bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Susceptibility of Adefovir-Associated Hepatitis B Virus Polymerase Mutations to other Antiviral Agents
Authors: Qi Xiaoping , Xiong Shelly , Yang Huiling , Miller Michael , Delaney William E
Published: April 2022

Background

Adefovir dipivoxil is a nucleotide prodrug approved for the treatment of chronic hepatitis B. During clinical trials, ADV-associated mutations were observed in 0, 3, 11, 18 and 29% of patients after 48, 96, 144, 192 and 240 weeks of therapy, respectively. Hepatitis B virus (HBV) polymerase mutations associated with virological breakthrough to ADV include rtA181V and rtN236T, which occur alone or in combination. The rtA181T mutation has also been observed at low frequency, alone or in combination with rtN236T.

Methods

To investigate the in vitro activity of adefovir and other anti-HBV agents against these mutants, we generated five stable cell lines that each expressed one of the following HBV mutants: rtN236T, rtA181V, rtA181V+rtN236T, rtA181T+rtN236T and rtA181T. Using these cell lines, we quantified in vitro changes in drug susceptibility for eight nucleotide/nucleoside analogues.

Results

The rtN236T mutant had 7-fold resistance to adefovir but remained sensitive to entecavir, telbivudine and torcitabine (≤3.2-fold reduced susceptibility). The A181V mutant had 4.3-fold resistance to adefovir and had reduced susceptibility to multiple other agents ranging from 3.2-fold (tenofovir) to >191-fold (clevudine). The A181V+rtN236T double mutant was the most highly resistant showing 18-fold resistance to adefovir and higher levels of resistance to other tested drugs with the exception of tenofovir (10-fold reduced susceptibility). Our results and preliminary clinical data suggest that patients with rtN236T or rtA181V remain susceptible to tenofovir, entecavir and lamivudine. Further clinical data are necessary to precisely define in vitro cutoffs indicative of clinically-relevant resistance, particularly for drugs in development such as emtricitabine, telbivudine, torcitabine and clevudine.
Complementary and alternative Medicine (CAM) for the Treatment of Chronic Hepatitis B and C: A Review
Authors: Modi Apurva A , Wright Elizabeth C , Seeff Leonard B
Published: April 2022

Complementary and alternative medicine (CAM) has been used for centuries in China and Japan to treat various illnesses, including viral hepatitis. Several therapeutic approaches constitute CAM, the most relevant for this review being the use of herbals. However, profound disagreements exist between conventional and alternative medicine practitioners regarding their value. Western medical advocates cite deep concerns about the purity of most herbals because of lack of standardized production, the paucity of pharmacokinetic data, the fact that few well-designed randomized, controlled trials of these products have been performed and the evidence that some herbals have been responsible for severe adverse effects. Nevertheless, many in the public, even in western countries, turn to the use of herbals, believing that they must be safe and effective because they are ‘natural’ and have been used for centuries, and because of dissatisfaction with conventional medicine. Accordingly, their use in western countries and the costs incurred have increased each year. While there is evidence that some herbals have physiological effects, there still is insufficient evidence to recommend their use. This paper reviews the classification, epidemiology and philosophy of CAM, and the reasons advanced for herbal use to treat viral hepatitis. The criteria necessary to develop a potential pharmacological agent are presented, as well as the requirements for conducting a scientifically valid treatment trial of herbals. Five herbals used in the past to treat viral hepatitis are reviewed and evaluated for the quality of their studies and mention is made of herbals known to have adverse effects.
Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers
Authors: Sekar Vanitha J , Pauw Martine De , Mariën Kris , Peeters Monika , Lefebvre Eric , Hoetelmans Richard MW
Published: April 2022

Background

This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista™]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers.

Methods

Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11–day 16 and TMC114/r once daily on day 17.

Results

When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15–17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated.

Conclusions

The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose.
Primary Resistance to Enfuvirtide (T20) in recently HIV-1 Infected, Antiretroviral-Naive Patients from the ANRS Aquitaine Cohort
Authors: Peuchant Olivia , Capdepont Sophie , Ragnaud Jean-Marie , Aurillac-Lavignolle Valérie , Thiébaut Rodolphe , Fleury Hervé , Masquelier Bernard ,   on behalf of the ANRS CO3 Aquitaine Cohort
Published: April 2022

Background

Transmission of HIV-1 variants with resistance to reverse transcriptase (RT) and protease inhibitors has been widely characterized in developed countries. However, no clear evidence of primary resistance to HIV-1 fusion inhibitors has been shown so far. We wished to investigate the possibility of genotypic resistance to enfuvirtide (T20) in a cohort of antiretroviral-naive, recently infected patients.

Methods

We included patients from the Aquitaine Cohort with an estimated date of seroconversion in 2004 and 2005, a plasma sample obtained less than 18 months after seroconversion and no prior history of antiretroviral therapy. RT, protease and gp41 sequences were determined by direct population sequencing from plasma samples and drug resistance mutations were reported.

Results

A total of 55 patients were included in the study. The overall prevalence of transmitted HIV-1 resistance was 20%. Two patients had viruses with resistance mutations to T20. The first case had an N42D mutation in the HR1 region of the gp41, along with transmitted resistance mutations in the protease (D30N, M36I, N88D) and in the RT (M41L, L210W, T215D). The second case had a G36D HR1 mutation, with no evidence of other drug resistance mutations.

Conclusion

We have shown the first cases of primary resistance to T20 in recently infected patients in southwestern France. Epidemiological surveillance of the transmission of drug-resistant HIV-1 should include the resistance to T20.
A Randomized Study of Antiviral Medication Switch at Lower-Versus Higher-Switch Thresholds: AIDS Clinical Trials Group Study A5115
Authors: Riddler Sharon A , Jiang Hongyu , Tenorio Allan , Huang Hairong , Kuritzkes Daniel R , PAcosta Edward , Landay Alan , Bastow Barbara , Haas David W , Tashima Karen T , Jain Mamta K , Deeks Steven G , Bartlett John A
Published: April 2022

Background

Clinical stability has been observed with continued antiretroviral therapy (ART) in the setting of partial virological suppression. The optimal time to switch treatment in patients with low but detectable HIV-1 RNA is not known.

Methods

Subjects on stable ART with HIV-1 RNA 200–10,000 copies/ml were randomized to an immediate treatment switch, or to a delayed switch when HIV-1 RNA increased to ≥10,000 copies/ml or CD4+ T-cell count decreased by 20%. The primary outcome measures were immune activation (proportion of CD8+ T-cells expressing CD38 at week 48) and evolution of genotypic drug resistance.

Results

The study failed to fully accrue the originally planned 108 subjects. Only 47 subjects were randomized to immediate- or delayed-switch arms. Of the subjects in the delayed-switch arm, 10/23 (43%) met the criteria for ART switch during the study (median follow-up 82 weeks). After 48 weeks of observation, the level of immune activation was comparable in the two arms. New resistance mutations were observed in 3/17 and 8/19 subjects in the immediate- and delayed-switch groups, respectively. The loss of future treatment options, however, was comparable in the delayed- and immediate-switch groups.

Conclusions

Individuals with partial viral suppression tend to remain immunologically stable, however, the accumulation of drug resistance mutations is an ongoing risk. Delayed switch in ART may be a reasonable short-term strategy for individuals with very limited treatment options.
Virological Response to Different Combination Regimes of Peginterferon α-2b and Lamivudine in Hepatitis B e Antigen Positive Chronic Hepatitis B
Authors: Chan Henry Lik-Yuen , Wong Vincent Wai-Sun , Chim Angel Mei-Ling , Choi Paul Cheung-Lung , Chan Hoi-Yun , Hui Alex Yui , Wong Grace Lai-Hung , Sung Joseph Jao-Yiu
Published: April 2022

Objective

To investigate whether simultaneous commencement of peginterferon α-2b and lamivudine treatment has more potent hepatitis B virus (HBV) DNA suppression than staggered regimes.

Methods

Thirty HBeAg-positive chronic hepatitis B patients were randomized in 1:1:1 ratio to 32-week peginterferon started simultaneously with lamivudine (group 1), eight weeks before lamivudine (group 2) or eight weeks after commencement of lamivudine (group 3). All patients received lamivudine until week 104.

Results

At week 52, the log HBV DNA reduction in group 1 (6.38) was more profound than that in group 2 (3.43, P=0.022) and tended to be superior to that in group 3 (4.44, P=0.060). HBeAg seroconversion developed in six (67%) patients in group 1, three (33%) patients in group 2 ( P=0.35 versus group 1) and one (10%) patient in group 3 ( P=0.037 versus group 1). At week 104, the log HBV DNA reduction in group 1 (6.13) versus that in group 2 (5.24) and group 3 (5.15) was insignificantly different. Lamivudine resistance was found in four (14%) patients at week 104. There was 1.22 and 2.52 median log reduction in covalently closed circular DNA and total intrahepatic HBV DNA, respectively, at week 104, but there was no difference among the three groups. At 24 weeks post-treatment, sustained HBeAg seroconversion was observed in five (56%), three (33%) and four (40%) of the patients in groups 1, 2 and 3, respectively ( P>0.05).

Conclusions

Simultaneous commencement of peginterferon and lamivudine tend to provide more profound viral suppression than staggered regimes in the early phase of treatment.
The Influence of HIV Infection and Antiretroviral Therapy on the Mitochondrial Membrane Potential of Peripheral Mononuclear Cells
Authors: Sternfeld Thomas , Schmid Mathias , Tischleder Annette , Mudra Susanne , Schlamp Angelika , Kost Bernd P , Gruber Rudolf , Youle Mike , Bogner Johannes R , Goebel Frank-Detlef
Published: April 2022

Objectives

Clinical disorders occurring in HIV-infected patients on antiretroviral therapy (ART) have been linked to mitochondrial dysfunction, for example, lactic acidosis and lipodystrophy. Mitochondrial membrane potential (ΔΨm) is the most direct measure of the state of energization of the mitochondria. We analysed ΔΨm of peripheral blood mononuclear cells (PBMCs) in HIV-negative, healthy subjects ( n=8), HIV-infected, treatment-naive patients ( n=30), and HIV-infected patients on ART ( n=58). The influence of ART was analysed in six patients who started their first regimen.

Methods

The ΔΨm of PBMC was measured by flow cytometry using the dye JC-1.

Results

The ΔΨm was significantly lower in HIV-infected patients than in HIV-negative controls. This difference was detected in both treated ( P=0.0001) and untreated patients ( P=0.001). The ΔΨm of PBMCs was highly correlated with CD4+ T-cell count in therapy-naive patients ( P=0.002, r=0.546) and in treated patients ( P=0.028, r=0.288). The ΔΨm increased significantly in therapy-naive patients after starting ART ( P=0.001). Patients with lipoatrophy had significantly lower ΔΨm than patients without lipodystrophy or with lipohypertrophy ( P=0.023).

Conclusions

In HIV-infected persons ΔΨm is significantly reduced. Patients with lipoatrophy have significantly reduced ΔΨm. This is the first study showing that the ΔΨm of PBMCs is highly correlated with CD4+ T-cell count in HIV infection.
The Short Hairpin RNA Driven by Polymerase II Suppresses both Wild-Type and Lamivudine-Resistant Hepatitis B Virus Strains
Authors: Ren Guang-Li , Fang Ying , Ma Heng-Hao , Lei Ying-Feng , Wang Dan , Xu Man-Chun , Wang Ping-Zhong , Huang Chang-Xing , Nie Qing-He , Sun Yong-Tao , Bai Xue-Fan
Published: April 2022

Background

Chronic infection with hepatitis B virus (HBV) is widespread because of the limited availability of therapeutic treatments. Although previous reports have suggested that RNA interference has promise as a treatment for HBV infection, further studies of long-term and off-target drug effects on HBV, especially on drug-resistant strains of HBV, are needed. Therefore, seven vectors that express short hairpin RNAs (shRNAs), driven by the polymerase II promoter, pSilencer4.1/HBV, were constructed to target open reading frames (ORFs) of the HBV C and S genes from wild-type and drug-resistant strains. Treatment efficiency was also assessed.

Methods

The pSilencer4.1/HBV vectors were investigated in HepG2.2.15 cells and transgenic mice that consistently produce wild-type HBV. Additionally, vectors that produce a lamivudine-resistant strain of HBV were developed and cotransfected, along with pSilencer/HBV, into both HepG2 cells and mice. The effects of polymerase-II-driven pSilencer4.1/HBV were compared with those of polymerase-III-driven pSilencer3.1/HBV at both the gene and protein level.

Results

pSilencer4.1/HBV inhibited the expression of viral protein, DNA and HBV subtype ayw mRNA in both HepG2.2.15 cells and transgenic mice. Toxicity, as well as off-target effects, did not occur after a short- to medium-term examination. Moreover, an HBV strain resistant to lamivudine, subtype adr, was suppressed by shRNA in both HepG2 cells and mice. In contrast to polymerase III, vectors that used polymerase II could drive efficient silencing without off-target effects.

Conclusions

Silencing by shRNA dramatically inhibited HBV expression and replication regardless of strain type. ShRNA could therefore be a promising treatment for HBV infection.
Mitochondrial Toxicity of Indinavir, Stavudine and Zidovudine Involves Multiple Cellular Targets in white and brown adipocytes
Authors: Viengchareun Say , Caron Martine , Auclair Martine , Kim Min Ji , Frachon Paule , Capeau Jacqueline , Lombès Marc , Lombès Anne
Published: April 2022

Objective

To evaluate the mechanisms of mitochondrial toxicity associated with antiretroviral treatment.

Methods

3T3–F442A white and T37i brown adipocytes were exposed to stavudine (10 μM), zidovudine (1 μM) and indinavir (10 μM), alone or in combination. Adipocyte fat content was measured with Oil Red O staining. Quantification of mRNA levels and of mitochondrial DNA content used PCR-based techniques. Mitochondrial activities were evaluated with respiration, ATP synthesis and spectrophotometric assays. Mitochondrial mass was assessed by the fluorescent probe MitoTracker Red.

Results

In both cell types, all the treatments induced a severe defect of adipogenesis (low lipid content and decreased markers of adipogenic maturation: peroxisome proliferator-activated receptor [PPAR]γ2 and aP2 but also uncoupling protein 1 in brown adipocytes) as well as altered mitochondrial function (decreased respiration rate and increased mitochondrial mass). Drug combination did not give additional toxicity. Brown adipocytes appeared more affected than white adipocytes (lower respiration rate and decreased ATP production). The mechanisms of mitochondrial toxicity differed with the drug and the cell type. Only stavudine induced severe mitochondrial DNA depletion in both cell types. With all the treatments, white adipocytes showed a decrease in the expression of mitochondrial and nuclear-DNA-encoded respiratory chain subunits (cytochrome c oxidase [CytOx]2 and CytOx4), whereas brown adipocytes maintained normal expression in accordance with their increase of the transcriptional factors of mitochondrial biogenesis nuclear respiratory factor 1 and PPARγ coactivator (PGC)1-related cofactor PRC, but not PGC1α.

Conclusion

Our results provide evidence for dissociation between mitochondrial activity, transcription and mitochondrial DNA content, highlighting the complexity of mitochondrial toxicity, which affects multiple cellular targets.
Safety and Immunogenicity from a Phase I Trial of Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine
Authors: Lin Jiang-Tao , Zhang Jian-San , Su Nan , Xu Jian-Guo , Wang Nan , Chen Jiang-Ting , Chen Xin , Liu Yu-Xuan , Gao Hong , Jia Yu-Ping , Liu Yan , Sun Rui-Hua , Wang Xu , Yu Dong-Zheng , Hai Rong , Gao Qiang , Ning Ye , Wang Hong-Xia , Li Ma-Chao , Kan Biao , Dong Guan-Mu , An Qi , Wang Ying-Qun , Han Jun , Qin Chuan , Yin Wei-Dong , Dong Xiao-Ping
Published: April 2022

Background

Emergence of severe acute respiratory syndrome (SARS) from the winter of 2002 to the spring of 2003 has caused a serious threat to public health.

Methods

To evaluate the safety and immunogenicity of the inactivated SARS coronavirus (SARS-CoV) vaccine, 36 subjects received two doses of 16 SARS-CoV units (SU) or 32 SU inactivated SARS-CoV vaccine, or placebo control.

Results

On day 42, the seroconversion reached 100% for both vaccine groups. On day 56, 100% of participants in the group receiving 16 SU and 91.1% in the group receiving 32 SU had seroconverted. The geometric mean titre of neutralizing antibody peaked 2 weeks after the second vaccination, but decreased 4 weeks later.

Conclusion

The inactivated vaccine was safe and well tolerated and can elicit SARS-CoV-specific neutralizing antibodies.
Transmission of Drug-Resistant HIV-1 from an Infected Individual to a Caregiver
Authors: Brumme Chanson J , Harrigan P Richard , Preston Emma C , Dong Winnie WY , Wynhoven Brian , Murphy Carol , Montaner Julio SG
Published: April 2022

Objective

To describe a suspected case of intrafamilial transmission of drug-resistant HIV-1 from an infected individual to his caregiver.

Methods

HIV-1 protease, reverse transcriptase, nef and gp41 DNA sequences were determined from plasma samples after RNA extraction and nested RT-PCR. Phylogenetic trees were generated using neighbour-joining methods.

Results

HIV-1 infection was diagnosed in an individual (index) following the death of her HIV-infected adopted son (source). The index case cared for her son in the 9 months prior to his death. No obvious instances of contact with bodily secretions or other traditional risk factors for HIV transmission were identified, although the index case had mild eczema. At time of death, the source case's HIV plasma viral load was >1,000,000 HIV copies/ml. Genotyping of the protease and reverse transcriptase of both the source and index samples revealed similar drug-resistance mutations despite the index case being antiretroviral-naive. Both source and index V3 genotypes were consistent with syncytium-inducing virus. The mean pairwise amino acid identity between the source and index samples was 97.0%, 99.2%, 92.6% and 94.6% in protease, reverse transcriptase, nef and gp41, respectively. The source and index sequences clustered together on phylogenetic trees when compared with 50 randomly selected sequences from British Columbia.

Conclusion

Although exceptionally rare, our case demonstrates transmission of drug-resistant HIV-1 from an infected individual to his caregiver in the absence of traditional risk factors. It should be noted that the source had a very high viral load during the terminal phase of his illness.
Mitochondrial Toxicity of Tenofovir, Emtricitabine and Abacavir Alone and in Combination with Additional Nucleoside Reverse Transcriptase Inhibitors
Authors: Venhoff Nils , Setzer Bernhard , Melkaoui Kerstina , Walker Ulrich A
Published: April 2022

Background

Some nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) combinations cause additive or synergistic interactions in vitro and in vivo.

Methods

We evaluated the mitochondrial toxicity of tenofovir (TFV), emtricitabine (FTC) and abacavir as carbovir (CBV) alone, with each other, and in combination with additional NRTIs. HepG2 human hepatoma cells were incubated with TFV, FTC, CBV, didanosine (ddI), stavudine (d4T), lamivudine (3TC) and zidovudine (AZT) at concentrations equivalent to 1 and 10x clinical steady-state peak plasma levels (Cmax). NRTIs were also used in double and triple combinations. Cell growth, lactate production, intracellular lipids, mtDNA and the mtDNA-encoded respiratory chain subunit II of cytochrome c oxidase (COXII) were monitored for 25 days.

Results

TFV and 3TC had no or minimal toxicity. FTC moderately reduced hepatocyte proliferation independent of effects on mtDNA. ddI and d4T induced a time- and dose-dependent loss of mtDNA and COXII, decreased cell growth and increased levels of lactate and intracellular lipids. CBV and AZT strongly impaired hepatocyte proliferation and increased lactate and lipid production, but did not induce mtDNA depletion. The dual combination of TFV plus 3TC had only minimal toxicity; TFV plus FTC slightly reduced cell proliferation without affecting mitochondrial parameters. All other combinations exhibited more pronounced adverse effects on mitochondrial endpoints. Toxic effects on mitochondrial parameters were observed in all combinations with ddI, d4T, AZT or CBV. TFV and 3TC both attenuated ddI-related cytotoxicity, but worsened the effects of CBV and AZT.

Conclusions

The data demonstrate unpredicted interactions between NRTIs with respect to toxicological endpoints and provide an argument against the liberal use of NRTI cocktails without first obtaining data from clinical trials.
Induction of Regulatory T-Cells and Interleukin-10-Producing Cells in Non-Responders to Pegylated Interferon-α Therapy for Chronic Hepatitis B
Authors: Sprengers Dave , Stoop Jeroen N , Binda Rekha S , Kusters Johannes G , Haagmans Bart L , Carotenuto Patrizia , Artsen Andre , Van Der Molen Renate G , Janssen Harry LA
Published: April 2022

Background

Treatment with interferon-α (IFN-α) leads to a response in only a minority of patients with chronic hepatitis B virus (HBV) infection, but the reasons for this are poorly understood. It was recently shown that in patients with chronic HBV infection, CD4+CD25+ regulatory T-cells (Treg) can suppress the HBV-specific immune response. We aimed to investigate whether in non-responders to IFN-α therapy Treg contribute to treatment failure by downregulating the HBV-specific T-cell responses.

Patients and methods

Fourteen patients positive for hepatitis B e antigen received pegylated IFN-α monotherapy for 52 weeks and were followed for 26 weeks.

Results

Compared with non-responders, responders displayed an increased HBV-specific T-helper cell proliferation. At the start of treatment there was no difference in the frequencies of CD4+CD25+ Treg between responders and non-responders. During therapy, the frequency of CD4+CD25+ Treg increased in non-responders, but not in responders. In contrast to the responders, the non-responders showed a significant increase in the frequency of interleukin-10-producing cells. Treg depletion resulted in increased proliferation capacity, but did not affect the frequency of interleukin-10-producing cells measured during the course of the treatment.

Conclusion

This study indicates that Treg might have an important role in HBV persistence during and after pegylated IFN-α therapy.
Pharmacokinetics and Pharmacodynamics of Combined use of Lopinavir/Ritonavir and Rosuvastatin in HIV-Infected Patients
Authors: Van Der Lee Manon , Sankatsing Raaj , Schippers Emile , Vogel Martin , Fätkenheuer Gerd , Van Der Ven Andre , Kroon Frank , Rockstroh Jürgen , Wyen Christoph , Bäumer Anselm , De Groot Eric , Koopmans Peter , Stroes Erik , Reiss Peter , Burger David
Published: April 2022

Background

Lopinavir/ritonavir-containing antiretro-viral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa.

Methods

HIV-infected patients on lopinavir/ritonavir (viral load <400 copies/ml) with total cholesterol (TC) >6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC<5.0 mmol/l, high-density lipoprotein-cholesterol >1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] <2.6 mmol/l and triglycerides <2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (Cmin) were determined at week 0, 4, 8 and 12 and rosuvastatin Cmin, at week 4, 8 and 12.

Results

Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin ( P=0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin Cmin for 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70–1.5), 2.5 (1.3–3.3) and 5.5 (3.3–8.8) ng/ml, respectively.

Conclusions

Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.
Decreasing CD4+ T-cell Count During Suppressed or Low-Level Viraemia in Patients with HIV Infection
Authors: Anderson Albert ML , Kosinski Andrzej S , Bartlett John A
Published: April 2022

Background

Suboptimal improvement in CD4+ T-cell count is not uncommon in HIV-infected patients with suppressed plasma HIV RNA levels, and a decrease in CD4+T-cell count in patients with suppressed or low-level viraemia has been observed.

Methods

Our objectives were to identify the prevalence of decreasing CD4+ T-cell counts during suppressed or low-level viraemia, to determine the frequency of clinical events during and immediately after such decreases, and to examine for associations with individual variables. A matched case-control study was undertaken using the Duke Infectious Diseases Clinic database ( n=3,949). Cases had at least two consecutive significant decreases in either CD4+ absolute count or CD4+ percentage, while also having plasma HIV RNA levels <1,000 copies/ml.

Results

The prevalence of decreasing CD4+ T-cell counts during suppressed or low-level viraemia was 1.22%. Only three HIV-associated clinical events occurred. The majority of cases had an increase in the CD4+ T-cell count immediately following the study period. The use of either zidovudine or stavudine was weakly associated with decreasing CD4+ T-cell counts in a multivariable analysis, but this association was not present in cases with only a decrease in CD4+ T-cell percentage.

Conclusions

Decreasing CD4+ T-cell counts during suppressed or low-level viraemia are rare, typically transient, and not associated with an increase in HIV-associated clinical events.
Respiratory Viral Infections in Transplant Recipients
Authors: Ison Michael G
Published: April 2022

A wide range of viruses affect the respiratory tract of transplant recipients, including adenovirus, influenza, human metapneumovirus, parainfluenza virus, respiratory syncytial virus (RSV) and rhinovirus. Prospective studies using contemporary diagnostic techniques have recently improved our understanding of the epidemiology and importance of these respiratory viruses among transplant recipients. From these studies, rhinovirus, in particular, has been shown to be one of the most common causes of infection in stem cell and lung transplant recipients. In addition to epidemiological data, recent studies have also advanced our understanding of management of influenza, adenovirus, and RSV infections among transplant recipients.
Neuraminidase Inhibitors and their Role in Avian and Pandemic Influenza
Authors: Crusat Martin , De Jong Menno D
Published: April 2022

Continuing occurrences of human infections with avian influenza A (H5N1) viruses have ignited increasing fears that the next influenza pandemic is imminent. Fortunately, options for antiviral prophylaxis and treatment have been improved dramatically since the previous pandemics by the availability of neuraminidase inhibitors such as zanamivir and oseltamivir. However, although the prophylactic and therapeutic efficacy of these drugs is well established for uncomplicated seasonal human influenza, clinical effectiveness seems limited for human H5N1 infections despite in vitro susceptibility and efficacy in animal studies. Factors which might contribute to this apparently limited efficacy include suboptimal dosing or routes of administration, suboptimal timing of treatment and the inability of antiviral drugs to interfere with immunopathology, and the development of drug resistance. Efforts to optimize the use of neuraminidase inhibitor treatment in H5N1 disease are urgently needed and might eventually aid in the judicious use of stockpiled neuraminidase inhibitors in the event of a pandemic.
Prospective Cohort Study of HIV Post-Exposure Prophylaxis for Sexual Assault Survivors
Authors: Loutfy Mona Rafik , Macdonald Sheila , Myhr Terri , Husson Heather , Du Mont Janice , Balla Shannon , Antoniou Tony , Rachlis Anita
Published: April 2022

Background

There is a lack of standardized programs for HIV counselling and post-exposure prophylaxis (PEP) in the setting of sexual assault.

Methods

We conducted an 18-month prospective cohort study assessing universal HIV counselling for all sexual assault survivors presenting to 18 Ontario Sexual Assault Treatment Centres. HIV PEP was universally offered to those at risk of HIV infection (high risk or unknown risk) presenting ≤72 h after the assault, using Combivir® one pill and Kaletra® three capsules twice a day for 28 days. Those who accepted HIV PEP were monitored via a schedule of frequent follow ups. The primary outcomes were acceptance and completion rates, and their predictors were determined using multivariable logistic regression. Adverse events (AE) were categorized using a standardized toxicity grading system.

Results

Of the 900 evaluable participants eligible for PEP, 798 (69 at high risk and 729 at unknown risk) were offered treatment. Acceptance rates were 66.7% ( n=46) and 41.3% ( n=301) for participants at high risk and unknown risk, respectively. Participants at high risk were 2.2 times more likely to accept PEP than those at unknown risk (adjusted odds ratio 2.2; 95% confidence interval 1.2–4.0; P=0.01). Overall, 23.9% high-risk ( n=11) and 33.2% unknown-risk participants ( n=100) completed PEP ( P=0.20). Predictors of acceptance and completion included assault by a stranger and participant anxiety. AEs were common, with 77.1% of participants reporting grade 2–4 symptoms.

Conclusion

A province-wide standardized program of universal HIV counselling and offering of PEP to sexual assault survivors with frequent follow up was successfully implemented and feasible.
Passive Immunization Protects Cynomolgus Macaques against Puumala Hantavirus Challenge
Authors: Klingström Jonas , Stoltz Malin , Hardestam Jonas , Ahlm Clas , Lundkvist Åke
Published: April 2022

Background

Hantaviruses cause two severe and often fatal human diseases: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Presently, there is no effective prevention available for HFRS or HPS. Here, we studied the effect of passive immunization on the course of infection in cynomolgus macaques challenged with wild-type Puumala hantavirus (PUUV-wt).

Methods

A pool of serum drawn from previously PUUV-wt-infected monkeys was used for immunization; a pool of serum from the same monkeys that was obtained before infection was used as a control. Immunizations were administered 3 days before and 15 days after challenge with PUUV-wt. After challenge, monkeys were sampled once a week and analysed for PUUV-infection markers.

Results

All three monkeys treated with non-immune serum became positive for PUUV RNA in plasma and showed PUUV nucleocapsid-specific immunoglobin M (IgM) responses after challenge. In contrast, no PUUV RNA or anti-PUUV-specific IgM response was detected in the three passively immunized monkeys. As seen in PUUV-infected humans, the control monkeys showed a marked decrease in the amount of platelets and increased levels of creatinine, interleukin (IL)-6, IL-10, and tumour necrosis factor (TNF) after inoculation. In contrast, no marked changes in the amount of platelets were observed in the immunized monkeys and they did not show increased levels of creatinine, IL-6, IL-10 and TNF after virus challenge.

Conclusion

The results show that passive immunization in monkeys, using serum from previously hantavirus-infected monkeys, can induce sterile protection and protect against pathogenesis. Convalescent-phase antibodies may represent a potential therapy that can induce immediate protection against HFRS and HPS.
Characterization of drug Resistance in Antiretroviral-Treated Patients Infected with HIV-1 CRF02_AG and AGK Subtypes in Mali and Burkina Faso
Authors:   the ATARAO group, Sylla Mohamed , Chamberland Annie , Boileau Catherine , Traoré Hamar A , Ag-Aboubacrine Souleyman , Cissé Mamadou , Koala Samual , Drabo Joseph , Diallo Ismael , Niamba Pascal , Tremblay-Sher Daniel , Machouf Nimâ , Rashed Sélim , Nickle David C , Nguyen Vinh-Kim , Tremblay Cécile L
Published: April 2022

Background

In a multicentred cohort of patients on antiretroviral therapy (ART) in Burkina Faso and Mali, we analysed the prevalence of HIV drug resistance mutations in patients failing a modified directly observed therapy (mDOT) protocol.

Methods

Patients on ART >6 months and with viral load (VL) >500 copies/ml were enrolled in a mDOT protocol. Genotypic resistance testing was performed on pre- and post-mDOT plasma samples of patients who still had VL >500 copies/ml after mDOT.

Results

Eight hundred and one patients from seven sites participated in the study. One hundred and thirteen patients (14.1%) had VL >500 copies/ml. Most patients were treated with lamivudine along with zidovudine or stavudine and efavirenz or nevirapine. Genotypes were available for 46 patients. The predominant HIV-1 subtypes were CRF02_AG in 26 (56.5%) and AGK/K/AK in 12 (26.1%) patients. The prevalence of drug resistance mutations by class were as follows for nucleoside reverse transcriptase inhibitors: 184I/V (82.6%), 215Y/F (32.6%), 219E/Q (19.6%), 70R (19.6%), 67N (21.7%), 41L (15.2%) and 151M(2.2%). For non-nucleoside reverse transcriptase inhibitors the prevalence was: 103N (50%) and 181C/I (19.6%). Phylogenetic analysis showed that, although the genetic distances were small among isolates, there was no clustering of a particular subtype in a specific region and that the high prevalence of AGK subtype in our drug-resistant population was not due to a circulating resistant strain.

Conclusion

Although CRF02_AG is the dominant clade in the Burkina Faso/Mali region, isolates with subtype K reverse transcriptase were frequent in our cohort. Drug resistance mutation pathways in subtype K reverse transcriptase need to be further evaluated in a larger cohort of non-B HIV-infected individuals.
The Risk of Developing Peripheral Neuropathy Induced by Nucleoside Reverse Transcriptase Inhibitors Decreases over Time: Evidence from the Delta Trial
Authors: Arenas-Pinto Alejandro , Bhaskaran Krishnan , Dunn David , Weller Ian VD
Published: April 2022

Background

Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI).

Methods

A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddI) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model.

Results

A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddI (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35–44 years compared with <30) and current CD4+ T-cell count (HR=2.27 for CD4+ T-cell counts <150 cell/mm3 compared with >350).

Conclusion

Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used.
Clevudine is Efficiently Phosphorylated to the Active Triphosphate form in Primary Human Hepatocytes
Authors: Niu Congrong , Murakami Eisuke , Furman Phillip A
Published: April 2022

Background

Clevudine (CLV) is a nucleoside analogue of the unnatural l-configuration that has demonstrated potent activity against hepatitis B virus (HBV) in vitro and in Phase III clinical studies. Human hepatoma cell lines are the only liver-derived cells in which CLV metabolism has been investigated. Here, we examine CLV metabolism in primary human hepatocytes, which better represent CLV metabolism in the liver.

Methods

HPLC analysis of primary human hepatocyte extracts incubated with radiolabelled CLV was used to determine the time course of CLV phosphorylation. Effects of the exogenous cell concentration of CLV on phosphorylation were assessed and the half-life of the CLV phosphorylated forms was determined.

Results

The major CLV metabolite formed in human primary hepatocytes was 5‘-monophosphate, whereas in the hepatoma cell lines the major metabolite was 5’-triphosphate. The level of CLV 5’-triphosphate was similar in both cell types. In primary hepatocytes the conversion of CLV 5’-monophosphate to the corresponding 5’-diphosphate was the rate-limiting step in CLV phosphorylation; the level of CLV phosphorylation was dependent upon exogenous drug concentration and exposure time. CLV 5’-triphosphate accumulated rapidly with peak levels observed after ∼8 h. When cells were incubated with 1 μM CLV, the approximate maximal plasma concentration achieved in individuals receiving the 30 mg dose, the average intracellular concentration of CLV 5’-triphosphate was 41.3 ±8.4 pmols/106 cells (∼10 μM). The initial half-life of CLV triphosphate was ∼11 h.

Conclusions

These results are consistent with once daily CLV dosing currently being used in Phase III clinical studies.
Living with HIV, Antiretroviral Treatment Experience and Tobacco Smoking: Results from a Multisite Cross-Sectional Study
Authors:   the EVIT Study Group, Duval Xavier , Baron Gabriel , Garelik Daniel , Villes Virginie , Dupré Thierry , Leport Catherine , Lert France , Peretti-Watel Patrick , Ravaud Philippe , Spire Bruno
Published: April 2022

Background

To assess the prevalence of and factors associated with tobacco smoking and dependence in HIV patients.

Methods

In a one-day cross-sectional national survey of a representative sample of 82 French units specialized in HIV-infected patient care, 727 consecutive outpatients were asked to complete a self-administered questionnaire, assessing smoking habits, dependence, cessation motivation, other substance abuse, sociocultural characteristics, life with HIV and its treatment. Smoking prevalence and dependence were assessed and compared with a representative sample of the general French population.

Results

The questionnaire was completed by 593 (82%) patients: 12% were active or ex-intravenous drug users, 37% were homosexual men, and 43% were active smokers (compared with 31% in the French population) of whom 56% were classified as moderately or highly dependent. Fourteen percent of smokers were highly motivated and free of other substance abuse and of depressive symptoms. Smoking was independently associated with male sex (odds ratio [OR]=2.38; 95% confidence interval [CI] 0.99–1.11), lower body mass index (OR 1.08; 95% CI 1.14–1.03), smoking environment (OR 4.75; 95% CI 3.02–7.49), excessive alcohol consumption (OR 2.50; 95% CI 1.20–5.23), illicit drug use (OR 2.43; 95% CI 1.41–4.19), HIV status disclosure to family (OR 1.81; 95% CI 1.16–2.85) and experience of rejection due to disclosure (OR 1.90; 95% CI 1.14–3.17). Disclosure and drug substitute usage were associated with high tobacco dependence.

Conclusions

Very few HIV smokers seem to be good candidates for a standard tobacco cessation program. Tobacco reduction or cessation strategies should be adapted to this population.
Insulin Resistance, Hepatic Lipid and Adipose Tissue Distribution in HIV-Infected Men
Authors: He Qing , Engelson Ellen S , Ionescu Gabriel , Glesby Marshall J , Albu Jeanine B , Kotler Donald P
Published: April 2022

Background

A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men.

Methods

We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations.

Results

Hepatic lipid content correlated significantly with total VAT (r=0.62, P=0.0014), but not with SAT (r=0.053, P=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, P=0.0004) and RPAT (r=0.53, P=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, P=0.057 and r=0.68, P=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR.

Conclusion

Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.
Cord Blood Lipids in Infants Born to HIV-1-Infected Women Treated with Combination Antiretroviral Therapy
Authors: Melvin Ann J , Kang Minhee , Hitti Jane , Livingston Elizabeth , Cohn Susan E , Stocker Vicki , Ross Allison C , Watts Heather , McComsey Grace A
Published: April 2022

Background

To investigate the effect of exposure to protease inhibitor (PI) therapy in utero on cord blood lipids in infants born to mothers enrolled in AIDS Clinical Trials Group protocol 5084, a prospective, multi-centre, observational study of antiretroviral therapy (ART) during pregnancy.

Methods

Clinical outcome was determined in 80 infants born to women treated with PIs and 73 infants born to women treated with other antiretrovirals during pregnancy. Cord blood serum from 117 of these infants was assayed for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1 (apoA1), apolipoprotein B100 (apoB) and lipoprotein (a). Covariates considered in the analysis included race/ethnicity, gestational age, infant gender, infant birth weight, mode of delivery, maternal tobacco and alcohol use, post-partum body mass index, and ART duration.

Results

Cord blood total and HDL cholesterol, triglyceride, apoA1, apoB, lipoprotein (a) and apoB/apoA1 ratio were not different between the two groups. Cord blood lipid levels in these HIV-exposed infants were similar to those reported in other neonatal cohorts. Controlling for race/ethnicity, infants born to women treated with PIs had higher LDL cholesterol than those born to women not treated with PIs (29 mg/dl versus 27 mg/dl, P=0.006).

Conclusion

Only LDL cholesterol was significantly higher in the cord blood of PI-exposed infants versus those not exposed to PIs in utero. As the difference between the two groups was small, the clinical relevance of the effect of maternal PI treatment on infant LDL cholesterol levels at birth is not clear.
Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens
Authors: Negredo Eugènia , Garrabou Glòria , Puig Jordi , Lòpez Sònia , Morén Constanza , Bellido Rocio , Ayen Rafaela , Cardellach Francesc , Miró Óscar , Clotet Bonaventura
Published: April 2022

The authors would like to report an error that appeared in the authorship of the above article. The first and second authors – Eugènia Negredo and Glòria Garrabou – should have been noted as making an equal contribution to this work.