different resistance patterns (V106I/A, K103R/E or Y188C/D/H) were detected regardless of NNRTI concentrations.

Conclusions

The emergence of NNRTI-associated mutations during TI appears to be associated with the variation of NNRTI plasma concentrations during the preceding treatment period. The selection of minority HIV-1 variants with different patterns of NNRTI resistance in the absence of drug pressure should be considered for the efficacy of future NNRTI-containing antiretroviral regimens.
HIV Coinfection and Antiretroviral Therapy Enhances Liver Steatosis in Patients with Hepatitis C, but Only in those Infected by HCV Genotype other than 3
Authors: Borghi Vanni , Puoti Massimo , Mussini Cristina , Bellelli Stefania , Angeletti Claudio , Sabbatini Francesca , Prati Francesca , Cossarizza Andrea , Esposito Roberto
Published: April 2022

Background

Liver steatosis is a common finding in hepatitis C virus (HCV) infection and is associated with an increased progression of the disease. However, HCV genotype 3 steatosis presents a peculiar and virus-induced pathogenesis. We analysed the effect of HIV coinfection and antiretroviral therapy on hepatic steatosis and the effect of the steatosis on fibrosis in patients with or without HCV genotype 3 infection.

Methods

All consecutive HIV-infected and uninfected patients who had undergone a liver biopsy for evaluation of HCV infection at the Infectious Diseases Clinic (Modena, Italy) were included in this study. Primary outcomes were the presence or absence of steatosis or the presence of moderate or advanced fibrosis.

Results

A total of 284 patients were enrolled: 187 infected by HCV and 97 coinfected with HIV and HCV. In HCV genotype 3 patients, only HCV-related variables, such as plasma HCV RNA levels (odds ratio [OR] per log10 1.68, P<0.001) and estimated duration of HCV infection (OR per year 1.17, P=0.004) were associated with steatosis. In patients infected with other HCV genotypes, steatosis was associated with older age (OR per 5 years 1.47, P<0.001), with exposure to d-drugs in HIV–HCV-coinfected patients (OR 2.60, P=0.04) and specifically exposure to stavudine (OR 2.76 HIV–HCV-coinfected versus not HIV-infected patients, P=0.04). Steatosis was independently associated with bridging fibrosis only in patients infected by HCV genotype other than 3 (OR 4.03, P=0.01).

Conclusions

Hepatic steatosis, in both HCV-monoinfected and in HIV–HCV-coinfected patients, is strongly correlated with HCV genotype 3, probably through interactions between HCV virus and liver cells. HIV-related increase of steatosis in patients with HCV is probably related to anti-retroviral drugs, especially stavudine, in patients infected by HCV genotype other than 3.
Prognostic Importance of Anaemia in HIV Type-1-Infected Patients Starting Antiretroviral Therapy: Collaborative Analysis of Prospective Cohort Studies
Authors:   The Antiretroviral Therapy Cohort Collaboration, Harris Ross J , Sterne Jonathan AC , Abgrall Sophie , Dabis François , Reiss Peter , Saag Michael , Phillips Andrew N , Chêne Geneviève , Gill John M , Justice Amy C , Rockstroh Jürgen , Sabin Caroline A , Mocroft Amanda , Bucher Heiner C , Hogg Robert S , Monforte Antonella D'Arminio , May Margaret , Egger Matthias
Published: April 2022

Background

In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined.

Methods

We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0–<11.0 g/dl and female 8.0–<10.0 g/ dl) and 2,971 (25%) had mild (male 11.0–<13.0 g/dl and female 10.0–<12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables.

Results

During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17–1.73), for moderate anaemia 2.56 (2.07–3.18) and for severe anaemia 5.26 (3.55–7.81). Corresponding figures for progression to AIDS were 1.60 (1.37–1.86), 2.00 (1.66–2.40) and 2.24 (1.46–3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months.

Conclusions

Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.
Low-dose Cidofovir for the Treatment of Polyomavirus-Associated Nephropathy: Two Case Reports and Review of the Literature
Authors: Lamoth Frédéric , Pascual Manuel , Erard Véronique , Venetz Jean-Pierre , Nseir Ghaleb , Meylan Pascal
Published: April 2022

Background

Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials.

Methods

Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (≥10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN.

Results

No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports.

Conclusions

In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.
Pharmacokinetics, Safety and Efficacy of Saquinavir/ Ritonavir 1,000/100 Mg Twice Daily as HIV Type-1 Therapy and Transmission Prophylaxis in Pregnancy
Authors: von Hentig Nils , Nisius Gabi , Lennemann Tessa , Khaykin Pavel , Stephan Christoph , Babacan Errol , Staszewski Schlomo , Kurowski Michael , Harder Sebastian , Haberl Annette
Published: April 2022

Background

A saquinavir/ritonavir-containing regimen is one option for the prevention of mother-to-child transmission of HIV during pregnancy. We evaluated the pharmaco-kinetics, efficacy and safety of saquinavir/ritonavir 1,000/100 mg twice daily plus nucleos(t)ide reverse transcriptase inhibitors in 13 women during late pregnancy and compared the results to those of 15 non-pregnant women.

Methods

Protease inhibitor plasma concentration profiles were assessed at 12 h using a standardized therapeutic drug monitoring procedure and measured by LC-MS/MS. Minimum and maximum concentrations (Cmin and Cmax), area under the plasma concentration–time curve (AUC0–12 h), and total clearance (CL total) were compared between the groups and correlated to demographic, physiological and clinical cofactors. Antiviral and immunological efficacy and safety were investigated.

Results

The geometric means (90% confidence interval [CI]) for saquinavir Cmin, Cmax and AUC0–12 h of pregnant versus non-pregnant women were 572 (437–717) versus 765 (485–1,052, P=0.064) ng/ml, 2,168 (1,594–2,807) versus 3,344 (2,429–4,350; P=0.045) ng/ml and 15,512 (11,657–19,943) versus 24,027 (17,454–31,548, P=0.029) ng•h/ml. The geometric means (90% CI) for ritonavir Cmin, Cmax and AUC0–12 h were 190 (148–234) versus 310 (240–381, P=0.011) ng/ml, 781 (580–999) versus 1,552 (1,127–2,007, P=0.004) ng/ml and 5,576 (4,303–7,006) versus 10,528 (8,131–13,177, P=0.003) ng•h/ml. Age, weight, saquinavir dose per weight and body mass index differed significantly; saquinavir Cmin and AUC0–12 h were correlated with ritonavir Cmin and saquinavir dose per weight. After a mean of 11 weeks treatment, 12 of 13 pregnant women had a viral load <400 copies/ml, which was similar to the results of non-pregnant women.

Conclusions

Although saquinavir plasma concentrations were significantly lower in pregnant women compared with non-pregnant women, all pregnant women displayed a saquinavir AUC0–12 h>10,000 ng•h/ml, 92.3% had a viral load <400 copies/ml at birth. Saquinavir was well tolerated by the mothers and all newborn children were HIV type-1 negative at 18 months of age.
Early warning indicators for HIV drug resistance in Malawi
Authors: Hedt Bethany L , Wadonda-Kabondo Nellie , Makombe Simon , Harries Anthony D , Schouten Erik J , Limbambala Eddie , Hochgesang Mindy , Aberle-Grasse John , Kamoto Kelita
Published: April 2022

Background

Malawi started rapid scale-up of antiretroviral therapy (ART) in 2004 and by December 2006 had initiated over 85,000 patients on treatment. Early warning indicator (EWI) reports can help to minimize the risk of emerging drug resistance.

Methods

Data collected during the routine quarterly supervision of 103 public sector sites was used to compile the first EWI report for HIV drug resistance (HIVDR) in Malawi, reflecting outcomes for October to December 2006.

Results

All sites reach the World Health Organization (WHO) targets for prescribing practices and drug supply continuity. The target for adherence was achieved by 85% of sites and 84% achieved the target for minimizing treatment defaults; however, less than half of all sites reach the WHO target for patient retention.

Conclusions

These results emphasize the importance of defaulter tracing and initiating treatment earlier in the course of HIV infection. As part of a comprehensive HIVDR monitoring programme, the Ministry of Health plans for on-going tracking of these indicators, as well as special data collection from the private sector. Plans are also underway to gather information on other recommended indicators that are not collected during routine supervision.
A novel sequential sampling technique for the surveillance of transmitted HIV drug resistance by cross-sectional survey for use in low resource settings
Authors: Myatt Mark , Bennett Diane E
Published: April 2022

This article describes the development of a novel sequential sampling method for the surveillance of transmitted HIV drug resistance by cross-sectional survey. Two commonly used sequential sampling methods are described and their applicability to the problem of classifying the prevalence of transmitted HIV drug resistance investigated. Both methods are rejected due to insufficient savings in sample size and operational complexity. A novel method is proposed and this is tested using computer-based simulation. This method provides useful sample size savings and operational simplicity and could provide the basis for a rapid and reliable survey method for classifying the prevalence of transmitted HIV drug resistance in circumstances where monitoring HIV drug resistance is an important issue, but resources do not allow full-scale surveillance to be established. The method is currently being used in several such settings.
Prognostic factors for virological response in antiretroviral therapy-naive patients in the MONARK Trial randomized to ritonavir-boosted lopinavir alone
Authors: Flandre Philippe , Delaugerre Constance , Ghosn Jade , Chaix Marie Laure , Horban Andrzej , Girard Pierre-Marie , Gladysz Andrzej , Cohen-Codar Isabelle , Van Philippe Ngo , Taburet Anne-Marie , Rouzioux Christine , Delfraissy Jean-François
Published: April 2022

Background

MONARK is a pilot randomized trial comparing the safety and efficacy of lopinavir/ritonavir (LPV/r) monotherapy to a standard triple-drug regimen as initial therapy. The primary endpoint was virological response (VR) defined as viral load (VL)<400 copies/ml at week 24 and VL<50 copies/ml at week 48. The objective of this study was to determine prognostic factors of VR in patients receiving LPV/r monotherapy.

Methods

Baseline characteristics, including demographics, HIV type-1 (HIV-1) subtype (B versus non-B), early VR up to week 4, LPV trough concentrations and compliance were investigated as prognostic factors for VR in patients receiving LPV/r monotherapy. Logistic regression was used to search for variables significantly associated with the occurrence of VR.

Results

VR was achieved in 53 out of 83 patients randomized to the LPV/r arm. The on-treatment analysis, using a multivariate model, indicated that having VL<400 copies/ml at week 4 and harbouring HIV-1 subtype B were independently associated with an increased probability of VR. No difference in early VL reduction was evidenced between patients harbouring B or non-B subtypes. The latter patients had more difficulty in adherence to therapy than the former patients. The intention-to-treat analysis showed similar results.

Conclusions

HIV-1 RNA measured at baseline or at week 4 and HIV-1 subtype (B versus non-B) were independent predictive factors of VR in patients starting therapy with LPV/r alone. Although based on a small sample size, results of this study showed that adherence to therapy is lower in patients harbouring non-B subtypes and appears to be a key factor of VR in the context of protease inhibitor monotherapy.
Genetic barriers for integrase inhibitor drug resistance in HIV type-1 B and CRF02_AG subtypes
Authors: Maïga Almoustapha-Issiaka , Malet Isabelle , Soulie Cathia , Derache Anne , Koita Victoria , Amellal Bahia , Tchertanov Luba , Delelis Olivier , Morand-Joubert Laurence , Mouscadet Jean-François , Murphy Robert , Cissé Mamadou , Katlama Christine , Calvez Vincent , Marcelin Anne-Genevieve
Published: April 2022

Background

HIV type-1 (HIV-1) integrase (IN) inhibitor resistance is the consequence of mutations that are selected in the viral IN gene targeted by antiretroviral drugs, such as raltegravir (RAL) and elvitegravir (EVG). The genetic barrier, defined as the number of viral mutations required to overcome the drug-selective pressure, is one of the important factors in the development of drug resistance. The genetic barrier for IN inhibitor resistance was compared between HIV-1 subtype B and HIV-1 subtype CRF02_AG, which is highly prevalent in West Africa and becoming more frequent in developed countries.

Methods

IN nucleotide sequences from 73 HIV-1 subtype B and 77 HIV-1 subtype CRF02_AG antiretroviral-naive patients were examined at 19 IN amino acid positions implicated in RAL and EVG resistance.

Results

The majority (14/19) of the studied positions showed a high degree of conservation of the predominant codon sequences leading to a similar genetic barrier between subtypes B and CRF02_AG. Nevertheless, at positions 140 and 151, the variability between subtypes affected the genetic barrier for the mutations G140C, G140S and V151I with a higher genetic barrier being calculated for subtype CRF02_AG.

Conclusions

The major IN mutations E92Q, Q148K/R/H, N155H and E157Q (implicated in the resistance of IN inhibitors RAL and EVG) are highly conserved between subtypes B and CRF02_AG and display a similar genetic barrier. However, subtype CRF02_AG showed a higher genetic barrier to acquire mutations G140S, G140C and V151I as compared with subtype B, which could play a role in the resistance to RAL and/or EVG.
Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone
Authors: Morfin Florence , Dupuis-Girod Sophie , Frobert Emilie , Mundweiler Stéphanie , Carrington David , Sedlacek Petr , Bierings Marc , Cetkovsky Petr , Kroes Aloys CM , van Tol Maarten JD , Thouvenot Danielle
Published: April 2022

Background

We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir. All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin. Here, we aimed to extend these investigations to clinical isolates.

Methods

In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection.

Results

Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain. Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species. Among patients who were treated with cidofovir for disseminated HAdV infection, ≥4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected.

Conclusions

Cidofovir is active in vitro in all HAdV clinical isolates. Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C. Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients.
Effect of Antiviral Treatment on Serum Markers of Liver Fibrosis in HIV–Hepatitis C virus-Coinfected Patients: The Fibrovic 2 Study – ANRS HC02
Authors: Halfon Philippe , Carrat Fabrice , Bédossa Pierre , Lambert Jérôme , Pénaranda Guillaume , Perronne Christian , Pol Stanislas , Cacoub Patrice
Published: April 2022

Background

Non-invasive liver fibrosis scores have been proposed as alternatives to liver biopsy (LB) in hepatitis C virus (HCV)-infected patients. Here, we aimed to assess the effect of antiviral treatment on non-invasive serological markers of liver fibrosis in HIV–HCV-coinfected patients.

Methods

We included 114 HIV–HCV-coinfected patients with LBs performed before and 6 months after the end of treatment (week 72; W72). Fibrotest, the Forn's index, age-platelet ratio index, SHASTA, FIB-4, Hepascore and Fibrometer scores were assessed. There were 29 (25%) patients who achieved sustained virological response (SVR).

Results

At baseline (BL), all non-invasive fibrosis scores except the Forn's index did not show significantly lower values in SVR patients. At W72, all non-invasive scores, except Hepascore, showed a significant decrease in SVR patients ( P<0.01). There was a significant difference in fibrosis stages on LBs between BL and W72 in SVR and non-SVR patients.

Conclusions

In HIV–HCV-coinfected patients, HCV clearance is associated with a significant reduction in non-invasive fibrosis serological markers, which most likely reflect the histological improvement associated with SVR. If confirmed, such results will reinforce the reliability of these markers in the follow-up after HCV treatment.
The pathogenesis of liver disease in the setting of HIV–hepatitis B virus coinfection
Authors: Iser David M , Lewin Sharon R
Published: April 2022

There are many potential reasons for increased liver-related mortality in HIV–hepatitis B virus (HBV) coinfection compared with either infection alone. HIV infects multiple cells in the liver and might potentially alter the life cycle of HBV, although evidence to date is limited. Unique mutations in HBV have been defined in HIV–HBV-coinfected individuals and might directly alter pathogenesis. In addition, an impaired HBV- specific T-cell immune response is likely to be important. The roles of microbial translocation, immune activation and increased hepatic stellate cell activation will be important areas for future study.
Evolution of drug resistance after virological failure of a first-line highly active antiretroviral therapy regimen in Uganda
Authors: Reynolds Steven J , Kityo Cissy , Mbamanya Frank , Dewar Robin , Ssali Francis , Quinn Thomas C , Mugyenyi Peter , Dybul Mark
Published: April 2022

Background

This study aimed to determine the extent of viral resistance over time among non-clade B HIV type-1-infected patients in Uganda who were maintained on first-line highly active antiretroviral therapy (HAART) following virological failure.

Methods

Genotyping was performed on 16 patients with virological failure who were enrolled in an open-label randomized clinical trial of short-cycle treatment interruption.

Results

All patients receiving efavirenz-containing HAART had ≥1 efavirenz resistance mutation develop during follow-up. The majority (13/15, 86%) developed lamivudine resistance during follow-up, but no thymidine analogue mutations (TAMs) developed during a median duration of virological failure of 325.5 days.

Conclusions

Genotype resistance to both efavirenz and lamivudine developed early during the course of treatment after virological failure. TAMs did not emerge early despite moderate exposure time to thymidine analogues during virological failure.
The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women
Authors: van der Lugt Jasper , Colbers Angela , Molto Jose , Hawkins David , van der Ende Marchina , Vogel Martin , Wyen Christoph , Schutz Malte , Koopmans Peter , Ruxrungtham Kiat , Richter Clemens , Burger David
Published: April 2022

Background

Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting.

Methods

A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 ±2), the third trimester (week 33 ±2) and post-partum (weeks 4–6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1.

Results

A total of 37 women were included in the analysis. Mean (±sd) values for saquinavir area under the curve (AUC0–12h) were 23.47 h•mg/l (11.92) at week 20 ( n=16), 23.65 h•mg/l (9.07) at week 33 ( n=31) and 25.00 h•mg/l (11.81) post-partum ( n=9). There was no significant difference in the saquinavir AUC0–12h when comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as <0.10 mg/l) were not observed throughout the study. No major safety concerns were noted.

Conclusions

Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.
Pregnancy outcomes in women with HIV type-1 receiving a lopinavir/ritonavir-containing regimen
Authors: Azria Elie , Moutafoff Constance , Schmitz Thomas , Le Meaux Jean Patrick , Krivine Anne , Pannier Emmanuelle , Firtion Ghislaine , Compagnucci Alexandra , Finkielsztejn Laurent , Taulera Olivier , Tsatsaris Vassilis , Cabrol Dominique , Launay Odile
Published: April 2022

Background

The pregnancy-related adverse effects of antiretroviral therapy (ART) have yielded discordant results, which could be explained in part by the heterogeneity of ART protocols. The objective of our study was to explore whether lopinavir/ritonavir (LPV/r) exposure during pregnancy is associated with adverse outcomes.

Methods

Data on 100 consecutive HIV type-1 (HIV-1)-infected women receiving LPV/r during pregnancy and who delivered after 15 weeks gestational age (GA) between January 2003 and June 2007 in a single centre were analysed. For each HIV-1-infected woman, two uninfected women matched by age, parity and geographical origin were selected among patients delivering during the same period. Preterm delivery (PTD), vasculoplacental complications, gestational glucose intolerance and post-partum complication rates were compared between cases and controls. Factors associated with PTD and post-partum complications were assessed in HIV-1-infected women by a logistic regression model.

Results

Rates of vasculoplacental complication and gestational glucose intolerance were not higher among HIV-1-infected women than in controls. PTD was higher in HIV-1-infected women (21%) than in controls (10%; P<0.01). In HIV-1-infected women, PTD was associated with HIV-1 RNA level ≥50 copies/ml at delivery (adjusted odds ratio 6.15, 95% confidence interval 1.83–20.63; P=0.003). No association was found between occurrence of PTD and LPV/r exposure before 14 weeks GA.

Conclusions

In this population of HIV-1-infected pregnant women receiving LPV/r, the risk of PTD was higher than in HIV-1-uninfected controls. As PTD risk was not associated with early exposure to LPV/r, these data support current guidelines to initiate ART earlier in pregnancy.
Predictive value of immune parameters before treatment interruption (TI) for CD4+ T-cell count change during TI in HIV infection
Authors: Huang Kenneth H , Loutfy Mona R , Boulet Salix , Toma Emil , Tsoukas Christos M , Bernard Nicole F
Published: April 2022

Background

Despite the contraindications, stopping treatment for HIV infection continues to be a common practice. Understanding whether T-cell proliferative capacity and phenotypic markers before treatment interruption (TI) can predict CD4+ T-cell count change and nadir during TI would be clinically useful.

Methods

This retrospective study included 27 HIV- infected patients in the chronic phase of infection while on combination antiretroviral therapy (cART) who underwent a TI. Peripheral blood mononuclear cells from a baseline pre-TI time point were screened for T-cell proliferation to cytomegalovirus (CMV) lysate, an HIV Gag p55 peptide pool as well as positive and negative control stimuli. CD28 and CD57 expression on CD4+ and CD8+ T-cells were measured.

Results

Baseline viral load, CD4+ T-cell count, pre-cART nadir CD4+ T-cell and percentage CD4+CD28+ T-cells were all predictive of the lowest CD4+ T-cell count during TI (Spearman's correlation P<0.05 for all analyses). In addition, CD4+ and CD8+ T-cells proliferation to CMV lysate, baseline CD4+ T-cell count and percentage CD4+CD57+ T-cells correlated negatively with CD4+ T-cell decrease during TI (Spearman's correlation P<0.05 for all analyses).

Conclusions

In treated chronic HIV-infected patients, pre-TI immune parameters are potential predictors for both the nadir CD4+ T-cell count and CD4+ T-cell count decrease during TI.
Evaluation of transmitted HIV drug resistance among recently-infected antenatal clinic attendees in four Central African countries
Authors: Aghokeng Avelin F , Vergne Laurence , Mpoudi-Ngole Eitel , Mbangue Madeleine , Deoudje Noe , Mokondji Etienne , Nambei Wilfrid S , Peyou-Ndi Marlyse M , Moka Jean-Jacques L , Delaporte Eric , Peeters Martine
Published: April 2022

Background

The rapid expansion of antiretroviral treatment in resource-limited settings is raising concerns regarding the emergence and transmission of HIV drug resistance (HIVDR). We evaluated the extent of transmission of drug-resistant HIV strains in four Central African countries: the Republic of Congo, Central African Republic, Chad and Cameroon.

Methods

The World Health Organization (WHO) HIVDR threshold survey was implemented in major treatment areas in each country. Pregnant women who were aged <25 years, who were at first pregnancy and who were HIV type-1-positive were enrolled at each site in 2006–2007 for geno-typing. HIVDR prevalence was categorized using the WHO threshold survey binomial sequential sampling method.

Results

The prevalence of HIVDR in Brazzaville and Bangui sites could not be classified because the eligible sample number was not reached. HIVDR prevalence was low (<5%) in N'Djamena for all drug classes. In Yaoundé, we found one individual with the D67D/N mutation and two with K103N. HIVDR prevalence was categorized as low (<5%) for protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), and moderate (≥5-≤15%) for non-NRTIs (NNRTIs). HIVDR prevalence in Douala was low for PIs and NNRTIs, and moderate for NRTIs as we identified one individual with M184V plus K101E plus G190A mutations and a second with D67D/N.

Conclusions

The moderate HIVDR prevalence found in Yaoundé and Douala indicate that efforts should be made in Cameroon to prevent HIVDR; however, additional surveys are needed to confirm this trend. This study highlighted challenges presented by the WHO methodology, such as additional costs, workload, difficulties in acquiring even small sample numbers and the necessity for better quality assurance of HIV testing and record keeping at antenatal clinics.
Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir treatment in HIV-1-infected children
Authors: la Porte Charles , van Heeswijk Rolf , Mitchell Charles D , Zhang Guijun , Parker Jackie , Rongkavilit Chokechai
Published: April 2022

Background

Once-daily lopinavir/ritonavir (LPV/r) is not approved for treatment of HIV paediatric patients. Once daily treatment in children might serve the same goals of patient comfort and adherence as in adults.

Methods

HIV type-1-infected children aged 6 months to 18 years, who were virologically suppressed on an LPV/r-containing regimen, were eligible. Treatment 1 consisted of once-daily LPV/r 460/115 mg/m2, plus two nucleoside reverse transcriptase inhibitors (NRTIs). Treatment 2 consisted of twice-daily LPV/r 230/57.5 mg/m2 plus two NRTIs. Patients were randomized either to start with treatment 1 followed by treatment 2 or vice versa. Full pharmaco-kinetic profiles were analysed for lopinavir and ritonavir with a validated HPLC tandem mass spectrometry assay.

Results

Seven patients (five girls and two boys) were included in the study. Median age was 9.8 years (range 5.8–15.5). For the once-daily treatment, the median (range) lopinavir 24 h area under the plasma concentration–time curve (AUC24h), maximum plasma concentration (Cmax) and 24 h plasma concentration (C24h) were 214.6 h•mg/l (114.2–289.2), 13.5 mg/l (8.3–17.5) and 3.4 mg/l (0.6–7.4), respectively. For the twice-daily treatment the median (range) lopinavir 12 h area under the plasma concentration–time curve (AUC12h), Cmax and 12 h plasma concentration (C12h) were 80.9 h•mg/l (23.3–135.9), 9.8 mg/l (3.4–15.2) and 5.7 mg/l (1.7– 9.7), respectively.

Conclusions

This study suggests that the pharmacokinetics of lopinavir after twice-daily and once-daily dosing are similar, with no observable difference in tolerability, in this group of patients between 5 and 15 years old.
The pattern of pegylated interferon-α2b and ribavirin treatment failure in cirrhotic patients depends on hepatitis C virus genotype
Authors: Aghemo Alessio , Rumi Maria Grazia , Monico Sara , Prati Gian Maria , D'Ambrosio Roberta , Donato Maria Francesca , Colombo Massimo
Published: April 2022

Background

Failure of anti-hepatitis C therapy encompasses both primary non-response and post-treatment relapse. Treatment failure to pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV) largely depends upon virus genotype, but the interaction between genotype, cirrhosis and pattern of treatment failure is unclear. We aimed to assess whether cirrhosis modifies the pattern of PEG-IFN-α2b and RBV treatment failure.

Methods

A total of 471 treatment-naive patients with histologically proven chronic hepatitis C virus (HCV) infection (106 with cirrhosis; 185 with HCV genotype 1 [HCV-1], 157 with HCV genotype 2 [HCV-2], 92 with HCV genotype 3 [HCV-3] and 37 with HCV genotype 4 [HCV-4]) were consecutively treated with PEG-IFN-α2b 1.5 μg weekly and weight-based RBV.

Results

The sustained virological response (SVR) rates were 31% in HCV-1 and HCV-4, 80% in HCV-2 and 72% in HCV-3, and were lower in cirrhotic than in non-cirrhotic HCV-1 and HCV-4 (17% versus 36%; P=0.01), and HCV-3 (33% versus 79%; P=0.001), but not HCV-2 (69% versus 83%; P=0.1) patients. Treatment failure was the consequence of lower end-of-treatment response rates (37% versus 53%; P=0.06) plus higher post-treatment relapse rates (55% versus 31%; P=0.07) in cirrhotic HCV-1 and HCV-4 patients and higher rates of post-treatment relapse in HCV-2 (29% versus 10%; P=0.01) and HCV-3 cirrhotic patients (61% versus 12%; P<0.001). By multi-variate analysis, HCV-1 and HCV-4 (odds ratio [OR] 7.44, 95% confidence interval [CI] 4.87–11.36), and cirrhosis (OR 3.00, 95% CI 1.80–5.00) were independent predictors of treatment failure.

Conclusions

Cirrhosis is an important moderator of SVR, accounting for different patterns of treatment failure in patients infected with different genotypes.
Time course of insulin resistance during antiviral therapy in non-diabetic, non-cirrhotic patients with genotype 1 HCV infection
Authors: Petta Salvatore , Cammà Calogero , Di Marco Vito , Cabibi Daniela , Ciminnisi Stefania , Caldarella Rosalia , Licata Anna , Massenti Maria Fatima , Marchesini Giulio , Craxì Antonio
Published: April 2022

Background

Genotype 1 (G1) hepatitis C virus (HCV) is associated with insulin resistance (IR) and its clearance seems to improve insulin sensitivity. We aimed to evaluate the time course of IR in response to antiviral therapy in non-diabetic, non-cirrhotic G1 HCV patients and to assess the effect of metabolic factors on sustained virological response (SVR).

Methods

A total of 83 consecutive treatment-naive G1 chronic hepatitis C (CHC) patients were evaluated by anthropometric and metabolic measurements, including IR using the homeostasis model assessment (HOMA). Patients were considered to have IR if HOMA was >2.7. All cases had a liver biopsy scored for staging, grading and steatosis. Anthropometric parameters and HOMA were re-evaluated at the end of antiviral therapy and at follow-up.

Results

SVR was achieved in 46 (55.4%) patients. By logistic regression, female gender (odds ratio [OR] 0.132, 95% confidence interval [CI] 0.33–0.529), γ-glutamyltransferase >50 IU (OR 0.217, 95% CI 0.066–0.720) and presence of steatosis (OR 0.134, 95% CI 0.028–0.654) were independent negative predictors of SVR, whereas low-density lipoprotein cholesterol >107 IU (OR 6.671, 95% CI 1.164–11.577) was a positive predictor of SVR. The proportion of patients with IR significantly decreased ( P=0.02) during antiviral therapy and at follow-up in patients achieving SVR. A similar trend, even if not significant, was observed in relapsers and non-responders.

Conclusions

In non-diabetic G1 HCV patients undergoing antiviral therapy, IR improved in all patients, independently of virological outcome. HCV viral clearance was an additional factor in IR improvement. Female gender, hepatic steatosis and other metabolic parameters, but not IR, were identified as negative predictors of SVR in this study.
Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1–5
Authors: Legrand-Abravanel Florence , Henquell Cécile , Le Guillou-Guillemette Hélène , Balan Viorica , Mirand Audrey , Dubois Martine , Lunel-Fabiani Francoise , Payan Christopher , Izopet Jacques
Published: April 2022

Background

The hepatitis C virus (HCV) RNA-dependent RNA polymerase, NS5B, is essential for virus RNA replication. It is thus an attractive therapeutic target. Several compound nucleoside analogues, non-nucleoside inhibitors and cyclosporine analogues are being developed to inhibit NS5B activity. However, nucleotide changes in the NS5B gene can confer resistance to them.

Methods

We investigated the prevalence of known substitutions conferring resistance in HCV polymerase in 124 treatment-naive French patients infected with HCV genotypes 1, 2, 3, 4 or 5 by sequencing the NS5B gene.

Results

None of the 124 HCV NS5B sequences analysed contained substitutions conferring resistance to nucleoside analogues; however, NS5B polymerases containing substitutions conferring resistance to non-nucleoside inhibitors were frequent within genotype 1 strains (17%) and very common in non-genotype 1 strains. Similarly, substitutions conferring resistance to cyclosporine analogues were more prevalent within the various genotypes.

Conclusions

Naturally occurring substitutions conferring resistance to NS5B inhibitors are common in treatment-naive patients infected with HCV genotype 1, 2, 3, 4 or 5. Their influence on treatment outcome should be assessed.
Lamivudine in the Management of Adults with Human Immunodeficiency Virus Type 1 Infection
Authors: Moyle Graeme J , Gazzard Brian G
Published: April 2022

Lamivudine is a nucleoside analogue reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1), HIV-2 and hepatitis B virus which demonstrates in vitro activity with a high therapeutic index in a range of T lymphocyte and haematopoietic precursor cell lines. It is synergistic in vitro with a range of other antiretrovirals including other nucleoside analogues, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, in two- and three-way combinations and is active against virus resistant to zidovudine and most other antiretrovirals. It exhibits excellent oral bioavailability and penetrates the CSF. In clinical use, lamivudine exhibits limited antiretroviral activity as a monotherapy, but in two-and three-drug combinations with other antiretrovirals it provides potent antiretroviral activity and significantly delays clinical events. Adverse events appear infrequent and are generally mild and self-limiting. Resistance to lamivudine develops rapidly in vitro and in vivo but may delay the development of zidovudine resistance. Dual zidovudine-lamivudine resistance is well documented both in vitro and in vivo although the mutation at codon 184 of reverse transcriptase characteristic of lamivudine resistance may, in some cases, transiently ‘reverse’ zidovudine resistance mediated through codons 215 and 41. Owing to concerns regarding selection of virus with cross-resistance to other nucleoside analogues (ddl, ddC and possibly abacavir), whether to use lamivudine in initial or second-line regimens is currently under debate.
Improvement in Immune Function due to Treatment with Indinavir despite Severe Immune Deficiency
Authors: Rothen Madeleine , Bisset Leslie R , Joller-Jemelka Helene I , Grob Peter , Lüthy Ruedi , Opravil Milos
Published: April 2022

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HlV)-infected patients with CD4 counts <50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to <400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55–258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51–1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.