bluuebunny/crossref_metadata_2025 huggingface dataset:
Virological and Immunological Responses to a Once-a-Day Antiretroviral Regimen with Didanosine, Lamivudine and Efavirenz
Authors: Maggiolo Franco , Migliorino Marco , Maserati Renato , Pan Angelo , Rizzi Marco , Pravettoni Grazia , Rizzi Laura , Suter Fredy ,   the Once Study Group, Gregis G , Quinzan G , Ripamonti D , Finazzi MG , Arici C , Bottura P , Caprioli S , Mamolo G , Marino V , Monolo G , Alipranni C , Maggioni C , Nicodano A , DeMicco G , Brianza E , Merlo M , Masciadra ML
Published: April 2022

Current antiretroviral drugs cannot eradicate HIV infections, and persons living with HIV are often faced with very demanding daily therapeutic schedules that can induce poor adherence. More conveniently dosed and patient-friendly regimens are needed. We investigated, in this 48-week pilot study, a once-a-day highly active antiretroviral therapy regimen of didanosine, lamivudine and efavirenz. Seventy-five consecutive antiretroviral-naive subjects were enrolled. Over the 48-week period, plasma HIV-RNA levels declined sharply, with a median decrease at the end of the observation time >3.4 log copies/ml. The proportion of patients achieving a plasma HIV-RNA level below the limit of detection (50 copies/ml) was 77% (intention to treat analysis) at the end of the study period. The mean CD4 cell count increased steadily over time from 251 to 459 cells/μl. Antiviral efficacy was similar in patients with a baseline HIV-RNA level above or below 100 000 copies/ml. However, patients with a baseline CD4 cell count <200 cells/μl showed a significantly worse virological response than that observed in patients with higher baseline CD4 counts. Overall 15 patients interrupted therapy. In four cases treatment interruption was due to lack of treatment response; three additional patients were lost to follow-up or withdrew informed consent. Eight patients stopped therapy because of adverse events. The once-daily combination of didanosine, lamivudine and efavirenz resulted in sustained viral suppression and was well-accepted by patients. This regimen may offer advantages in selected difficult-to-treat populations, allows directly observed therapy and can be a safe and effective alternative in antiretroviral-naive patients. These encouraging pilot results need to be confirmed in a comparative clinical trial.
A Randomized Clinical Trial Comparing Nelfinavir Or Nevirapine Associated to Zidovudine/Lamivudine in HIV-Infected Naive Patients (The Combine Study)
Authors: Podzamczer Daniel , Ferrer Elena , Consiglio Ezequiel , Gatell José Mariá , Perez Pepa , Perez José Luis , Luna Elena , González Alicia , Pedrol Enric , Lozano Luisa , Ocaña Imma , Llibre Josep María , Casiró Arnaldo , Aranda Miquel , Barrufet Pilar , Martínez-Lacasa Javier , Miró José María , Badía Xavier , Casado Alfonso , Lupo Sergio , Cahn Pedro , Maños Manel , Estela Jordi ,   the Combine Study Team (members listed in Appendix), Barberá MJ , Santín M , Gudiol F , Hidalgo M , Knobel H , Azuaje C , Ribera E , Roget M , Force Lluis , Dalmau D , Suarez C
Published: April 2022

Background

Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed.

Objective

To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients.

Design

Randomized, open-label, multicentre trial.

Setting

Twelve centres in Spain (9) and Argentina (3).

Patients

One hundred and forty-two HIV-infected naive patients without AIDS.

Interventions

Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis.

Results

At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5–71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65–85) in the zidovudine/lamivudine/nevirapine arm ( P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3–61.7) and 65% (95% CI 54.2–76.2), respectively ( P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100 000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/ nevirapine in 25%, due to toxicity ( P>0.2).

Conclusions

Our results suggest that zidovudine/ lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.
Adherence to Antiretroviral Therapy and Outcomes in HIV-Infected Patients Enrolled in An Induction/Maintenance Randomized Trial
Authors: Flandre Philippe , Peytavin Gilles , Meiffredy Vincent , Saidi Yacine , Descamps Diane , Delagnes Martine , Brun-Vézinet Françoise , Raffi François ,   for the Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team
Published: April 2022

Objective

To examine the effect of adherence to therapy on early virological response, later virological failure, and occurrence of adverse events in HIV-infected patients.

Design

A randomized trial of 3-month induction period of zidovudine/lamivudine/indinavir followed by a maintenance phase of zidovudine/lamivudine/indinavir, zidovudine/lamivudine or zidovudine/indinavir.

Main outcomes

Adherence was assessed by pill count. In the induction phase, early virological response was defined as plasma HIV-RNA<500 copies/ml at month 2 and in the maintenance phase, virological failure was defined as plasma HIV-RNA >500 copies/ml in two consecutive specimens.

Results

The median adherence rate was 97% in both induction ( n=366) and maintenance phase ( n=237). In the maintenance phase, pairwise comparisons showed a lower adherence rate in zidovudine/lamivudine/indinavir versus zidovudine/lamivudine ( P=0.03), or versus zidovudine/indinavir ( P=0.05). Only 13% of patients had an adherence over the maintenance phase of 80% or lower, while 40% of patients occasionally had an adherence rate of 80% or lower during this phase. Among the 362 patients with documented HIV-RNA at month 2, 86% had an early virological response. Adherence of 80% or greater was the only variable statistically predictive to early virological response ( P<0.001), while baseline CD4, baseline HIV-RNA, and adherence of 95% or greater were not associated to virological response. In the maintenance phase, adherence, baseline HIV-RNA, HIV-RNA at month 3 and treatment groups were independently predictive to time to virological failure. Analysis by randomized groups indicated that difficulty in adherence (<80%) was predictive to time to failure ( P<0.001) only in both indinavir-containing regimens. Occurrence of two or more severe adverse events (grade 3 and 4) was higher in patients with poor adherence although not statistically associated ( P=0.12), while no association was found with minor adverse events.

Conclusion

Adherence rate was globally lower in patients maintaining the original triple-drug therapy compared with those receiving less intensive regimens. Adherence rate was a time-dependent variable. Adherence to antiviral regimen of 80% or greater was predictive to early virological response, and adherence rate lower than 80% or 95% was predictive to virological failure, especially in indinavir-containing regimens. Occurrence of adverse events was not clearly associated to adherence.
Association of Antiretroviral Resistance Genotypes with Response to Therapy – Comparison of Three Models
Authors: Quigg Marlynne , Frost Simon DW , McDonagh Susan , Burns Sheila M , Clutterbuck Daniel , McMillan Alexander , Leen Clifford S , Brown Andrew J Leigh
Published: April 2022

Genotype-based resistance assays are commonly used to aid treatment in HIV-infected individuals failing anti-retroviral therapy. The relationship between genotype and antiretroviral therapy comes mostly from in vitro assays of the response to a single drugs although there is a need for a prediction of clinical response to combination therapy. We have compared three different methods of analysing genotype data as a predictor of clinical response in a small clinical cohort of highly antiretro-viral-experienced individuals failing therapy. No method performed well beyond 8 weeks into a new therapeutic regimen. A model based on the number of ‘primary’ mutations was statistically significant, but a multiple regression model, which identified specific mutations explained threefold more variation in response. Optimal prediction in this dataset was given by a model obtained from a classification tree analysis, in which genotype at amino acid sites 135 and 202 were combined with amino acid site 184, which explained over 50% of the deviance in the data and had a classification success of 86%.
Analysis of the Virological Response with Respect to Baseline Viral Phenotype and Genotype in Protease Inhibitor-Experienced HIV-1-Infected Patients Receiving Lopinavir/Ritonavir Therapy
Authors: Kempf Dale J , Isaacson Jeffrey D , King Martin S , Brun Scott C , Sylte Jacquelyn , Richards Bruce , Bernstein Barry , Rode Richard , Sun Eugene
Published: April 2022

The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a ‘dropouts as censored’ analysis, plasma HIV RNA ≤400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline lopinavir mutation score of 0–5, 6–7 and ≥8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to lopinavir/ritonavir.
Metabolic and Immunological Effects of Antiretroviral Agents in Healthy Individuals Receiving Post-Exposure Prophylaxis
Authors: García Felipe , Plana Montserrat , Mestre Gabriel , Cruceta Anna , Martinez Esteban , Miró José M , Mallolas Josep , Tuset Montserrat , Pumarola Tomas , Gallart Teresa , Gatell José M
Published: April 2022

We have assessed metabolic and immunological effects of a nelfinavir-containing regimen in healthy HIV-1-uninfected individuals receiving post-exposure prophylaxis. Our data suggest that this regimen is well tolerated and did not modify the lipid or hepatic profiles. This antiretroviral regimen seems to have no effect on lymphocyte T cell subsets, however, it could have an immune-modulator role, inducing an increase in the proliferative responses to mitogens.
Gene Expression of Genital Human Papillomaviruses and Considerations on Potential Antiviral Approaches
Authors: Bernard Hans-Ulrich
Published: April 2022

Genital human papillomaviruses (HPVs) are carcinogenic to humans and are associated with most cases of cervical cancer, genital and laryngeal warts, and certain cutaneous neoplastic lesions. Five of the more than 50 known genital HPV types, HPV-6, -11, -16, -18 and -31, have become the models to study gene expression. The comparison of the studies of these five viruses and analyses of the genomic sequences of those genital HPV types that have not been transcriptionally studied make it likely that genital HPVs share most strategies for regulating their transcription. These strategies are quite different from those of unrelated human and animal papillomaviruses. Among these common properties are (i) a specific promoter structure allowing for fine-tuned negative feedback, (ii) a transcriptional enhancer that is specific for epithelial cells, (iii) regulation by progesterone and glucocorticoid hormones, (iv) silencers, whose principal function appears to be transcriptional repression in the basal layer of infected epithelia, (v) specifically positioned nucleosomes that mediate the functions of some enhancer and the silencer factors, (vi) nuclear matrix attachment regions that can, under different conditions, repress or stimulate transcription, and (vii) as yet poorly understood late promoters positioned very remote from the late genes. Most of these properties are controlled by cellular proteins that, due to their simultaneous importance for cellular processes, may not be useful as HPV-specific drug targets. It should be possible, however, to target complex cis-responsive elements unique to these HPV genomes by nucleotide sequence-specific molecules, such as antisense RNA, polyamides and artificial transcription factors. The application of small molecule-based drugs may be restricted to target proteins encoded by the HPV DNA, such as the replication factor E1 and the transcription/replication factor E2.
Analysis of Virological Efficacy in Trials of Antiretroviral Regimens: Drawbacks of Not Including Viral Load Measurements after Premature Discontinuation of Therapy
Authors: Kirk Ole , Pedersen Court , Law Matthew , Gulick Roy M , Moyle Graeme , Montaner Julio , Eron Joseph J , Phillips Andrew N , Lundgren Jens D
Published: April 2022

Objectives

To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle.

Material

Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) starting their first HAART regimen.

Methods

Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified as responders (ITT/s=f); and 2) patients with a pVL below a given cut-off at week 48 whether they remained on initial assigned therapy or switched therapy were responders (ITT/s incl). In both analyses, patients with missing data at week 48 were classified as failures (i.e., non-responders).

Results

According to ITT/s=f, 22–70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data ( n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT/s=f, and 41–72% according to ITT/s incl. Among those who discontinued the therapy to be evaluated in these two trials, 13–45% (cohort: 39–74%) subsequently experienced a virological response at week 48. The subsequent response rates were associated with the reason for discontinuation (toxicity versus confirmed virological failure: 63 vs 33%), varied largely across regimens and were not associated with the discontinuation rate.

Conclusions

Discontinuation of follow-up at switch from the therapy to be evaluated remains common in anti-retroviral treatment trials, but leads to an imprecise and incomplete assessment of the intrinsic effect of a given regimen. Complete follow-up of all patients should be encouraged strongly as this will allow for several complementary analytic approaches and a focus on optimal treatment strategies rather than specific regimens.
Evolution of Antiretroviral Phenotypic and Genotypic Drug Resistance in Antiretroviral-Naive HIV-1-Infected Children Treated with Abacavir/Lamivudine, Zidovudine/Lamivudine or Abacavir/Zidovudine, with or without Nelfinavir (The Penta 5 Trial)
Authors: Gibb Diana M , Walker A Sarah , Kaye Steve , De Rossi Anita , Ait-Khaled Mounir , Pillay Deenan , Muñoz-Fernandez Maria Angeles , Loveday Clive , Compagnucci Alexandra , Dunn David T , Babiker Abdel G
Published: April 2022

Purpose and methods

To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with ‘Virtual Phenotype’ interpretation).

Results

At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare.

Conclusions

Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
Adipocyte-Derived Hormone Levels in HIV Lipodystrophy
Authors: Kosmiski Lisa , Kuritzkes Daniel , Lichtenstein Kenneth , Eckel Robert
Published: April 2022

Objective

Despite evidence for the role of adipocyte-derived hormones in insulin resistance, little is known about their levels in human lipodystrophic states. We examined the relationships of plasma leptin and adiponectin levels to fat distribution and insulin sensitivity in the HIV lipodystrophy syndrome.

Design

Cross-sectional study

Setting

HIV primary care practices

Patients

HIV-infected men with (n=13) and without (12) lipodystrophy and healthy uninfected controls (12). Main outcome measures: Plasma adiponectin and leptin levels were measured in the fasting state. Body composition was assessed by physical examination, dual-energy x-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test.

Results

Leptin levels were significantly higher in HIV-infected men with lipodystrophy as compared to HIV-infected controls (5.2 vs 3.0 ng/ml, P=0.01). Across the entire study population, leptin levels were positively correlated with measures of general adiposity. In the HIV-infected patients, leptin levels were negatively correlated with SI after adjustment for fat mass (r=-0.38, P=0.07). Adiponectin levels were significantly lower in HIV-infected men with lipodystrophy as compared to both HIV-infected and healthy controls (1.6 vs 3.4 μg/ml, P<0.05 and 1.6 vs 6.7 μg/ml, P<0.001, respectively). Adiponectin levels, after adjustment for fat mass, were correlated with measures of fat distribution. Finally, in the HIV-infected patients, adiponectin levels were significantly and positively correlated with SI after adjustment for fat mass (r=0.75, P≤0.001), and adiponectin level was also an independent determinant of SI.

Conclusions

Plasma leptin and adiponectin levels are altered in the HIV lipodystrophy syndrome. Adiponectin deficiency may play a role in the insulin resistance associated with HIV lipodystrophy.
Normal Erythropoietin Response in Chronic Hepatitis C Patients with Ribavirin-Induced Anaemia
Authors: Mangoni Emanuele Durante , Marrone Aldo , Saviano Donatella , Vecchio Carmen Del , Utili Riccardo , Ruggiero Giuseppe
Published: April 2022

Background

Ribavirin administration for chronic hepatitis C is associated with the development of haemolytic anaemia, which affects treatment efficacy and tolerability. In a pilot study, the exogenous administration of erythropoietin has been shown to be beneficial, reducing the rate of ribavirin dose reduction. How ribavirin administration affects normal erythropoietin production has not been determined.

Aim

To investigate the endogenous erythropoietin response in hepatitis C patients with ribavirin-induced anaemia.

Methods

Serum erythropoietin was measured before and during interferon–ribavirin treatment in 18 HCV-positive subjects. Mathematical analysis and modelling were applied to compare the degree of erythropoietin increase in HCV-positive and in otherwise healthy anaemic patients, and estimate the endogenous excess erythropoietin production in response to ribavirin-induced anaemia.

Results

Erythropoietin concentration increased significantly in response to anaemia caused by ribavirin. The physiological erythropoietin response to the ribavirin-induced anaemia was as adequate in HCV-positive subjects as it is in anaemic subjects without liver disease. The recommended exogenous erythropoietin dose appears three-times greater than the endogenous erythropoietin boost.

Conclusion

Chronic liver damage by HCV does not affect the physiological erythropoietin response to ribavirin-induced anaemia. While the rationale for erythropoietin treatment of ribavirin-induced anaemia is not straightforward, the currently recommended dosing regimen should be reassessed.
Shifts in Cell-Associated HIV-1 Rna but Not in Episomal HIV-1 Dna Correlate with New Cycles of HIV-1 Infection in vivo
Authors: Fischer Marek , Trkola Alexandra , Joos Beda , Hafner Roland , Joller Helen , Muesing Mark A , Kaufman David R , Berli Esther , Hirschel Bernard , Weber Rainer , Günthard Huldrych F ,   The Swiss HIV-1 Cohort Study
Published: April 2022

The significance of distinct classes of HIV-1 nucleic acids as correlates of recent HIV-1 replication was assessed in peripheral blood mononuclear cells (PBMC) obtained from 14 patients during 2 weeks of structured interruption of antiretroviral therapy (STI) and 2 weeks of resuming therapy. Levels of HIV RNA in plasma (HIV-RNAplasma) and of unspliced cell-associated HIV-1 RNA (HIV-UsRNAPBMC) were significantly increased as a result of STI, whereas no significant shifts in the levels of 2-LTR episomal HIV-1 DNA (2-LTR circles) and total late HIV-1 reverse transcripts (late-DNA) were observed. Thus, limited viral replication had occurred, which had no effect on the pool size of infected cells in the periphery. Levels of 2-LTR circles did not reflect rapid changes in HIV-1 replication. In contrast, expression of HIV-UsRNAPBMC increased during STI and consequently provides a more sensitive, albeit not absolute cellular marker of ongoing HIV-1 replication.
Changes in Viral Load in People with Virological Failure who Remain on the Same Haart Regimen
Authors: Cozzi-Lepri Alessandro , Phillips Andrew N , Miller Veronica , Katlama Christine , Ledergerber Bruno , Vella Stefano , Weber Jonathan , Bruun Johan N , Kirk Ole , Clotet Bonaventura , Lundgren Jens D
Published: April 2022

Objectives

To assess the rate of change in viral load and CD4 count over time in HIV-infected patients experiencing virological failure on a HAART regimen.

Design

Study population included patients from EuroSIDA, a large, multicentre, observational study enrolling HIV-infected patients across Europe.

Methods

Median change in viral load and CD4 count per month were estimated using the viral load and CD4 measurements obtained over a 12-month period after confirmed virological failure between 3 and 4 log10 copies/ml in a population of 488 HIV-infected patients who were left on a failing HAART regimen.

Results

The estimated median viral load change in our study population was 0.024 log10 copies/ml per month, statistically different from 0 (P=0.0001). In 20.9% of the patients studied viral load showed a tendency to decrease, in 47.8% showed a tendency to increase by a positive rate no higher than 0.04 log10 copies/ml per month and in the remaining 31.3% showed a tendency to increase by a rate greater than 0.04 log10 copies/ml per month. On average, CD4 counts were estimated to remain stable (decrease at a slow rate of about –0.53 cells/μl per month).

Conclusions

In patients that remained on a stable, but virologically failing HAART regimen (with viral load ranging 1000–10000 copies/ml), the viral load over the ensuing 12-month period increased at a relatively slow rate. In contrast, the CD4 count remained stable, possibly because of partial but sustained viral suppression below the viral load natural set-point. The time-course of selecting more replication-competent virus in patients with virological failure remains to be fully clarified.
K65R with and without S68: A New Resistance Profile in Vivo Detected in Most Patients Failing Abacavir, Didanosine and Stavudine
Authors: Røge Birgit T , Katzenstein Terese L , Obel Niels , Nielsen Henrik , Kirk Ole , Pedersen Court , Mathiesen Lars , Lundgren Jens , Gerstoft Jan
Published: April 2022

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated.

We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene™ HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay.

Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950).

At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range.

All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M.

Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.
Safety and Efficacy of Nebulized Zanamivir in Hospitalized Patients with Serious Influenza
Authors:   NIAID Collaborative Antiviral Study Group, Ison Michael G , Gnann John W , Nagy-Agren Stephanie , Treanor John , Paya Carlos , Steigbigel Roy , Elliott Michael , Weiss Heidi L , Hayden Frederick G
Published: April 2022

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrolment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.
Intracellular Indinavir Pharmacokinetics in HIV-Infected Patients: Comparison with Plasma Pharmacokinetics
Authors: Hennessy Martina , Clarke Susan , Spiers J Paul , Mulcahy Fiona , Kelleher Dermot , Meadon Emma , Maher Bridget , Bergin Colm , Khoo Saye , Tjia John , Hoggard Patrick , Back David , Barry Michael
Published: April 2022

Objective

To determine intracellular concentrations of indinavir (IDV) and investigate the relationship between plasma and intracellular IDV pharmacokinetics in HIV-infected patients.

Methods

A pharmacokinetic study of 10 patients receiving IDV plus dual nucleoside analogue therapy. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and cell counts estimated. IDV was extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular IDV samples were assayed by high performance liquid chromatography linked to mass spectrometry. Data were subjected to non-compartmental pharmacokinetic analysis.

Results

The mean intracellular IDV area under the curve over 8 h (AUC0-8) was lower than the plasma AUC0-8 (7574 ±1003 vs 25060 ±4171 ng/ml/h; P<0.004). However, both the elimination half-life (t1/2) and the mean residence time (MRT) of IDV intracellularly were prolonged compared with plasma (t1/2: 2.0 ±0.3 vs 1.2 ±0.09 h; MRT: 3.6 ±0.6 vs 2.1 ±0.1 h; P<0.05). All patients were responsive to therapy at the time of the study, as assessed by HIV plasma RNA levels. Individual plasma versus intracellular time course results suggest that, due to the prolonged intracellular half-life, some patients may achieve acceptable intracellular IDV concentrations despite sub-therapeutic plasma levels. Similarly, potentially inadequate intracellular concentrations may occur despite therapeutic plasma concentrations.

Conclusions

There is no significant intracellular accumulation of IDV within the lymphocytes of HIV-1-infected patients relative to plasma. However, intracellular concentrations are compatible with reported IDV-free drug concentrations in plasma. The intracellular elimination half-life and mean residence time of IDV are significantly prolonged compared with plasma. This may in part explain why certain patients maintain adequate viral suppression despite sub-therapeutic plasma IDV levels.
Pharmacokinetics of Nelfinavir in Children: Influencing Factors and dose Implications
Authors: Bergshoeff Alina S , Fraaij Pieter LA , van Rossum Annemarie MC , Wolfs Tom FW , Geelen Sibyl PM , de Groot Ronald , Burger David M
Published: April 2022

Objectives

The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels.

Methods

HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0–8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0–8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (Cl*F/kg) were calculated.

Results

Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l*h, which has previously been associated with an increased virological failure rate in children. With children aged <2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8<12.5 mg/l*h [odds ratio (OR) (95% CI): 2.44 (0.41–14.7) and 8.7 (0.79–95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r=0.89, P<0.001). C8 >0.69 mg/l predicted an AUC0-8 >12.5 mg/l*h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight.

Conclusion

Nelfinavir PK show high interindividual variability in children. Children <2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.
Increase of HIV-1 Pro-Viral Dna per Million Peripheral Blood Mononuclear Cells in Patients with Advanced HIV Disease (Cd4<200 Cells/Mm3) Receiving Interleukin 2 Combined with Haart Versus Haart Alone (Anrs-082 Trial)
Authors: Delaugerre Constance , Gourlain Karine , Tubiana Roland , Carcelain Guislaine , Marcelin Anne-Geneviève , Chouquet Cécile , Mouroux Mireille , Duvivier Claudine , Autran Brigitte , Costagliola Dominique , Katlama Christine , Calvez Vincent
Published: April 2022

Objective

To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro-viral DNA quantification in HIV-1-infected patients with CD4<200/mm3.

Patients and methods

Seventy patients with CD4<200 cells/mm3 and CV<1000 copies/ml were enrolled in a 6-month randomized controlled study to evaluate the subcutaneous injection of IL-2 in addition to HAART versus HAART alone. Then, in a non-comparative phase from week 28 to week 80, IL-2 was proposed to patients from both groups. The HIV-1 pro-viral DNA was quantified at baseline, week 24 and week 50 by a real-time polymerase chain reaction (PCR) assay in peripheral blood mononuclear cells (PBMC). Analysis of resistance mutations was performed at baseline and after 6-months of IL-2.

Results

HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10, P=0.009) compared to a slight decrease in patients treated with HAART alone (–0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia.

Conclusion

Administration of IL-2 combined with HAART in HIV-1 infected-patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance.
A Controlled Phase Ii Trial Assessing Three Doses of Enfuvirtide (T-20) in Combination with Abacavir, Amprenavir, Ritonavir and Efavirenz in Non-Nucleoside Reverse Transcriptase Inhibitor-Naive HIV-Infected Adults
Authors: Lalezari Jacob P , DeJesus Edwin , Northfelt Donald W , Richmond Gary , Wolfe Peter , Haubrich Richard , Henry David , Powderly William , Becker Stephen , Thompson Melanie , Valentine Fred , Wright David , Carlson Margrit , Riddler Sharon , Haas Frances F , DeMasi Ralph , Sista Prakash R , Salgo Miklos , Delehanty John
Published: April 2022

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacoki-netics of enfuvirtide, administered by subcutaneous (SC) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks.

Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs.

Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was –2.24 log10 copies/ml for the combined enfuvirtide groups compared with –1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA ≤400 copies/ml versus 36.8% of patients in the control group.

These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.
Increased Mitochondrial Dna Content in Peripheral Blood Lymphocytes from HIV-Infected Patients with Lipodystrophy
Authors: Cossarizza Andrea , Riva Agostino , Pinti Marcello , Ammannato Silvia , Fedeli Paolo , Mussini Cristina , Esposito Roberto , Galli Massimo
Published: April 2022

We have evaluated mitochondrial (mt) DNA content in CD4 and CD8 peripheral blood lymphocytes (PBLs) from HIV-infected patients taking highly active antiretroviral therapy (HAART) who display different types of adipose tissue alterations. A cross-sectional study was performed in a total of 23 patients with lipodystrophy (LD): nine patients with fat accumulation, six patients with fat loss, eight patients with combined form, who were compared to 11 individuals infected by HIV without LD (HIV-positive) and 10 seronegative controls (CTRL). PBLs were obtained by standard methods, that is, gradient density centrifugation on Ficoll, and CD4 or CD8 cells were positively isolated by magnetic sorting to eliminate the contamination of platelets. mtDNA content was then measured by an original assay based upon real-time PCR. mtDNA content was significantly increased in CD4 T cells from patients with LD, while no differences were present between CD4 and CD8 cells from HIV-positive and CTRL individuals. Nor were any differences found when comparing LD or HIV-positive patients treated with stavudine or zidovudine, or taking D-drugs or non D-drugs. Patients with fat accumulation had significantly higher mtDNA content compared to HIV-positive and CTRL, this phenomenon regarding both CD4 and CD8 PBLs. Considering all HIV-positive patients (including LD), mtDNA content showed a significant, positive correlation with cholesterolaemia but not with triglyceridaemia and glycaemia. Relatively high mtDNA content in LD patients, as well as the correlation between mtDNA content and cholesterol in all HIV-positive subjects, suggest the involvement of mitochondria in such a pathology. However, further studies are needed to confirm these initial observations and ascertain whether the quantification of mtDNA in PBL is a useful and reliable marker to investigate and monitor HAART-related changes in fat distribution.
Mitochondrial Proliferation, Dna Depletion and Adipocyte Differentiation in Subcutaneous Adipose Tissue of HIV-Positive Haart Recipients
Authors: Pace Craig S , Martin Annalise M , Hammond Emma L , Mamotte Cyril D , Nolan David A , Mallal Simon A
Published: April 2022

Objectives

To examine the in vivo effects of highly active antiretroviral therapy (HAART) regimens on adipose tissue mitochondrial DNA (mtDNA) depletion, mitochondrial organellar proliferation, and markers of adipocyte differentiation and phenotype.

Design and methods

DNA and mRNA quantification using real-time PCR methods was performed on adipose tissue samples from 31 HIV-infected individuals, of whom 11 were treatment-naive and 20 were receiving HAART. mtDNA depletion was measured as mtDNA copies/cell, and mitochondrial proliferation by quantification of mitochondrial protein mass. Regulation of mitochondrial biogenesis was assessed by NRF-1 and mtTFA mRNA. PPAR γ, UCP2 and UCP1 mRNA expression was used to assess adipocyte differentiation and phenotype.

Results

Stavudine-based HAART recipients ( n=10) displayed significant mtDNA depletion (12.8% of control, P<0.001), mildly increased mitochondrial protein mass (2.6-fold of control, P=0.032) and decreased expression of PPARγ (53.9% of control, P=0.021), UCP2 (62.2% of control, P=0.024) and UCP3 (51.8% of control, P=0.047) mRNA compared with controls. Zidovudine-based HAART recipients ( n=7) also displayed significant mtDNA depletion (34.45% of control, P=0.031), increased mitochondrial protein mass (5.7-fold of control, P=0.009), and markedly increased UCP1 (18-fold of control, P=0.009) mRNA. Elevated UCP1 mRNA expression was found to be associated with non-stavudine (zidovudine or abacavir), protease inhibitor (PI)-containing HAART (95-fold of non-stavudine, non-PI-containing HAART, P=0.006).

Conclusion

Differential effects of stavudine and zidovudine therapy on mtDNA depletion and expression of adipocyte differentiation markers PPARγ and UCP2 were observed, consistent with increased adipose tissue toxicity associated with stavudine therapy. Increased UCP1 mRNA, a marker of brown adipose tissue phenotype, was associated with non-stavudine, PI-containing HAART, and may represent an adaptive response to the increased fatty acid flux associated with PI therapy, and may contribute to the increased resting energy expenditure reported in such patients.
Once-A-Day Therapy for HIV Infection: A Controlled, Randomized Study in Antiretroviral-Naive HIV-1-Infected Patients
Authors: Maggiolo Franco , Ripamonti Diego , Gregis Gianpietro , Quinzan Gianpaolo , Callegaro Annapaola , Arici Claudio , Ravasio Laura , Suter Fredy
Published: April 2022

Background

Complex antiretroviral regimens require optimal adherence to maintain long-lasting effectiveness. Simpler regimens, possibly with easy schedule and low pill burden, are needed for the long-term treatment of HIV infection.

Objective

To assess the efficacy and tolerability of a once-a-day highly active antiretroviral therapy (HAART) compared with two other conventional twice-a-day regimens.

Methods

In a prospective and randomized study, anti-retroviral-naive patients received either EFV+ddI+3TC (once-a-day regimen; OD), or EFV+Combivir® (twice-a-day and low-pill burden regimen; BID-low) or NFV+Combivir (twice-a-day and high-pill burden regimen; BID-high). Primary outcome was the proportion of patients with viral load <50 copies/ml at week 52 of follow-up. Results were evaluated according to intention-to-treat and on-treatment analysis.

Results

Thirty-four patients in each arm were enrolled. Baseline characteristics were similar in the three groups. The proportion of patients with viral load <50 copies/ml at week 52 were 74.4, 74.4 and 50.0% for OD group, BID-low group and BID-high group, respectively ( P=0.02, ITT analysis). According to on-treatment analysis, the same figures were 88.9, 85.7 and 60% ( P<0.02). Overall, 26 (25.5%) patients discontinued treatment for different reasons and immune recovery was similar in all study arms.

Conclusions

Once-a-day HAART with ddI+3TC+EFV is a safe and effective alternative to twice-a-day regimens. Once-a-day therapy, with its simple daily schedule, may be proposed as one of the first choice treatments in HIV infection.
High Incidence of Non-B and Recombinant HIV-1 Strains in Newly Diagnosed Patients in Galicia, Spain: Study of Genotypic Resistance
Authors: Pérez-Alvarez Lucía , Carmona Rocío , Muñoz Mercedes , Delgado Elena , Thomson Michael M , Contreras Gerardo , Pedreira José D , Real Rafael Rodríguez , de Parga Elena Vázquez , Medrano Leandro , Taboada José Antonio , Nájera Rafael ,   the Spanish Group for Antiretroviral Resistance Studies in Galicia, Agulla A , Mariño A , López-Calvo S , Pedreira JD , Aguilera A , Losada E , Prieto A , Corredoira J , López- Alvarez MJ , Rodríguez A , Bustillo M , García-Costa J , Fernández-Rodríguez R , Rodríguez R , Miralles C , Ocampo A , Rodríguez-Real R , Díz-Aren J , de Castro R Ojea , Morano LE , Pérez-Rodríguez R , Rodríguez A , Torres J
Published: April 2022

The objectives of this study are to describe the incidence of non-B and recombinant HIV-1 strains in newly diagnosed HIV-1 infections in Galicia, northwest of Spain, during a 2-year period (May 2000 to June 2002), and the frequency of resistance-associated mutations in reverse transcriptase (RT) and protease (PR) genes, analysing the polymorphisms more frequently detected in non-B and recombinant viruses. All newly diagnosed HIV-1-infected patients attending the nine public hospitals of the seven main cities of Galicia were included in this study. RT, PR and V3 regions from HIV-1 RNA plasma were amplified and sequenced, being the corrected sequences sent to the Stanford HIV RT and Protease Sequence Database. Nineteen of 85 patients (22.3%) were infected by non-B or recombinant viruses: three subtype C, two G, one F1, one Dpol/A1V3, five CRF02_AG, one CRF14_BG, five BGpol/BV3 and one UKpol/UV3 (U, unknown fragment). Eleven of these 19 patients (57.9%) were foreign individuals living in Galicia infected through heterosexual contact, and the other eight (42.1%) were Spanish intravenous drug users who had shared injection equipment. Five of 85 patients (5.9%), all infected with B subtype viruses, showed resistance-associated mutations in RT (M184V, M41L, L210W, T215Y/D and K219Q). In one patient (1.2%) infected with a subtype G strain, resistance-associated mutations in PR (K20I+M36I+M46I+V82I) were detected. In subtype B viruses resistance mutations in PR were not detected. Several polymorphisms in RT: D123S, Q174K, D177E, T200A, V245Q, and PR: I13V, K20I, M36I, R41K, H69K, L89M were detected more frequently in non-B and recombinants than in B strains ( P<0.01 to P<0.001). This study reports a high incidence (22.3%) of newly diagnosed patients infected by different non-B and recombinant HIV-1 strains, in a geographical area of Spain, showing also a high frequency of polymorphisms in RT and PR genes.