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Objectives: Blood level of pancreatic stone protein (PSP) is a promising biomarker of sepsis both in adults and children. The aim of our study was to investigate the diagnostic accuracy of PSP in children with suspected sepsis and to compare diagnostic performance with other sepsis biomarkers approved for clinical use, that is, procalcitonin (PCT) and C-reactive protein (CRP)., Design: Prospective study., Setting: PICU and pediatric emergency department., Intervention: Blood levels of PSP were measured using a nanofluidic point-of-care immunoassay (abioSCOPE, Abionic SA, Switzerland) within 24 hours of admission., Measurements and Main Results: We studied 99 children aged between older than 1 month and younger than 18 years with signs and symptoms of systemic inflammatory response syndrome (irrespective of associated organ dysfunction). The prevalence of sepsis was 35 of 99 (35.4%). Patients with sepsis had higher PSP levels ( p < 0.001) than patients with systemic inflammation of noninfectious cause. In this analysis, the optimal cutoff for the diagnosis of sepsis using PSP was 123 ng/mL, which resulted in a sensitivity of 0.63 (95% CI, 0.43-0.80), specificity of 0.89 (95% CI, 0.77-0.95). The PSP test area under the receiver operating characteristic curve (AUROC) was 0.82 (95% CI, 0.73-0.91) and, by comparison, procalcitonin and CRP AUROC were 0.70 (95% CI, 0.58-0.82) and 0.72 (95% CI, 0.60-0.84), respectively. Overall, the pretest to posttest probability of sepsis with a positive test changed from 0.35 to 0.73., Conclusions: In this single-center prospective pediatric cohort, admitted to the high intensive care and to the PICU, our findings suggested the potential use of PSP as a sepsis biomarker. However, because of the clinical diagnostic uncertainty with a positive result, further investigation is needed particularly in combination with other biomarkers., Competing Interests: Dr. Cecchetti received support for article research from the National Institutes of Health; he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

This study aimed to compare viral suppression (VS) between children, adolescents, and adults in the frame of transition to dolutegravir (DTG)-based antiretroviral therapy (ART) in the Cameroonian context. A comparative cross-sectional study was conducted from January 2021 through May 2022 amongst ART-experienced patients received at the Chantal BIYA International Reference Centre in Yaounde-Cameroon, for viral load (VL) monitoring. VS was defined as VL < 1000 copies/mL and viral undetectability as VL < 50 copies/mL. Chi-square and multivariate binary logistic regression models were used to identify factors associated with VS. Data were analyzed using SPSS v.20.0 (SPSS Inc., Chicago, Illinois), with P < .05 considered significant. A total of 9034 patients (72.2% females) were enrolled. In all, there were 8585 (95.0%) adults, 227 (2.5%) adolescents, and 222 (2.5%) children; 1627 (18.0%) were on non-nucleoside reverse transcriptase-based, 290 (3.2%) on PI-based, and 7117 (78.8%) on DTG-based ART. Of those on DTG-based ART, only 82 (1.2%) were children, 138 (1.9%) adolescents, and 6897 (96.9%) adults. Median (interquartile range) duration on ART was 24 (12-72) months (24 months on Tenofovir + Lamivudine + Dolutegravir [TLD], 36 months on other first lines, and 84 months on protease inhibitors boosted with ritonavir-based regimens). Overall, VS was 89.8% (95% confidence interval: 89.2-90.5) and viral undetectability was 75.7% (95% confidence interval: 74.8-76.7). Based on ART regimen, VS on Non-nucleoside reverse transcriptase-based, protease inhibitors boosted with ritonavir-based, and DTG-based therapy was respectively 86.4%, 59.7%, and 91.8%, P < .0001. Based on ART duration, VS was respectively 51.7% (≤24 months) versus 48.3% (≥25 months), P < .0001. By gender, VS was 90.9% (5929) in females versus 87.0% (2183) in males, P < .0001; by age-range, VS moved from 64.8% (144) in children, 74.4% (169) adolescents, to 90.8% (7799) adults, P < .0001. Following multivariate analysis, VS was associated with adulthood, female gender, TLD regimens, and combination antiretroviral therapy duration > 24 months (P < .05). In Cameroon, ART response indicates encouraging rates of VS (about 9/10) and viral undetectability (about 3/4), driven essentially by access to TLD based regimens. However, ART response was very poor in children, underscoring the need for scaling-up pediatric DTG-based regimens., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc., Design and Methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination., Results: Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35)., Conclusion: CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Zero risk of linked HIV transmission in serodiscordant couples when the HIV-infected partner had viral load less than 200 copies/ml ('U status') was found in observational studies. We aimed at estimating the proportion of time in which 'U status' was maintained and identifying factors associated with the risk of losing it., Design: Observational cohort study., Methods: We included participants in the ICONA cohort who had reached an established 'U status' (viral load ≤200 copies/ml for >6 months) as of December 2010. The outcome was the number of person-days of follow-up (PDFU) above a viral load greater than 200 copies/ml, relative to the total number of PDFU observed. A logistic regression model was used to identify factors independently associated with the risk of losing 'U status'., Results: Eight thousand, two hundred and forty-one persons living with HIV were included in the analysis who contributed 2 670 888 PDFU. Of these, 1648 (20%) were women, 768 (9%) were people who inject drugs (PWID), and 2066 (25%) were foreign-born. The median of viral load measurements was 9 (IQR: 4-15). Overall, only 3.1% of PDFU were observed when viral load was above 200 copies/ml. The proportion of PDFU with viral load more than 200 copies/ml was higher than average in women (5.3%), unemployed (5.4%), PWID (4.7%), and in people with more than three previous virologic failures (6.3%). These variables were significant predictors of losing 'U status' in the multivariable logistic regression., Conclusion: Our results reinforce the validity of the U=U message in real-world setting. However, we identified subsets of our study population at higher risk of losing the 'U status' for whom additional efforts are needed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

With limited and low-genetic barrier drugs used for the prevention of mother-to-child transmission (PMTCT) of HIV in sub-Saharan Africa, vertically transmitted HIV-1 drug-resistance (HIVDR) is concerning and might prompt optimal pediatric strategies.The aim of this study was to ascertain HIVDR and viral-tropism in majority and minority populations among Cameroonian vertically infected children.A comparative analysis among 18 HIV-infected children (7 from PMTCT-exposed mothers and 11 from mothers without PMTCT-exposure) was performed. HIVDR and HIV-1 co-receptor usage was evaluated by analyzing sequences obtained by both Sanger sequencing and ultra-deep 454-pyrosequencing (UDPS), set at 1% threshold.Overall, median (interquartile range) age, viremia, and CD4 count were 6 (4-10) years, 5.5 (4.9-6.0) log10 copies/mL, and 526 (282-645) cells/mm, respectively. All children had wild-type viruses through both Sanger sequencing and UDPS, except for 1 PMTCT-exposed infant harboring minority K103N (8.31%), born to a mother exposed to AZT+3TC+NVP. X4-tropic viruses were found in 5 of 15 (33.3%) children (including 2 cases detected only by UDPS). Rate of X4-tropic viruses was 0% (0/6) below 5 years (also as minority species), and became relatively high above 5 years (55.6% [5/9], P = .040. X4-tropic viruses were higher with CD4 ≤15% (4/9 [44.4%]) versus CD4 >15% (1/6 [16.7%], P = .580); similarly for CD4 ≤200 (3/4 [75%]) versus CD4 >200 (2/11 [18.2%] cells/mm, P = .077.NGS has the ability of excluding NRTI- and NNRTI-mutations as minority species in all but 1 children, thus supporting the safe use of these drug-classes in those without such mutations, henceforth sparing ritonavir-boosted protease inhibitors or integrase inhibitors for the few remaining cases. In children under five years, X4-tropic variants would be rare, suggesting vertical-transmission with CCR5-tropic viruses and possible maraviroc usage at younger ages.

Objective: The impact of HIV-1 tropism on the emergence of non-AIDS events was evaluated in a cohort of 116 antiretroviral therapy (ART) responder patients., Methods: The patients were followed for the emergence of hypertension, renal impairment, metabolic and bone disorders (defined as non-AIDS events) each 8 weeks at standard visits. A V3 plasma sequence genotype analysis was performed at the time of ART initiation and the geno2pheno algorithm with the results that defines the false-positive rate (FPR) was used to infer HIV tropism. The associations between the non-AIDS events and the FPR at baseline were evaluated using the χ test for trend. A Cox-regression analysis using the counting process formulation of Andersen and Gill was performed to define whether the emergence of non-AIDS events was correlated to FPR., Results: The prevalence of at least one non-AIDS event resulted higher in patients with a FPR below 10% than in patients with a R5 virus (P = 0.033). Patients with a FPR below 5.0% most frequently developed non-AIDS events during ART (P = 0.01). A higher prevalence of patients with at least two AIDS events was found in the group of patients with a FPR below 5.0% with respect to the others (P < 0.001). At multivariate Cox-regression analysis, having an X4 virus and age were independently associated with a higher probability of non-AIDS event development., Conclusion: This study shows that an X4 virus, particularly a FPR less than 5%, is related to non-AIDS events development. Further studies are warranted to understand the mechanisms underlying this phenomenon.

Purpose of Review: This article examines the dynamics and factors underlying hepatitis C virus (HCV) resistance, along with their impact on daily clinical management of HCV-infected patients., Recent Findings: Across available treatment-regimens, GT-3 is the most difficult-to-cure genotype, but also genotype-1a may show lower success-rates compared with genotype-1b. Natural resistance to NS3, NS5A and NS5B inhibitors may contribute to treatment failures. The Q80K NS3-protease mutation affects sensibility to simeprevir + peg-interferon/ribavirin combinations. It reaches up to 48% prevalence in genotype-1a in some studies (but it is lower in other). Resistant variants (particularly in NS5A) developed at failure can persist, in a substantial proportion of patients, even 3 years after treatment-discontinuation, potentially affecting readministration of the same direct-acting antiviral agent (DAA)-class. This will become an issue for those patients failing all-oral regimens with multiple-resistant viruses., Summary: Recent data support the importance of an accurate genotype and genotype-1 subtype (1a/1b) assignment prior therapy. Resistance testing at baseline has no clear indication so far in clinical practice for all-DAA regimens selection, while it remains a valuable option at the retreatment of patients who failed DAA-containing regimens, provided that data are generated to inform treatment decisions based on the results of resistance testing. In this context, long-term RAVs persistence after failure should be taken into account.

Objective: To study the role of cervicovaginal infections in women with cytological reports of atypical squamous cells of undetermined significance (ASC-US)., Materials and Methods: The study included 220 women admitted to the Clinic of Microscopy, Cervicovaginal and Vulvar Pathology of the Department of Gynecology and Obstetrics of the Tor Vergata University Hospital, Rome, Italy, enrolled between October 2012 and July 2013., Results: Among the enrolled women, 105 women (47.7%) had ASC-US cytology, whereas 115 women (52.3%) had negative cytology. Microscopy showed infections more frequently in women with ASC-US than in those with negative cytology: 70.5% (74/105) vs 36% (41/115); p < .001. Cocci were present in 73.3% (77/105) of the women with ASC-US and in 43.5% (50/115) of those with negative cytology; p < .001. According to Ison score, 84% (88/105) of ASC-US was grade 0 vs 22% (25/115) of negative cytology, p < .001. Human papillomavirus was detected in 35% of the women with ASC-US. A statistically significant correlation between high pH and vaginal infections was found in women aged 20 to 29 (p = .003) and those 50 years or older in both cytological report groups; p < .001., Conclusions: Cervicovaginal infections are associated with a cytological report of ASC-US. Direct microscopy of vaginal specimens allowing immediate evaluation of the vaginal microflora and infectious agents may be a useful tool in managing women with cytological reports of ASC-US.

Background: Fixed-dose combination antiretroviral therapy administered as a single-tablet regimen (STR) may improve virologic suppression rates. The effect of STRs on development of resistance when virologic failure occurs on STRs is not known., Objectives: To compare the rate of emergent drug resistance mutations (DRMs) on first-line therapy with coformulated tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz (EFV) as an STR versus TDF, lamivudine (3TC) or FTC, and EFV given as non-STR., Methods: Patients from eight cohorts and four randomized clinical trials who received first-line antiretroviral therapy with Atripla (STR group) or with TDF + FTC/3TC + EFV (non-STR group) were eligible if a genotypic resistance test was available immediately after the first episode of viral failure. The DRM list from the 2013 version of IAS-USA was used., Results: One hundred and eighty-six patients were included in the final analysis, 122 (65.6%) from eight cohorts and 64 (34.1%) from four randomized clinical trials. The overall proportion of patients with at least one DRM at viral failure was 67.7%, including 53.4% (31 of 58) in the STR group vs. 74.2% (95 of 128) in the non-STR group (P = 0.005). Among patients exclusively from cohorts, at least one DRM was detected in 53.4% (31 of 58) in the STR group vs. 78.1% (50 of 64) in the non-STR group (P = 0.004). DRMs for individual drugs were: TDF, 15.5 vs. 16.4% (P = 0.87); 3TC/FTC, 31 vs. 35.2% (P = 0.58); and NNRTI, 51.7 vs. 65.6% (P = 0.07). The proportion of patients with an M184V/I among the 128 patients who received FTC was 32.8 vs. 36.2% among the 58 treated with 3TC (P = 0.65)., Conclusions: Compared to patients receiving the STR-Atripla, those receiving the same components individually in a non-STR regimen have a statistically significantly increased risk of selecting for DRMs associated with their drugs on failure.

Purpose of Review: Understanding the mechanisms that underlie resistance development to novel drugs is essential to a better clinical management of resistant viruses and to prevent further resistance development and spread., Recent Findings: Integrase inhibitors and CCR5 antagonists are the more recent antiretroviral classes developed. The HIV-1 integrase, responsible for the chromosomal integration of the newly synthesized double-stranded viral DNA into the host genomic DNA, represents a new and important target; and two integrase inhibitors (INIs), raltegravir and elvitegravir, have been shown promising results in clinical trials. Viral entry is also an attractive step for the development of new drugs against HIV variants resistant to current antiretroviral drugs, and two CCR5 antagonists have been designed to inhibit HIV-1 binding to R5 co-receptor and are under clinical investigation., Summary: Drug resistance to INIs occurs through the selection of mutations within HIV integrase. The kinetic of selection seems rapid and one mutation alone is able to confer resistance to integrase inhibitor, suggesting that this class of drug has a low genetic barrier. Two ways could explain the failure of the CCR5 antagonist class: a rapid outgrowth of pre-existing archived X4 virus or the selection of a resistance to CCR5 antagonists through amino acid changes in V3 loop.

Objective: Inadequate CD4 cell count recovery despite full HIV RNA control occurs in 30% of HAART-treated HIV-infected patients. A better understanding of the relationship between T-cell dynamics and the HIV intracellular reservoir in HIV-infected patients failing to recover CD4 cell count following long-term HAART, is required., Methods: In a cross-sectional study T-cell turnover and homeostatic parameters featuring discordant responses were investigated in 27 immunologic non-responders (INR; CD4 count, < or = 200 cells/microl; HIV RNA, < or = 50 copies/ml), 15 virological non-responders (VNR; CD4 count, > or = 350 cells/microl; HIV RNA, > or = 10 000) and 22 full responders (FR; CD4 count, > or = 500 cells/microl; HIV RNA, < or = 50 copies/ml)., Results: INR displayed significantly higher activated CD38CD8 than FR (P < 0.05) and was comparable to VNR (P > 0.05). As compared with VNR and FR, INR displayed the highest level of proliferating Ki67CD4 and apoptotic CD4 cells (P < 0.05). VNR presented lower proliferation and apoptosis than FR and INR. INR displayed the lowest levels of naive T cells (P < 0.05) and a predominant memory pattern. Despite the memory/activated/apoptotic phenotype, INR showed a statistically non-significant reduction in T-cell receptor excision circles (TREC) compared to FR (P > 0.05), and substantially heightened interleukin (IL)-7 (P < 0.05), while VNR showed higher naive T-cell counts and TREC. Moreover, the reservoir of infected CD4 cells was increased in INR, with a trend toward highest intracellular HIV DNA within total, naive and memory CD4 cells., Conclusions: The lack of CD4 cell count recovery in INR seems to reflect a highly activated apoptotic T-cell compartment, with elevated IL-7 and thymic impairment. High levels of intracellular HIV-DNA in INR could be strictly involved in the lack of T-cell reconstitution. Immune correlates of an ultimate direction of the response to HAART, could be exploited in clinical practice for the most effective management of discordant patients, to amend immune imbalances and to improve clinical outcome.

Objective: To verify whether a synthetic therapeutic killer decapeptide (KP), a functional mimotope of a yeast killer toxin with wide-spectrum microbicidal activity, inclusive of AIDS-related opportunistic micro-organisms, through interaction with beta-glucan receptors, which has been found to possess sequence homology with critical segments in gp160 V1/V2 and V3 loops, may also be inhibiting HIV-1 replication., Methods: Primary peripheral blood mononuclear cells (PBMCs) cultures established from HIV-1-infected patients were treated with KP in comparison with zidovudine and supernatants and cells were harvested for analysis of HIV RNA and proviral contents, respectively. Virus production in exogenous in-vitro PBMCs infection with lymphocytotropic and monocytotropic HIV-1 strains was also assessed in presence of KP by enzyme-linked immunosorbent assay HIV p24 gag antigen detection. The binding affinity of KP to CD4, CCR5 and CXCR4 was evaluated on CD4-CCR5 or CD4-CXCR4 transfected astroglioma cell lines., Results: KP was shown to be devoid of cytotoxicity on PBMCs and to inhibit HIV-1 replication in PBMCs of a patient in the acute phase of infection. The antiretroviral activity of KP, which proved to be more potent than zidovudine at micromolar concentrations, is abolished by beta 1,3-glucan but not by beta 1,6-glucan. Down-regulation of CCR5 co-receptor, and/or physical block of the gp120-receptor interaction are possible mechanisms of KP activity., Conclusion: KP appears to be the first antibody-derived short peptide displaying an inhibitory activity against HIV-1 and related opportunistic micro-organisms by different mechanisms of action.

Objective: To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure., Design: Observational, longitudinal cohort study., Methods: HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Cox's model., Results: Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12-29), Kaplan-Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Cox's model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76-16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death., Conclusions: Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.

Objective: To define the extent of amino acid protease (PR) conservation in vivo in the absence and presence of pharmacological pressure in a large patient cohort., Methods: Plasma-derived complete protein PR sequences from a well-defined cohort of 1096 HIV-1 infected individuals (457 drug-naive and 639 under antiretroviral therapy including PR-inhibitors) were obtained and analysed, and are discussed in a structural context., Results: In naive patients, the PR sequence showed conservation (< 1% variability) in 68 out of 99 (69%) residues. Five large conserved regions were observed, one (P1-P9) at the N-terminal site, another (E21-V32) comprised the catalytic active-site, a third (P44-V56) contained the flap, a fourth contained the region G78-N88, and another (G94-F99) contained the C-terminal site. In PR-inhibitor treated patients, the appearance of mutations primarily associated with drug resistance determined a decrease of amino acid invariance to 45 out of 99 residues (45% conservation). The overall degree of enzyme conservation, when compared to the PR sequences in drug-naive patients, was preserved at the N- and C-terminal regions, whereas the other large conserved areas decreased to smaller domains containing, respectively, the active-site residues D25-D29, the tip of the flap G49-G52, and the G78-P81 and G86-R87 turns., Conclusions: Amino acid conservation in HIV PR can be minimally present in 45 residues out of 99. Identification of these invariable residues, with crucial roles in dimer stability, protein flexibility and catalytic activity, and their mapping on the three-dimensional structure of the enzyme will help guide the design of novel resistance-evading drugs.

Objective: To investigate the impact of 215 HIV-1 revertants on the risk of virological failure of the first thymidine analog-containing highly active antiretroviral therapy (HAART)., Design: The study included 491 HIV-1 subjects of the Italian Cohort Naive for Antiretrovirals, 405 of whom received a genotypic assay before therapy and had a virological follow-up., Methods: Pre-treatment genotypic resistance was assessed by sequencing of the whole protease (PR) and reverse transcriptase (RT) region., Results: Three (3.2%) and 13 (3.3%) individuals with recent (n = 95) and chronic (n = 396) HIV-1 infection carried an HIV-1 strain with 215 revertants (215D/C/E/A/V), respectively. In contrast, nucleoside associated mutations were higher in the former (15.8%) compared with the latter group (6.8%) (P = 0.005). A multivariable regression model, considering pre-HAART viral load levels, use of saquinavir-hard gel as the only PI, use of zidovudine, number of other RT and PR mutations, indicated that patients carrying 215 revertants had an increased risk of virological failure compared with those not carrying such mutants (adjusted relative hazard = 2.97 95% confidence interval, 1.11-7.94, P = 0.03). Among patients with 215 revertants, who experienced virological failure, four out of seven showed the emergence of the 215Y resistant mutation. The probability of 215Y occurrence was different between patients carrying 215 revertants compared with those who did not carried these mutants (P = 0.006)., Conclusions: HIV-1 215 revertants with an increased ability for selecting 215Y mutation are associated with a higher risk of virological failure and may lead to the appearance of virus carrying 215Y/F mutation in vivo. These findings suggest that 215 revertant viruses may compromise the efficacy of the first thymidine analog-containing regimen.

Purpose of Review: Genotypic assays are widely used tools for determining HIV-1 drug resistance and for guiding treatment. Several systems have been developed to interpret the complex influence of amino acid substitutions in HIV reverse transcriptase or protease on the phenotypic susceptibility or clinical response to the 18 available antiretroviral agents. In this review we analyse both studies comparing interpretations by different systems and studies showing correlation of interpretations with clinical outcome, in order to identify discordance and how this may affect prediction of subsequent therapy outcomes., Recent Findings: During the last year, several studies analysing interpretation systems, individually or comparatively, have shown substantial variability of the predicted drug activities and therapeutic outcomes. Discrepant interpretation was detected mostly for nucleoside reverse transcriptase inhibitors and rarely for non-nucleoside reverse transcriptase inhibitors. Better correlation with treatment outcome was found with most recently updated systems, while a weaker prediction was found with systems interpreting activity of nucleoside reverse transcriptase inhibitors solely on the basis of phenotypic susceptibility. Virological, patient-related and treatment-related factors can all affect the results of systems' clinical validations. Refinement of resistance interpretation is possible by introducing rules derived from genotype-outcomes correlation or, at least for protease inhibitors, genotype-phenotype correlation., Summary: Papers showing clinical validation of the available interpretation systems are presented with a critical view to help the readers' evaluation of their possible use. There is a need for developing a consensus towards common interpretations. Large clinical and virological databases with quality data will be useful for future improvements.

A rebound in the plasma and seminal viral load was detected in 12 patients after the interruption of effective highly active antiretroviral therapy. The viral rebound was generally higher in plasma, although the highest level observed during interruption was higher in semen in two patients. The reintroduction of therapy was followed by an overall decrease in HIV-RNA in plasma and semen. One to 2 months after restarting treatment, four out of seven patients showed undetectable HIV-RNA in semen.

Objective: To determine the effectiveness of antiretroviral therapy in controlling cerebrospinal fluid (CSF) HIV-1 replication and to assess factors related to virological response in advanced patients., Design: A cross-sectional and longitudinal study., Methods: Consecutive paired CSF and plasma samples from HIV-1-infected patients were collected before starting or changing highly active antiretroviral therapy (HAART)., Results: In the cross-sectional analysis 75 patients were included, 55 (73%) with neurological disease, 28 (37%) naive for antiretroviral agents. A significant correlation between plasma and CSF levels at baseline was observed only in antiretroviral-experienced patients. The absence of neurological disease, lower plasma HIV-1 load and a previous exposure to indinavir were all associated with a baseline CSF HIV-1-RNA level less than 80 copies/ml at multivariate analysis. In 29 patients included in the longitudinal study a significant reduction in CSF HIV-1 RNA was observed. Plasma HIV-1-RNA change, CSF HIV-1-RNA level at baseline, overall months of antiretroviral treatment and the magnitude of difference between plasma and CSF HIV-1-RNA levels were all correlated to CSF HIV-1-RNA change during treatment. A significant difference in the magnitude of CSF HIV-1-RNA reduction was observed according to naive status and to the use of three or more drugs penetrating the blood-brain barrier., Conclusion: HAART effectively reduces HIV-1 replication in CSF. A variable response to antiretroviral therapy was observed in CSF, reflecting a different compartmentalization of infection during treatment. Naive status and the use of CNS-penetrating drugs substantially enhance antiviral response. A negative interaction between virological response and the duration of antiretroviral treatment suggests long-term selection of drug-resistant CSF HIV-1 strains.

Objective: To assess the prevalence of mutations in the reverse-transcriptase (RT) and protease (PR) region in a cohort of chronically-infected HIV-positive patients requiring highly active antiretroviral therapy (HAART)., Methods: The study included 347 patients enrolled in the Italian Cohort of Antiretroviral Naive patients (I.CO.NA) who had to initiate HAART. The whole PR-region, and amino acids 1-320 of RT-region were sequenced from plasma samples at baseline., Results: Median CD4-lymphocytes and HIV-RNA at baseline were 231 x 10(6) cells/l and 4.89 log(10) copies/ml; 307 of 347 (88.5%) patients carried no mutations in the RT region, whereas 40 (11.5%) carried one or more mutations associated with resistance to nucleoside-RT inhibitor (NRTI) (7.8%), or non-nucleoside-RTI (NNRTI) (4.9%), with four patients carrying mutations to both classes. Among mutations associated with high-level resistance to RTI, T215Y was found in only two patients, M184V in two cases, T69D and T215C in other two cases (one each), and K103N in only one patient, for a total of six patients (one carrying both T215Y and M184V) (1.7%). Seventy-six patients (21.9%) carried no mutations in the PR region, whereas 271 (78.1%) had one or more mutations. Primary mutations associated with substantial resistance to protease inhibitors were found in only five of 347 patients (1.4%) (M46V/L, I54V, V82A/I); all the other patients carried only secondary mutations (L10F/I/V, M36I, L63P, A71T/V, V77I)., Conclusions: Prevalence of mutations associated with high-level resistance to antiretroviral drugs is low in HIV-infected patients with long-term infection. This suggests no preclusion in principle to any antiretroviral drug at the time of decision of the first therapeutic regimen.

Background: Highly active antiretroviral therapy (HAART) can suppress viral replication and prolong patient life substantially. However, HAART can fail for a number of reasons, including incomplete adherence, pharmacokinetic factors and the emergence of resistance. Because the number of possible antiretroviral combinations is limited, the use of existing treatment options must be optimized. Whether the application of therapeutic drug monitoring (TDM) in routine clinical practice may help with this purpose remains a subject of debate. However, TDM has been introduced in some centres despite the lack of guidelines for optimal use of this test., Objective: In October 2000, a panel of experts met in Perugia, Italy, to discuss the key issues surrounding the introduction of TDM into routine clinical practice. The purpose of the meeting was to achieve a consensus among panel members on the following issues: (i) validity of data suggesting the utility of TDM in HAART; (ii) patient categories and clinical settings in which TDM may be of most benefit; (iii) target levels of antiretroviral agents; (iv) influence of covariables on target levels of drugs; (v) blood sampling and dosage adjustment strategies; and (vi) future research steps needed to elucidate issues regarding the applicability of TDM in clinical practice., Outcome: This report, which has been updated to include data published or presented at conferences up to the end of August 2001, summarizes the data presented and issues discussed at the meeting. This article will guide the reader through the data and discussions that have allowed the panel to formulate a series of position statements regarding the current status and future applications of TDM in antiretroviral therapy. These statements have been formulated to provide suggestions for the design of future TDM clinical trials, as well as to provide useful points of reflection for centres in which TDM is already in use.

Epirubicin (Epi-DX), a new analog of doxorubicin, was administered I.V. once q 3 weeks at the dose of 90 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-two percent of patients with favorable histology and 67% with unfavorable histology achieved complete or partial remissions, with an overall response rate of 75%. Gastrointestinal and hematologic toxicity was generally mild to moderate. Reversible ST-T changes were observed only in two patients. Epi-DX has high activity in patients with NHL, and further studies in combination with other agents are recommended.

The possibility of improving treatment results using an alternating combination chemotherapy was explored in 40 evaluable patients with advanced soft tissue sarcomas. Treatment regimen consisted of adriamycin and DTIC alternating with vincristine, actinomycin D, and cyclophosphamide. Four patients achieved a complete response and eight achieved a partial response, with an overall response rate of 30%. The median duration of response was 14 months. The median survival time was 28 months for responders compared with 7 months for nonresponders (p = 0.001). Toxicity was predominantly limited to nausea, vomiting, and myelosuppression. Although this alternating regimen failed to improve response rates over other combinations, survival times observed in the present study should provide impetus to evaluate further the concept of sequential noncross-resistant combinations.