bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Long-Term Lamivudine in Chronic Hepatitis B Virus-Infected Children
Authors: Ozgenç Funda , Arikan Cigdem , Sertoz Ruchan Yazan , Nart Deniz , Aydogdu Sema , Yagci Rasit Vural
Published: April 2022

Objective

To evaluate, retrospectively, biochemical, serological and histological responses in chronic hepatitis B (CHB)-infected children who received combination therapy and continued with prolonged treatment with lamivudine (3TC).

Patients and methods

CHB infection was defined as the presence of hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA in serum screened at 3-month intervals for at least 1 year, serum alanine aminotransferase (ALT) levels >1.5 times the normal limit and CHB with histological activity index (HAI) >5 by liver biopsy. A total of 99 children with CHB infection were treated with IFN-α (three times a week, 5 MU/m2) and 3TC (4 mg/kg/d) orally for 6 months. End of therapy response (CR) was defined as ALT normalization, HBV-DNA clearance and e seroconversion. Partial responders (PR) were defined as patients who had ALT normalization and HBV-DNA clearance, but who had not had e seroconversion. Forty-five children with PR at the end of the sixth month continued to receive 3TC alone thereafter. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. The response rate, side effects and the breakthrough infection rate were examined on prolonged 3TC treatment. Liver biopsy was held in 29 patients at median 32 (14–66) months of 3TC; pre- and post-treatment liver histology was compared.

Results

Pre- and post-treatment evaluation was carried out in 45 children [mean age: 11 ±4.2 years, 31 males (69%), 14 females (31%)] with PR at the end of the sixth month of combination therapy. The initial mean ALT values and HAI scores were 75.6 ±60 IU/l and 8 ±3.3, respectively. 3TC was continued for median 33 (14–66) months and CR was achieved in 15.6% (7/45) and 5.6% (2/36) at the end of first and second year, and 0% (none) at the end of third and fourth year, respectively. Breakthrough incidence was detected in six (13.3%) cases at 12 months and increased to 69.4% ( n=25) and 82.4% ( n=14) at the end of the second and third years, respectively. Patients with breakthrough continued to receive 3TC. Seroconversion and CR of the mutant virus was achieved in one patient (2.9%) at month 46 of treatment with 3TC. Liver biopsy was held in 29 cases at median 32 (14–66) months of 3TC. Pre- and post-treatment mean HAI scores were 8 ±3.3 and 3.9 ±2.1, respectively ( P=0.000). Mean necrosing scores were not different at the beginning and end of therapy ( P=1.0). Inflammation, bridging and fibrosis scores decreased to 0.8 ±0.6, 1.3 ±1.2 and 0.6 ±0.8, respectively ( P=0.000, P=0.002, P=0.000).

Conclusion

The long-term 3TC usage in children with PR does not induce complete response and is associated with high breakthrough incidence. However, histological improvement is achieved and/or sustained even in children with HBV DNA breakthrough.
Superior Therapeutic Efficacy of Alphavirus-Mediated Immunization against Human Papilloma Virus Type 16 Antigens in a Murine Tumour Model: Effects of the Route of Immunization
Authors: Daemen Toos , Riezebos-Brilman Annelies , Regts Joke , Dontje Bert , van der Zee Ate , Wilschut Jan
Published: April 2022

In our efforts to develop a strong, effective immune response against cervical carcinoma and premalignant disease, we study the use of recombinant Semliki Forest virus (SFV) encoding the oncoproteins E6 and E7 from high-risk human papilloma viruses (HPVs). Optimal immunization conditions are required for immunotherapeutic treatment of cervical cancer as it has been postulated that cervical cancer patients are immune-suppressed and/or immunologically tolerant for HPV. We previously generated an optimized construct encoding a fusion protein of HPV16 E6 and E7 and a translational enhancer (enhE6,7). Immunization of mice with SFV-enhE6,7 was shown to induce cytoxic T cell (CTL) responses and resulted in the eradication of established tumours. We now demonstrate, using HPV16-specific MHC class I tetramers, that high pCTL frequencies can be induced. However, this induction is strongly influenced by the route of immunization applied. Whilst in bulk CTL assays, requiring in vitro restimulation, CTL activity can be observed upon sc, ip, iv and im immunization, detectable pCTL frequencies, without in vitro restimulation, are only induced upon im and iv immunization. The route of immunization also strongly influences the dose of viral vector needed to induce CTLs and tumour therapy. As few as 5x104 SFV-enhE6,7, primed and boosted iv, are needed to eradicate tumours in six out of seven mice treated. Furthermore, exponentially growing tumours of approximately 500 mm3 in size were seen to completely resolve and even tumours as large as 1500 mm3 decreased to one-third of their size. Apart from this potency, SFV vectors can safely be used for the expression of oncoproteins such as E6 and E7, since the viral RNA is not integrated in the host genome. Thus SFV-enhE6,7 meets with the criteria that a vaccine against cervical cancer should be safe and induce a very strong, long-lasting CTL response, strong enough to eradicate existing tumours.
Lipodystrophy in Patients with HIV-1 Infection: Effect of Stopping Protease Inhibitors on Tnf-α and Tnf-Receptor Levels, and on Metabolic Parameters
Authors: Maher Bridget , Lloyd Judy , Wilkins Edmund GL , Fraser William D , Back David , Park B Kevin , Pirmohamed Munir
Published: April 2022

Objective

To evaluate the effects of stopping treatment with protease inhibitors (PIs) on tumour necrosis factor (TNF)-α and TNF-receptor levels, and on the metabolic and morphological abnormalities seen in patients with lipodystrophy.

Design

Longitudinal study.

Methods

Ten HIV-positive patients with lipodystrophy (LD) were studied whilst on PIs (LD1) and 3 months after stopping PIs (LD2) together with 10 HIV-positive subjects on PIs without LD (controls). TNF-α and TNF-receptor levels, insulin resistance parameters, lipid and hormonal profiles, body composition and fat distribution were measured in all subjects.

Results

TNF-α, TNF-receptor I (-RI) and TNF-RII levels were significantly lower in controls ( P=0.02) than in subjects with LD, and there was a significant decrease in TNF-RI and TNF-RII levels ( P=0.01 and 0.03, respectively) on stopping PIs. Insulin levels and the homeostasis model assessment for insulin resistance (HOMA-IR) index were significantly higher in LD1 subjects ( P=0.02) than in controls but did not alter when PIs were stopped. Bioelectrical impedance analysis showed a significant decrease on stopping PIs but CT scans showed no significant difference in fat distribution. Apart from high-density lipoprotein, there was no change in lipid parameters on stopping PIs. There was no difference in the level of testosterone, sex hormone binding globulin and cortisol between the three groups.

Conclusion

Our results show that TNF-α activity in patients with LD is modulated by PIs. This was not accompanied by significant changes in body habitus or insulin resistance, although this may have been a consequence of the short follow-up in this study.
Influence of Single-Nucleotide Polymorphisms in the Multidrug Resistance-1 Gene on the Cellular Export of Nelfinavir and Its Clinical Implication for Highly Active Antiretroviral Therapy
Authors: Zhu Dayong , Taguchi-Nakamura Hitomi , Goto Mieko , Odawara Takashi , Nakamura Tetsuya , Yamada Harumi , Kotaki Hajime , Sugiura Wataru , Iwamoto Aikichi , Kitamura Yoshihiro
Published: April 2022

Protease inhibitors (PIs) such as nelfinavir (NFV) suppress HIV replication. PIs are substrates of P-glycoprotein (P-gp), the product of the multidrug-resistance-1 ( MDR1) gene. Three single-nucleotide polymorphisms (SNPs) are present in exons of the MDR1 gene: MDR1 1236, MDR1 2677 and MDR1 3435. We speculated that these genetic polymorphisms affected PI concentration in the cell. To verify this hypothesis, we first genotyped these SNPs in 79 Japanese patients by the SNaPshot method and found incomplete linkage disequilibrium between the SNPs. Because the SNP at MDR1 3435 has been reported to be associated with P-gp expression, we evaluated the effect of that SNP on the export of NFV from HIV-positive patients’ lymphoblastoid cell lines by measuring time-dependent decrease in the amount of intracellular NFV by high-performance liquid chromatography. We found the intracellular concentration of NFV in lymphoblastoid cell lines (LCLs) with the homozygous T/T genotype at MDR1 3435 were higher than that with C/C genotype with statistical significance. This suggests that the activity of P-gp in patients’ LCL cells with the MDR1 3435 T/T genotype was lower. In a retrospective study we evaluated the effect of the SNPs on CD4 cell count recovery in response to antiretroviral treatment with PIs, and obtained statistically significant evidence that suggested marginal association of the SNP at MDR1 1236 but not at MDR1 2677 or MDR1 3435. As in vitro results were not consistent with the clinical evaluation, clinical importance of MDR1 genotyping for antiretroviral therapy remains to be investigated in a larger, case-controlled study.
Updated European Recommendations for the Clinical Use of HIV Drug Resistance Testing
Authors: Vandamme A-M , Sönnerborg A , Ait-Khaled M , Albert J , Asjo B , Bacheler L , Banhegyi D , Boucher C , Brun-Vézinet F , Camacho R , Clevenbergh P , Clumeck N , Dedes N , Luca A De , Doerr HW , Faudon J-L , Gatti G , Gerstoft J , Hall WW , Hatzakis A , Hellmann N , Horban A , Lundgren JD , Kempf D , Miller M , Miller V , Myers TW , Nielsen C , Opravil M , Palmisano L , Perno CF , Phillips A , Pillay D , Pumarola T , Ruiz L , Salminen M , Schapiro J , Schmidt B , Schmit J-C , Schuurman R , Shulse E , Soriano V , Staszewski S , Vella S , Youle M , Ziermann R , Perrin L
Published: April 2022

In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.
Optimal Frequency of Cd4 Cell Count and HIV Rna Monitoring Prior to Initiation of Antiretroviral Therapy in HIV-Infected Patients
Authors:   For The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Investigators, Kimmel April D , Goldie Sue J , Walensky Rochelle P , Losina Elena , Weinstein Milton C , Paltiel A David , Zhang Hong , Freedberg Kenneth A
Published: April 2022

Context

Guidelines regarding the frequency of CD4 cell count and HIV RNA monitoring in HIV-infected patients vary, with recommended strategies ranging from every 2 to every 6 months.

Objective

To determine optimal CD4 cell count and HIV RNA monitoring frequency in HIV-infected patients prior to antiretroviral therapy initiation. Design: Cost-effectiveness (CE) analysis using an HIV simulation model incorporating CD4 cell count and HIV RNA as immunological and virological predictors of clinical outcomes.

Setting

Hypothetical clinical setting.

Patients

Simulated cohort based on initial clinical presentation of HIV-infected patients in the US.

Intervention

CD4 cell count and HIV RNA monitoring at frequencies ranging from every 2 to 24 months prior to antiretroviral initiation, as well as accelerated monitoring frequencies as CD4 cell counts approach a specified treatment threshold.

Outcome measures

Life expectancy, quality-adjusted life expectancy and costs.

Results

For patients presenting with median CD4 cell count 546/mm3 and median HIV RNA 4.8 log10 copies/ml, incremental CE ratios ranged from US$37800/quality-adjusted life year (QALY) gained for a constant testing frequency of every 18 months compared with every 24 months, to US$303300/QALY gained for a constant testing frequency of every 2 months compared with every 4 months when starting treatment at a CD4 cell count of 350/mm3. Monitoring every 12 months until a warning CD4 cell count threshold of 450/mm3 followed by every 3 months until 350/mm3 had an incremental CE ratio of US$74700/QALY gained. When starting antiretroviral therapy at CD4 cell count 200/mm3, monitoring every 12 months until 300/mm3 followed by every 2 months until treatment initiation yielded an incremental CE ratio of US$52200/QALY gained compared with the next best strategy. Increasing monitoring frequency as CD4 cell counts approached a treatment threshold yielded greater incremental clinical benefit for less cost than strategies using a constant frequency.

Conclusions

Monitoring HIV-infected patients every 12 months until 100 CD4 cells/mm3 prior to a specified treatment threshold followed by more frequent monitoring every 2 or 3 months until antiretroviral therapy initiation is both more effective and cost-effective than the current standard of care.
Depression and Clinical Progression in HIV-Infected Drug Users Treated with Highly Active Antiretroviral Therapy
Authors:   the MANIF 2000 Study Group, Bouhnik Anne-Déborah , Préau Marie , Vincent Emmanuelle , Carrieri Maria Patrizia , Gallais Hervé , Lepeu Gérard , Gastaut Jean-Albert , Moatti Jean-Paul , Spire Bruno
Published: April 2022

Objective

To disentangle the impact of adherence from that of injecting drug status and depressive syndrome on HIV clinical progression in a cohort of highly active anti-retroviral therapy (HAART)-treated HIV patients infected through drug use.

Design

MANIF 2000 is a French cohort of HIV-infected drug users with scheduled medical visits every 6 months. Only patients enrolled in the MANIF 2000 cohort who had a CD4 cell count >200 cells/μl at HAART initiation were selected. The follow-up period included all post-HAART initiation visits.

Methods

HIV clinical progression was defined as either AIDS-related death or reaching a CD4 level <200 cells/μl. Adherence was assessed using a self-administered questionnaire and a structured face-to-face interview. Depressive symptoms were evaluated by a Center for Epidemiologic Studies Depression Scale (CES-D) score at each visit. Cox proportional hazards model was used to calculate crude and adjusted relative hazards and 95% confidence intervals and thus identify independent predictors of clinical progression.

Results

Of the 305 HAART-treated patients in the cohort, 243 had CD4 cell count >200 cells/μl at HAART initiation. At the first visit after HAART initiation, median CD4 cell count was 466 cells/μl and 45% had undetectable viral load. Injecting drug users accounted for 17% of the study group. Over the follow-up period, 32 patients experienced HIV clinical progression. Probable depression was encountered in 46% of patients and non-adherence in 31% of the sample. After adjustment on baseline CD4 cell count, predictors of clinical progression were: having a higher level of cumulative non-adherence over the follow-up period [HR (95% CI)=1.2 (1.1–1.3) per 10% increase] and having a high score of depressive symptoms following HAART initiation [HR (95% CI)=5.3 (2.21–3.0)]. Conclusions: Although depressive syndrome is known to influence non-adherence behaviours that are amongst the major reasons for clinical progression, it is also a predictor of clinical progression in HIV-infected intravenous drug users on HAART, independently of non-adherence behaviours. HIV care providers should be more sensitive to depressive symptoms in order to detect them early and supply HIV patients with specific care. Further research is needed to determine whether treating depressive symptoms may improve adherence and thus delay disease progression and mortality.
Relationship between Changes in Thymic Emigrants and Cell-Associated HIV-1 Dna in HIV-1-Infected Children Initiating Antiretroviral Therapy
Authors:   for the Paediatric European Network for Treatment of AIDS (PENTA), De Rossi Anita , Walker A Sarah , Forni Davide De , Klein Nigel , Gibb Diana M , Aboulker J-P , Babiker A , Compagnucci A , Darbyshire J , Debré M , Gersten M , Giaquinto C , Gibb DM , Jones A , Aboulker J-P , Babiker A , Blanche S , Bohlin A-B , Butler K , Castelli-Gattinara G , Clayden P , Darbyshire J , Debré M , de Groot R , Faye A , Giaquinto C , Gibb DM , Griscelli C , Grosch-Wörner I , Levy J , Lyall H , Mellado Pena M , Nadal D , Peckham C , Ramos Amador JT , Rosado L , Rudin C , Scherpbier H , Sharland M , Tovo PA , Valerius N , Wintergerst U , Boucher C , Clerici M , de Rossi A , Klein N , Loveday C , Muñoz-Fernandez M , Pillay D , Rouzioux C , Babiker A , Darbyshire J , Gibb DM , Harper L , Johnson D , Kelleher P , McGee L , Poland A , Walker AS , Aboulker J-P , Carrière I , Compagnucci A , Debré M , Eliette V , Leonardo S , Moulinier C , Saidi Y , Galli L , Foot A , Kershaw H , Caul O , Tarnow-Mordi W , Petrie J , McIntyre P , Appleyard K , Gibb DM , Novelli V , Klein N , McGee L , Ewen S , Johnson M , Gibb DM , Cooper E , Fisher T , Barrie R , Norman J , King D , Larsson-Sciard E-L
Published: April 2022

Objectives and methods

To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy (ART) initiation.

Results

At baseline, HIV-1 DNA was higher in children with higher TREC ( P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses ( P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1 DNA declines in children with higher baseline TREC ( P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART ( P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline ( P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression.

Conclusions

Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.
HIV-1 Infection Leads to Increased HLA-E Expression Resulting in Impaired Function of Natural Killer Cells
Authors: Nattermann Jacob , Nischalke Hans Dieter , Hofmeister Valeska , Kupfer Bernd , Ahlenstiel Golo , Feldmann Georg , Rockstroh Jürgen , Weiss Elisabeth H , Sauerbruch Tilman , Spengler Ulrich
Published: April 2022

HIV has evolved several strategies to evade recognition by the host immune system including down-regulation of major histocompatibility complex (MHC) class I molecules. However, reduced expression of MHC class I molecules may stimulate natural killer (NK) cell lysis in cells of haematopoietic lineage. Here, we describe how HIV counteracts stimulation of NK cells by stabilizing surface expression of the non-classical MHC class I molecule, HLA-E. We demonstrate enhanced expression of HLA-E on lymphocytes from HIV-infected patients and show that in vitro infection of lymphocytes with HIV results in up-regulation of HLA-E expression and reduced susceptibility to NK cell cytotoxicity. Using HLA-E transfected K-562 cells, we identified the well-known HIV T-cell epitope p24 aa14-22a as a ligand for HLA-E that stabilizes surface expression of HLA-E, favouring inhibition of NK cell cytotoxicity.

These results propose HIV-mediated up-regulation of HLA-E expression as an additional evasion strategy targeting the antiviral activities of NK cells, which may contribute to the capability of the virus in establishing chronic infection.
Area-Under-The-Curve for Peginterferon Alpha-2A and Peginterferon Alpha-2B is Not Related to Body Weight in Treatment-Naive Patients with Chronic Hepatitis C
Authors: Bruno Raffaele , Sacchi Paolo , Maiocchi Laura , Zocchetti Cristina , Ciappina Valentina , Patruno Savino , Filice Gaetano
Published: April 2022

One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response. This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently: peginterferon alpha-2a is flat-dosed at 180 μg regardless of body weight, whereas peginterferon alpha-2b is dosed by body weight at 0.5–1.5 μg/kg. Body-weight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response. To test this hypothesis, we measured the area-under-the-curve (AUC) for both drugs as part of a previously reported pharmacokinetics study. In total, 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks. Patients were randomly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 μg ( n=10) or peginterferon alpha-2b 1.0 μg/kg ( n=12). Ribavirin was dosed by body weight at 1000 mg/day (≤75 kg) or 1200 mg/day (>75 kg). We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b. Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [coefficient of variation (CV): 37.5%] and, despite dosing by body weight, for peginterferon alpha-2b (CV: 36.8%). Thus, there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a, and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b.
Sensitivity of Primary R5 HIV-1 to Inhibition by Rantes Correlates with Sensitivity to Small-Molecule R5 Inhibitors
Authors: Koning Fransje A , Koevoets Cindy , van der Vorst Teun JK , Schuitemaker Hanneke
Published: April 2022

In approximately 50% of HIV-1 subtype B-infected individuals, progression to AIDS is preceded by the emergence of CXCR4-using (X4) variants, whereas the rest progress to AIDS in the presence of CCR5-using (R5) variants only. In a previous study, we showed that during disease progression in the presence of R5 variants only, HIV-1 variants emerge with a decreased sensitivity to inhibition by RANTES, a natural ligand of CCR5 that inhibits cellular entry of R5 variants. This observation was of potential clinical relevance as HIV-1 small-molecule R5 entry inhibitors are a new class of drugs that, in analogy to RANTES, target the binding and subsequent entry of HIV into the target cell. Here we show that R5 HIV-1 sensitivity to RANTES correlates with sensitivity to the R5 small-molecule inhibitor AD101. HIV-1 small-molecule entry inhibitors are a new class of drugs that target the binding and subsequent entry of HIV into the target cell. Furthermore, we found that R5 variants obtained from individuals who later developed X4 variants were less sensitive to AD101 inhibition compared with R5 variants obtained from individuals who never developed X4 variants. These results may have implications for the evaluation of R5 inhibitors in future clinical trials.
Impact of Human Immunodeficiency Virus Type 1 Subtype on First-Line Antiretroviral Therapy Effectiveness
Authors: Bocket Laurence , Cheret Antoine , Deuffic-Burban Sylvie , Choisy Philippe , Gerard Yann , de la Tribonnière Xavier , Viget Nathalie , Ajana Faïzo , Goffard Anne , Barin Francis , Mouton Yves , Yazdanpanah Yazdan
Published: April 2022

Objective

The effectiveness of antiretroviral treatment (ART) was compared in 416 naive patients from a French clinical cohort infected with B and non-B HIV-1 subtypes.

Methods

Time to HIV viral load (VL) undetectability was calculated for each subtype group. Three other parameters were estimated 3, 6 and 12 months after enrolment: clinical progression (that is, AIDS-defining events or death), changes in CD4 cell counts from baseline and proportion of patients achieving an undetectable VL (<400 HIV-RNA copies/ml).

Results

In this cohort, 317 patients (76%) were infected with a B subtype and 99 (24%) with a non-B subtype. Median time to VL undetectability was similar in the B subtype group [147 days, 95% confidence interval (CI) 119–165] and non-B subtype group (168 days, 95% CI: 105–234; P=0.16). After adjusting for AIDS-defining events at enrolment, baseline CD4 cell counts and VL, and for the treatment on which patients were initiated, no association was found between HIV subtypes and time to VL undetectability (B subtype vs non-B subtype: hazard ratio=0.80, 95% CI: 0.62–1.02, P=0.07). In the 3, 6 and 12 months after enrolment, subtype had no impact on clinical progression, CD4 cell count or VL responses to ART. This suggests that B and non-B subtypes do not affect first-line therapy efficacy, which is encouraging in view of the worldwide spread of non-B HIV-1 subtypes and the increasing availability of ART in developing countries. However, in this study we did not take into account individual non-B subtype species, therefore further studies should be designed to evaluate the efficacy of these regimens in patients with particular non-B subtypes.
Plasma Pharmacokinetics of Once- versus Twice-Daily Lamivudine and Abacavir: Simplification of Combination Treatment in HIV-1-Infected Children (Penta-13)
Authors: Bergshoeff Alina , Burger David , Verweij Corrien , Farrelly Laura , Flynn Jacquie , Le Prevost Marthe , Walker Sarah , Novelli Vas , Lyall Hermione , Khoo Saye , Gibb Di
Published: April 2022

Background

There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children.

Methods

Children aged 2–13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0–24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response.

Results

24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1–12.8) years] had evaluable PK data for 3TC ( n=19) and/or ABC ( n=14). GMRs of 3TC and ABC AUC0–24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2–6 versus 6–13 years old ( P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2–6 versus 6–13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24.

Conclusion

AUC0–24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.
The Steady-State Pharmacokinetics of Nelfinavir in Combination with Tenofovir in HIV-Infected Patients
Authors: Kruse Guido , Esser Stefan , Stocker Hartmut , Breske Antje , Koerber Andreas , Kopperman Maija , Wiehler Heidi , Ross Birgit , Möcklinghoff Christiane , Hill Andrew , Becker Mark , Kurowski Michael
Published: April 2022

Background

The nucleotide analogue, tenofovir, has been shown to lower plasma atazanavir levels in pharmacokinetic trials, an interaction that may be partly reversed by the addition of ritonavir, whereas plasma tenofovir levels are themselves raised when the drug is combined with lopinavir/ritonavir.

Objective

To investigate the effect of tenofovir coadministration on the steady-state pharmacokinetics of nelfinavir in HIV-infected patients.

Methods

Eighteen patients received nelfinavir 1250 mg twice daily plus prescribed nucleoside reverse transcriptase inhibitors for at least 14 days, with pharmacokinetic measurements performed on day 15. Treatment with nelfinavir was continued for another 7 days with the addition of 300 mg tenofovir once daily. Pharmacokinetic measurements were repeated on day 22. Plasma samples were analysed by liquid chromatography–tandem mass spectrometry for nelfinavir, its primary metabolite, M8, and tenofovir. The parameters AUC0–12, C0, Cmax and Tmax were compared for nelfinavir with and without tenofovir by calculating geometric mean ratios (GMRs) of the pharmacokinetic parameters with associated 95% confidence intervals (95% CIs). Safety was assessed throughout the study.

Results

The addition of tenofovir to the nelfinavir-based regimen had no effect on the pharmacokinetics of nelfinavir. The GMR of the nelfinavir AUC0–12 values was 0.97 (95% CI: 0.80–1.17). There was a slight decrease in M8 metabolite (AUC0–12 ratio, 0.87; 95% CI: 0.68–1.11) but this was not significant. No serious adverse events occurred through the study period.

Conclusion

Nelfinavir does not require dose adjustment when coadministered with tenofovir and appears to be well-tolerated by HIV-infected patients.
The Influence of the M184V Mutation in HIV-1 Reverse Transcriptase on the Virological Outcome of Highly Active Antiretroviral Therapy Regimens with Or without Didanosine
Authors: Sproat Michael , Pozniak Anton L , Peeters Monika , Winters Bart , Hoetelmans Richard , Graham Neil M , Gazzard Brian G
Published: April 2022

Background

In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddI). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddI- and non-ddI-containing regimens in the presence or absence of the M184V mutation.

Methods

Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddI-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by ‘real phenotype’ resistance test results.

Results

Amongst patients on ddI-containing HAART, median fold changes in phenotypic susceptibility to ddI were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddI, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddI-containing HAART than in those on HAART without ddI ( P<0.05).

Conclusions

While the M184V did increase the fold resistance of HIV to ddI, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
Influence of Metabolic Syndrome, Viral Genotype and Antiviral Therapy on Superimposed Fatty Liver Disease in Chronic Hepatitis C
Authors: Liu Chun-Jen , Jeng Yung-Ming , Chen Pei-Jer , Lai Ming-Yang , Yang Hung-Chih , Huang Wen-Ling , Kao Jia-Horng , Chen Ding-Shinn
Published: April 2022

Background/aims

The prevalence and clinical implications of non-alcoholic fatty liver disease in patients with chronic hepatitis C remain unknown in Taiwan.

Methods

We addressed the relevant issues by analysing 95 naive Taiwanese patients infected with either hepatitis C virus (HCV) genotype 1 ( n=57) or 2 ( n=38), receiving interferon alone ( n=41) or in combination with ribavirin ( n=54) therapy. A single pathologist scored steatosis and steatohepatitis at baseline and 24 weeks after antiviral treatment.

Results

At baseline, steatosis and steatohepatitis were present in 44 (46%) and four (4%) patients, respectively. Variables associated with steatosis in logistical regression were hyperglycaemia ( P=0.01), hypertriglyceridaemia ( P=004) and body mass index ≥27 ( P=0.009), but not HCV genotype or viral load. The grade of steatosis correlated well with the number of metabolic syndrome parameters ( P=0.018). Interferon monotherapy, advanced age and HCV genotype 1, but not steatosis, correlated with lower sustained response rate. After treatment, steatosis improved in 19 and worsened in nine, which also did not correlate with HCV genotype ( P=0.850) or sustained response to antiviral therapy ( P=0.246).

Conclusions

Hepatic steatosis in Taiwanese patients with chronic hepatitis C was associated with features of the metabolic syndrome, but did not correlate with HCV genotype, advanced fibrosis or the response to antiviral therapy.
The Relationship between Cd4 Cell Count Nadirs and the Toxicity Profiles of Antiretroviral Regimens
Authors: Smith Colette J , Sabin Caroline A , Lampe Fiona C , Shah Sapna , Tyrer Mervyn , Youle Mike S , Cropley Ian , Johnson Margaret A , Phillips Andrew N
Published: April 2022

Background

It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities.

Methods

Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by >1mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by >2.5 times the upper limit of normal), triglycerides (by >1 mmol/l) and decreases in haemoglobin (by >2 g/dl) were assessed.

Results

377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99–1.10; P=0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0–100, 100–200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (1%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons ( P=0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49–0.92; P=0.01).

Discussion

Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.
Interactive Selective Pressures of Hla-Restricted Immune Responses and Antiretroviral Drugs on HIV-1
Authors: John Mina , Moore Corey B , James Ian R , Mallal Simon A
Published: April 2022

HIV-specific cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition and antiretroviral drugs exert selection pressure on HIV-1 in vivo. The selection of CTL escape mutations strongly underpins the failure of CTL control in most untreated infections whilst drug-resistance mutations predict failure of drug control. These two evolutionary forces share common target residues in HIV-1 at which their selection effects could be synergistic or antagonistic, such that the propensity to develop drug resistance and virological treatment failure may be influenced by HLA type. We examined HIV-1 reverse transcriptase (RT) and protease sequences in a large clinical observational cohort of 487 HIV-infected individuals and found evidence of site-specific interactions between specific antiretroviral drug exposures, HLA alleles and HIV sequence diversity at population level. Such interactions may have general and specific implications for explaining in vivo/in vitro discordance of drug resistance, host-specific susceptibility to drug resistance, individualization of therapy and therapeutic vaccine design.
Therapeutic Drug Monitoring and Drug–Drug Interactions Involving Antiretroviral Drugs
Authors: Boffito Marta , Acosta Edward , Burger David , Fletcher Courtney V , Flexner Charles , Garaffo Rodolphe , Gatti Giorgio , Kurowski Michael , Perno Carlo Federico , Peytavin Gilles , Regazzi Mario , Back David
Published: April 2022

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM.

In April 2004, a panel of experts met for the second time in Rome, Italy. This was following the inaugural meeting in Perugia, Italy, in October 2000, which resulted in the manuscript published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review and update the numerous questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. A major focus of the meeting was to discuss and critically analyse recent and precedent clinical drug–drug interaction data to provide a clear framework of the pharmacological basis of how one drug may impact the disposition of another.

This report, which has been updated to include material published or presented at international conferences up to the end of December 2004, reviews recent pivotal pharmacokinetic interaction data and provides advice to clinical care providers on how some drug–drug interactions may be prevented, avoided or managed, and, when data are available, on what dose adjustments and interventions should be performed.
Protection of Mammalian Cells from Severe Acute Respiratory Syndrome Coronavirus Infection by Equine Neutralizing Antibody
Authors: Wang Xiliang , Ni Bing , Du Xinan , Zhao Guangyu , Gao Wenda , Shi Xinfu , Zhang Songle , Zhang Liangyan , Wang Dong , Luo Deyan , Xing Li , Jiang Haiyan , Li Wanling , Jiang Man , Mao Liwei , He Yangdong , Xiao Yu , Wu Yuzhang
Published: April 2022

The aetiological agent for severe acute respiratory syndrome (SARS) has been determined to be a new type of coronavirus (SARS-CoV) that infects a wide range of mammalian hosts. Up to now, there have been no specific drugs to protect against SARS-CoV infection, thus developing effective strategies against this newly emerged viral infection warrants urgent efforts. Adoptive immune therapy with pathogen-specific heterologous immunoglobulin has been successfully used to control the dissemination of many viral infections. To investigate whether a neutralizing antibody against SARS-CoV raised in an artiodactylous host can have a protective role on primate cells, we prepared serum IgGs and their pepsin-digested F(ab’)2 fragments from horses inoculated with purified SARS-CoV (BJ-01 strain). The protective effect of the F(ab’)2 fragments against SARS-CoV infection was determined in cultured Vero E6 cells by cytopathic effect (CPE), MTT and plaque-forming assays and in a Balb/c mouse model by CPE and quantitative RT-PCR. The results showed the neutralization titres of F(ab’)2 from three horses all reached at least 1:1600, and 50 μg of the F(ab’)2 fragments could completely neutralize 1x104 TCID50 SARS-CoV in vivo. Additionally, we observed that F(ab’)2 against BJ-01 strain could also protect cells from infection by the variant GZ-01 strain in vitro and in vivo. Our work has provided experimental support for testing the protective equine immunoglobulin in future large primate or human trials.
A Prospective Study of Efficacy and Safety of Once-Daily Saquinavir/Ritonavir plus Two Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Thai Patients
Authors:   for the Staccato Study Group, Phanuphak Praphan , Ubolyam Sasiwimol , Sankote Jongkol , Pongprayoon Patcharee , Saenawat Sukontha , Wicharuk Saijai , Nonenoy Siriporn , Wannachai Natnipa , Chautrakarn Sineenart , Chuenyam Theshinee , Jeanpan Nittaya , Nuchapong Thantip , Jupimai Thidarat , le Braz Michelle , Bunyaprawit Parichat , Putthawong Suchittra , Penglimoon Yaowaluk , Seekaow Napawan , Karakate Wipawan , Khongsawad Sopha , Kiatatchasai Wiphawee , Ananworanich Jintanat , Hill Andrew , Siangphoe Umaporn , Ruxrungtham Kiat , Prasithsirikul Wisit , Chetchotisakd Ploenchan , Kiertiburanakul Sasisopin , Munsakul Warangkana , Raksakulkarn Phitsanu , Tansuphasawadikul Somboon , Nuesch Reto , Cooper David A. , Hirschel Bernard
Published: April 2022

Objective

To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies.

Design

Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200–350 at screening were enrolled in this open-label 24week study.

Methods

Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities. Results: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/μl and HIV RNA 50 118 (4.7 log10) copies/ml. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/μl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 ( P=0.957) or absolute HIV RNA at week 24 ( P=0.77).

Conclusion

First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.
The Impact of Haematopoietic Growth Factors on the Management and Efficacy of Antiviral Treatment in Patients with Hepatitis C Virus
Authors: Lebray Pascal , Nalpas Bertrand , Vallet-Pichard Anaïs , Broissand Christine , Sobesky Rodolphe , Serpaggi Jeanne , Fontaine Hélèn , Pol Stanislas
Published: April 2022

Aim

To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity.

Methods

This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use.

Results

In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a base-line neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively).

Conclusion

HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.