Multiclass Drug Resistance Research Articles

Clinical Perspective on Human Immunodeficiency Virus Care of Ukrainian War Refugees in Poland.

The Russian invasion of Ukraine forced migration for safety, protection, and assistance. Poland is the primary sheltering country for Ukrainian refugees, providing support including medical care, which resulted in the rapid ∼15% increase in the number of followed-up people with human immunodeficiency virus (HIV) (PWH) in the country. Here, we present the national experience on HIV care provided for refugees from Ukraine. Clinical, antiretroviral, immunological, and virologic data from 955 Ukrainian PWH entering care in Poland since February 2022 were analyzed. The dataset included both antiretroviral-treated (n = 851) and newly diagnosed (n = 104) patients. In 76 cases, protease/reverse transcriptase/integrase sequencing was performed to identify drug resistance and subtype. Most (70.05%) of the patients were female, with a predominance of heterosexual (70.3%) transmissions. Anti-hepatitis C antibody and hepatitis B antigen were present in 28.7% and 2.9% of the patients, respectively. A history of tuberculosis was reported in 10.1% of cases. Among previously treated patients, the viral suppression rate was 89.6%; 77.3% of newly HIV diagnosed cases were diagnosed late (with lymphocyte CD4 count <350 cells/μL or AIDS). The A6 variant was observed in 89.0% of sequences. Transmitted mutations in the reverse transcriptase were found in 15.4% treatment-naive cases. Two patients with treatment failure exhibited multiclass drug resistance. Migration from Ukraine influences the characteristics of HIV epidemics in Europe, with an increase in the proportion of women and hepatitis C coinfected patients. Antiretroviral treatment efficacy among previously treated refugees was high, with new HIV cases frequently diagnosed late. The A6 subtype was the most common variant.

Prevalence and factors associated with HIV-1 multi-drug resistance over the past two decades in the Italian ARCA database

Despite successful antiretroviral therapy (ART), patients infected with human immunodeficiency virus (HIV) can develop multi-class drug resistance (MDR). This retrospective study aimed to explore the prevalence of HIV-1 drug resistance over the past two decades by focusing on HIV-MDR and its predictors. ART-experienced patients with HIV with results from at least one plasma genotypic resistance test (GRT) from 1998 to 2018, from the Antiviral Response Cohort Analysis database, were included in this study. The temporal trend of resistance to any drug class was evaluated by considering all GRTs. Prevalence and predictors of HIV-MDR were analysed by consideration of cumulative GRTs. Among 15 628 isolates from 6802 patients, resistance to at least one drug class decreased sharply from 1998 to 2010 (1998–2001: 78%; 2008–2010: 59%; P<0.001) and then remained relatively constant at approximately 50% from 2011 to 2018, with the proportion of isolates with HIV-MDR also stable (approximately 9%).By evaluating factors associated with cumulative HIV-MDR, the following factors were found to be associated with increased risk of HIV-MDR on multi-variate analysis: male gender; sexual and vertical transmission; number of previous protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-NRTIs; previous exposure to integrase strand transfer inhibitors, enfuvirtide and maraviroc; and co-infection with hepatitis B virus. In contrast, a nadir CD4 cell count ≥200 cells/mm3, starting first-line ART in 2008 or later and co-infection with hepatitis C virus were associated with lower risk of HIV-MDR. In conclusion, this study revealed that HIV-1 drug resistance has been stable since 2011 despite its dramatic decrease over the past two decades. HIV-MDR is still present, although at a lower rate, suggesting the need for continuous surveillance and accurate management of ART-experienced patients with HIV.

Exosomes in the Pathogenesis and Treatment of Multiple Myeloma in the Context of the Bone Marrow Microenvironment.

Multiple myeloma (MM), the second most common hematological malignancy, is an incurable cancer of plasma cells. MM cells diffusely involves the bone marrow (BM) and establish a close interaction with the BM niche that in turn supports MM survival, proliferation, dissemination and drug resistance. In spite of remarkable progress in understanding MM biology and developing drugs targeting MM in the context of the BM niche, acquisition of multi-class drug resistance is almost universally inevitable. Exosomes are small, secreted vesicles that have been shown to mediate bidirectional transfer of proteins, lipids, and nucleic acids between BM microenvironment and MM, supporting MM pathogenesis by promoting angiogenesis, osteolysis, and drug resistance. Exosome content has been shown to differ between MM patients and healthy donors and could potentially serve as both cancer biomarker and target for novel therapies. Furthermore, the natural nanostructure and modifiable surface properties of exosomes make them good candidates for drug delivery or novel immunomodulatory therapy. In this review we will discuss the current knowledge regarding exosome’s role in MM pathogenesis and its potential role as a novel biomarker and therapeutic tool in MM.

Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance.

Direct acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment, but drug resistance could undermine proposed global elimination targets. Real‐world studies are needed to inform the impact of widespread DAA treatment on antiviral resistance in the community. The prevalence and range of posttreatment resistance‐associated substitutions (RASs) was determined in Australian patients with open access to DAAs through a wide range of prescribers. NS3, NS5A, and NS5B regions were amplified by polymerase chain reaction and analyzed by population sequencing. Clinically relevant RASs were identified using online databases (ReCALL and Geno2Pheno[hcv]). Of 572 samples, 60% were from genotype 3 and 27% from genotype 1a. Ninety‐two percent of people failed a DAA regimen containing an NS5A inhibitor, including 10% with a pangenotype regimen. NS5A RASs were detected in 72% of people with genotype 1 and 80% with genotype 3. For genotype 1, there was a range of RASs across the NS5A region, while for genotype 3, the Y93H RAS predominated (72%). The prevalence of NS3 RASs was higher in people exposed to an NS3 inhibitor (35% vs. 3.9%; P < 0.0001). NS5B resistance was rare, with a single case of sofosbuvir resistance. Multiclass drug resistance was found in 33% of people exposed to both NS3 and NS5A inhibitors. Conclusion: The high prevalence of NS5A RASs among people failing DAA therapy reinforces the importance of specific retreatment regimens, ideally guided by resistance testing. The impact of multiclass drug resistance on retreatment in people exposed to both NS3 and NS5A inhibitors needs to be assessed in real‐world studies. Surveillance for increasing antiviral resistance during treatment scale‐up is essential to maintain the efficacy of current DAA regimens.

Long-term Experience and Outcomes of Programmatic Antiretroviral Therapy for Human Immunodeficiency Virus Type 2 Infection in Senegal, West Africa.

Programmatic treatment outcome data for people living with human immunodeficiency virus type 2 (HIV-2) in West Africa, where the virus is most prevalent, are scarce. Adults with HIV-2 initiating or receiving antiretroviral therapy (ART) through the Senegalese national AIDS program were invited to participate in this prospective, longitudinal observational cohort study. We analyzed HIV-2 viral loads, CD4 cell counts, antiretroviral drug resistance, loss to follow-up, and mortality. We also examined changes in treatment guidelines over time and assessed progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets for HIV-2. We enrolled 291 participants at 2 sites for 926.0 person-years of follow-up over 13 years. Median follow-up time was 2.2 years per participant. There were 21 deaths reported (7.2%), and 117 individuals (40.2%) were lost to follow-up, including 43 (14.7%) who had an initial visit but never returned for follow-up. CD4 counts and HIV-2 viral suppression (< 50 copies/mL) at enrollment increased over calendar time. Over the study period, 76.7% of plasma viral loads for participants receiving ART were suppressed, and median CD4 gain was 84 cells/μL in participants' first 2 years on study. Since the UNAIDS 90-90-90 strategy was published, 88.1% of viral loads were suppressed. Fifteen percent of patients experienced virologic failure with no known resistance mutations, while 56% had evidence of multiclass drug resistance. Participants in the Senegalese national AIDS program are initiating ART earlier in the course of disease, and more modern therapeutic regimens have improved outcomes among those receiving therapy. Despite these achievements, HIV-2 treatment remains suboptimal, and significant challenges to improving care remain.

Learning Robust Multilabel Sample Specific Distances for Identifying HIV-1 Drug Resistance.

AIDS is a syndrome caused by the HIV. During the progression of AIDS, a patient's immune system is weakened, which increases the patient's susceptibility to infections and diseases. Although antiretroviral drugs can effectively suppress HIV, the virus mutates very quickly and can become resistant to treatment. In addition, the virus can also become resistant to other treatments not currently being used through mutations, which is known in the clinical research community as cross-resistance. Since a single HIV strain can be resistant to multiple drugs, this problem is naturally represented as a multilabel classification problem. Given this multilabel relationship, traditional single-label classification methods often fail to effectively identify the drug resistances that may develop after a particular virus mutation. In this work, we propose a novel multilabel Robust Sample Specific Distance (RSSD) method to identify multiclass HIV drug resistance. Our method is novel in that it can illustrate the relative strength of the drug resistance of a reverse transcriptase (RT) sequence against a given drug nucleoside analog and learn the distance metrics for all the drug resistances. To learn the proposed RSSDs, we formulate a learning objective that maximizes the ratio of the summations of a number of ℓ1-norm distances, which is difficult to solve in general. To solve this optimization problem, we derive an efficient, nongreedy iterative algorithm with rigorously proved convergence. Our new method has been verified on a public HIV type 1 drug resistance data set with over 600 RT sequences and five nucleoside analogs. We compared our method against several state-of-the-art multilabel classification methods, and the experimental results have demonstrated the effectiveness of our proposed method.

540. Investigating the Mechanism of a Unique Human Immunodeficiency Virus-1 (HIV-1) Entry Inhibitor, MF275

BackgroundHIV-1 entry into cells is mediated by sequential binding of target cell CD4 and CCR5 or CXCR4 to the metastable envelope (Env) trimer of gp120-gp41 heterodimers (Figure 1). We determined that MF275, a single diastereomer of the small molecule entry inhibitor PF-68742, is necessary and sufficient to inhibit entry of a subset of HIV-1 strains. We investigated the mechanism of MF275.MethodsRecombinant luciferase-expressing HIV-1 pseudotyped by wild-type or mutant HIV-1 Envs was incubated with MF275, other entry inhibitors, and/or antibodies. The virus-inhibitor mixture was added to CD4+ CCR5+ or CD4− CCR5+ target cells and luciferase activity measured.ResultsUnlike other entry inhibitors, MF275 not only reversibly inhibited the infection of CD4+ CCR5+ cells by some HIV-1 strains, but also irreversibly enhanced the infection of CD4− CCR5+ cells by others. In both cases, the strain susceptibility profiles were unique from those of CD4-mimetics, BMS-378806, and maraviroc. Furthermore, MF275 activity was not affected by mutations conferring resistance to other entry inhibitors and vice versa. In line with its activating activity, MF275 sensitized susceptible Envs to neutralization by a variety of broadly neutralizing antibodies against different epitopes. Changes in the gp120 C5 and gp41 FP regions conferred resistance to MF275 inhibition but not activation. Furthermore, sensitivity to other entry inhibitors in the presence of MF275 indicated that inhibition and activation target different conformational intermediates along the entry pathway, with the former targeting the prehairpin intermediate.ConclusionMF275 is unique among HIV-1 entry inhibitors. Depending on the conformation of the target Env, which appears related to the gp120-gp41 interface, MF275 mediates inhibition or activation via distinct mechanisms (Figure 2). Further characterization of the MF275 mechanisms and binding site/s will advance understanding of the HIV-1 entry pathway as well as assist optimization of its clinical utility as an antiretroviral in multi-class drug resistance and potentially as an adjunct to vaccines. Disclosures All authors: No reported disclosures.

Ibalizumab.

Antiretroviral options for patients infected with multiclass resistant HIV-1 warrant the development of new agents with unique mechanisms of action and modes of delivery. Here we review one such agent, ibalizumab, a parenteral CD4 postattachment inhibitor that has demonstrated efficacy as part of combination antiretroviral therapy in the treatment of HIV-1. In a phase III clinical trial in HIV-infected participants with multiclass antiretroviral drug resistance, the intravenous administration of ibalizumab led to declines in plasma HIV-1 RNA more than 0.5 log in 83% of participants at 1 week. An optimized background antiretroviral regimen was then added, and plasma HIV-1 RNA became less than 50 copies/ml in 43% of participants at 24 weeks. Adverse effects of ibalizumab were uncommon and generally low grade. Ibalizumab was approved by the US Food and Drug Administration on March 16, 2018, under the trade name Trogarzo. Ibalizumab has demonstrated both safety and efficacy in the treatment of HIV-1 infection. Its primary use will be in the setting of multidrug resistant virus as part of combination antiretroviral therapy. Further enhancements of ibalizumab to prolong its clearance and broaden its activity are in development.

P-E5 Whole genome deep sequencing of HIV reveals extensive multi-class drug resistance in Nigerian patients failing first-line antiretroviral therapy

Background: Whole genome deep sequencing (WGS) could improve understanding of treatment failure and the emergence of resistance by revealing the distribution of mutations throughout the viral population over time. Methods: Adult patients receiving 1L ART (2 NRTI and 1 NNRTI) at the University of Abuja Teaching Hospital, Nigeria, were included if they had experienced virological failure (HIV-1 RNA &gt;1000 copies/mL, at least 6 months after ART initiation, confirmed by clinician-driven testing), and had a stored plasma sample available for WGS. Results: Sixty participants were sampled during 1L failure (73% female; median age 30 (interquartile ratio [IQR] 28–35); median CD4+ cell count 110 cells/mm3 (IQR 63–191); median 28 months after ART initiation (IQR 18–41)). At 1L failure, 57% of participants had thymidine analogue mutations (TAMs), with 30% harbouring 3 or more TAMs, 95% had other (non-TAM) NRTI mutations and 100% had NNRTI mutations. The most common mutations were M184V, Y181C, G190A, K65R and K103N. Overall, 17% (61/367) of the mutations identified were low-level minority variants (present at 2%–20% of the intra-host viral population), which would not have been detected by standard resistance testing methods, 24% (88/367) were present at 20%–90% frequency, and 59% (218/367) were dominant majority variants representing &gt;90% of the participant's viral population. Conclusions: Diverse Nigerian HIV clades exhibit multi-class drug resistance at 1LART failure. The predominance of high-frequency mutations suggests that emergent resistance had become fixed in the viral population by the time of sampling.

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.

Impact of Fixed-Dose Combinations of Antiretrovirals on Prevalence Trends of HIV Resistance: A 7 Year Follow-Up Study

Objectives: To determine the effectiveness of the introduction of fixed-dose combinations of antiretrovirals (FDCAs) in reducing resistance, and to describe trends of resistance-associated mutations (RAMs) in relation to drug exposure and the risk factors associated with multi-class drug resistance (MCDR) in Catalonia (Spain). Methods: Observational prospective study of HIV Resistance in Catalonia from 2002 to 2008. We included 2,718 HIV+ patients (≥16 years of age) with virological failure (Viral Load>1000 copies/ml). Differences between the Pre-FDCAs period (2002-2005) and the Post-FDCAs period (2005-2008) were assessed by multivariate logistic regressions. Prevalence of resistances and exposure to ARVs. trends were also assessed by test of trend Results: We observed a downward trend from 2002 to 2008 in all class-resistance mutations and RAMS (p<0.0001). This trend coincides with a reduction in exposure to older ARVs., and with an increase in exposure to newer drugs. Multivariate analyses showed the Post-FDCAs period as an independent protective factor for the presence of any resistance, for MCDR, and for major mutations of reverse transcriptase and protease, with Odds Ratios (95% CI) between 0.32 (0.26-0.39) and 0.67 (0.51-0.86). Male sex, sexual transmission group, older age, duration of HIV infection, number of treatment failures and exposure to three-class drugs are also risk factors for the presence of MCDR. Conclusions: There was an important reduction of the risk of class-resistances, MCDR and RAMs in the Post- FDCAs period independently of others factors. Reductions in specific mutations are related to changes in antiretroviral use. These results support the use of FDCAs for the treatment of HIV infection.

Transmitted antiretroviral drug resistance mutations in newly diagnosed HIV-1 positive patients in Turkey.

IntroductionThe objective of this study was to determine the transmitted drug resistance mutations (TDRMs) in newly diagnosed HIV-1 positive patients in Turkey.Materials and MethodsThe study was carried out between 2009 and 2014 and antiretroviral naïve 774 HIV-1 infected patients from 19 Infectious Diseases and Clinical Microbiology Departments in Turkey were included; gender: 664 (86%) male, median age: 37 (range; 1–77), median CD4+T-cell: 360 (range; 1–1320) count/mm3, median HIV-RNA load: 2.10+E6 (range; 4.2+E2–7.41+E8) IU/mL. HIV-1 drug resistance mutations were detected by population based sequencing of the reverse transcriptase (codon 41–238) and protease (codon 1–99) domains of pol gene of HIV-1, and analyzed according to the criteria by the World Health Organization 2009 list of surveillance drug resistance mutations [1].ResultsThe patients had TDRMs to NRTIs (K65R, M184V), NNRTIs (K101E, K103N/S, G190A/E/S, Y181I/C, Y188H/L) and PIs (M46L, I54V, L76V, V82L/T, N83D, I84V, L90M). The prevalence of overall TDRMs was 6.7% (52/774). Resistance mutations were found to be 0.7% (6/774), 4.1% (32/774) and 2.1% (17/774) to NRTIs, NNRTIs and PIs drug groups, respectively. Three patients had NRTIs+NNRTs resistance mutations (M184V+K103N) as multi-class drug resistance. However, thymidine analogue resistance mutations (TAMs) determined two distinct genotypic profiles in the HIV-1 reverse transcriptase: TAM1: M41L, L210W and T215Y, and TAM2: D67N, K70R, K219E/Q, and T215F. The prevalence of TAM1 and TAM2 were 7.7% (60/774) and 4.3% (34/774), respectively.ConclusionsThe TDRMs prevalence of antiretroviral naïve HIV-1 infected patients may be suggested current situation of Turkey. These long-term and large-scale results show that the resistance testing must be an integral part of the management of HIV infection in Turkey.

Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance.

Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation.

In vivo analysis of GenePro, a lentivral therapeutic vaccine

Despite advances in HIV commercial therapies, including fixed-dose combinations, unprecedented proportions of HIV patients remain without therapeutic options due to lack of access to treatment and epidemiologically significant proportions of multi-class drug resistance that are driving morbidity levels in both developed and resource-poor settings. The need to emphasize the development of therapeutic options with the potential to abrogate these correlating trends are receiving insufficient dedication of resources, as new clinical strategies do not address these enduring disparities. GenePro, a therapeutic vaccine candidate, has shown preclinical efficacy via publicly sponsored research that demonstrates the potential to address a current therapeutic issue.

The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea

BackgroundHighly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been used in South Korea since 1997. Currently, more than 20 types of antiretroviral drugs are used in the treatment of human immunodeficiency virus-infected/acquired immune deficiency syndrome patients in South Korea. Despite the rapid development of various antiretroviral drugs, many drug-resistant variants have been reported after initiating HAART, and the efficiency of HAART is limited by these variants. ObjectivesTo investigate and estimate the annual antiretroviral drug resistance and prevalence of antiretroviral multi-class drug resistance in Korean patients with experience of treatment. Study designThe amplified HIV-1 pol gene in 535 patients requested for genotypic drug resistance testing from 2004 to 2009 by the Korea Centers for Disease Control and Prevention was sequenced and analyzed annually and totally. The prevalence of antiretroviral drug resistance was estimated based on “SIR” interpretation of the Stanford sequence database. ResultsOf viruses derived from 787 specimens, 380 samples (48.3%) showed at least one drug class-related resistance. Predicted NRTI drug resistance was highest at 41.9%. NNRTI showed 27.2% resistance with 23.3% for PI. The percent of annual drug resistance showed similar pattern and slightly declined except 2004 and 2005. The prevalence of multi-class drug resistance against each drug class was: NRTI/NNRTI/PI, 9.8%; NRTI/PI, 21.9%; NNRTI/PI, 10.4%; and NRTI/NNRTI, 21.5%. ConclusionsAbout 50% and less than 10% of patients infected with HIV-1 have multidrug and multiclass resistance linked to 16 antiretroviral drugs, respectively. The significance of this study lies in its larger-scale examination of the prevalence of drug-resistant variants and multidrug resistance in HAART-experienced patients in South Korea.

HIV drug resistance: problems and perspectives

Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.

Rates of emergence of HIV drug resistance in resource-limited settings: a systematic review.

The increasing availability of antiretroviral therapy (ART) has improved survival and quality of life for many infected with HIV, but can also engender drug resistance. This review summarizes the available information on drug resistance in adults in resource-limited settings. The online databases PubMed and Google Scholar, pertinent conference abstracts and references from relevant articles were searched for publications available before November 2011. Data collected after ART rollout were reviewed. A total of 7 studies fulfilled the criteria for the analysis of acquired drug resistance and 22 fulfilled the criteria for the analysis of transmitted drug resistance (TDR). Acquired resistance was detected in 7.2% of patients on ART for 6-11 months, 11.1% at 12-23 months, 15.0% at 24-35 months, and 20.7% at ≥ 36 months. Multi-class drug resistance increased steadily with time on ART. The overall rate of TDR in all resource-limited countries studied was 6.6% (469/7,063). Patients in countries in which ART had been available for ≥ 5 years were 1.7 × more likely to have TDR than those living in a country where ART had been available for <5 years (P<0.001). The reported prevalence of TDR was 5.7% (233/4,069) in Africa, 7.6% (160/2,094) in Asia and 8.4% (76/900) in Brazil. The emergence of drug resistance following access to ART in resource-limited settings resembles what was seen in resource-rich countries and highlights the need for virological monitoring for drug failure, drug resistance testing and alternative drug regimens that have proven beneficial in these resource-rich settings.

First‐line antiretroviral treatment outcome in a patient presenting an HIV‐1/2 multiclass drug resistant infection

BackgroundWith the expansion of HIV‐2 epidemic beyond African countries, co‐infection with HIV‐1 becomes a global challenge. We have recently identified an HIV‐1/2 dual infection with both viruses bearing multiclass drug resistance in an untreated patient [1]. We now present the patient's combined antiretroviral treatment (cART) outcome after 6 months follow‐up.Patient and MethodsClinical samples were obtained upon informed consent from a 23‐year‐old man living in Guinea‐Bissau until March 2011 when he moved to Switzerland. As previously reported [1], HIV‐1/2 co‐infection was confirmed by HIV‐1 PCR (21.000 copies/ml) and total HIV‐1/2 viremia (4.351 nU/ml) by product‐enhanced reverse transcriptase (PERT) assay. The patient denied previous HIV testing or exposure to antiretroviral drugs. Dual infection consisted of HIV‐1 CRF02_AG bearing resistance mutations M184V/V90I and HIV‐2 clade A, harboring K65R/D67N mutations as amplified from proviral‐DNA. Baseline CD4 + T‐cell count was 408 cell/mm3. We initiated cART in accordance to drug resistance mutations (see below). Treatment compliance was assessed with an electronic pillbox device and drug‐plasma concentrations. Clinical and laboratory follow up were done at weeks 2, 4, 9, 12 and 24.ResultscART was initiated with tenofovir/emtricitabine (TDF/FTC), boosted‐darunavir (DRV/r) and raltegravir(RAL). Treatment compliance was fluctuant during the first 3 months after which it remained stable with an average monthly intake of 92%. Antiretroviral drug‐plasma concentrations were traced at percentile 25th. HIV‐1 viremia became undetectable at week 12. Additionally, HIV‐2 viremia was retrospectively assessed by real‐time RT‐PCR at two independent laboratories showing undetectable values across the study period including baseline. Thus, baseline viremia, as assessed by the PERT test for particle‐associated reverse transcriptase activity was due to HIV‐1 alone. CD4 + T‐cell count was 559 cell/mm3 at week 24. Laboratory assessments showed a neutrophile drop to 0.96 at week 4, fully restored at week 9.ConclusionThis case of HIV‐1/2 dual infection underscores the importance of assessing genotypic analysis of both viruses ahead to treatment choice. It also highlights viral load platforms constraints when it comes to clinical monitoring of HIV‐1/2 co‐infection in western settings. Overall, first‐line salvage treatment was well tolerated and suppressed HIV‐1 resistant clade allowing recovery of CD4+ T‐cell count.

Susceptibility rate to tigecycline and antibiotic-resistance among Klebsiella pneumoniae strains isolated in Intensive Care Unit

Antibiotic resistance in Klebsiella pneumoniae strains is an increasing problem in a lot of hospitals. It is a public health emergency because it relates with high mortality rate among patients in Intensive Care Unit (ICU). From 1/1/2009 to 31/08/2010, in ICU of SS Annunziata Hospital of Taranto, 140 isolated Klebsiella pneumoniae strains were detected. The strain identification and antimicrobial susceptibility testing were performed using a Vitek2 automated system. These isolate showed a low level of susceptibility to levofloxacin (3.4%), ciprofloxacin (6.2%), ceftazidime (2.8%) and piperacillin/tazobactam (8%). We reported also that the 10% and 13.9% of them were susceptible to meropenem and imipenem. An anti-Klebsiella pneumoniae activity in vitro to tigecycline was present in 64.6% of isolates while almost all strains (56/58) tested to colistin were susceptible. In order to our data of worryng high multiclass drug resistance including tygecicline, it needs to apply appropriate measures of surveillance and antibiotic prescription to avoid rapid spread of these mutiresistant strains in other areas.

Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients

Fluoroquinolone antibiotics are widely used in our communities and healthcare facilities. This review focuses upon the relationship between fluoroquinolone use and the rising prevalence in neutropenic cancer patients of multidrug resistant pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, Clostridium difficile, and aerobic Gram-negative bacilli. Fluoroquinolones such as ciprofloxacin or levofloxacin are efficacious for the prevention and treatment of neutropenic fever syndromes, including infections due to aerobic Gram-negative bacilli. Recent clinical practice guidelines recommend their prophylactic use in acute leukaemia patients receiving intensive remission-induction, postremission consolidation, or salvage induction therapy, and haematopoietic stem cell transplant recipients during pre-engraftment when the duration of profound neutropenia (absolute neutrophil count <0.1 × 10(9)/l) is at least 7 days. These same agents combined with amoxicillin/clavulanate are recommended for oral outpatient empirical antibacterial treatment of febrile neutropenic patients at low risk for medical complications. Fluoroquinolone-resistant Enterobacteriaceae is linked to community fluoroquinolone consumption. Prophylaxis efficacy is reduced when the prevalence of fluoroquinolone Gram-negative bacillary resistance exceeds 20%. Widespread use encourages the transmissibility of multiclass antimicrobial resistance genes among Gram-negative bacilli. Fluoroquinolone-driven colonization with MRSA enhances the risk of subsequent infection, the use of vancomycin, and risk of colonization by vancomycin-resistant Enterococcus spp. The relative roles of widespread fluoroquinolone use and ineffective infection prevention and control practices in encouraging the spread of virulent C. difficile-associated diarrhoea in healthcare facilities remain controversial. Widespread use of antibacterial agents of one class can encourage multiclass drug resistance, which reduces prophylaxis and treatment efficacy in neutropenic cancer patients.