P-glycoprotein in blood CD4 cells of HIV-1-infected patients treated with protease inhibitors

Objective

Many factors are involved in the virological failure of antiretroviral treatments such as low pharmacological plasma levels of drugs, poor adherence to therapy and emergence of viral resistance. P‐glycoprotein (P‐gp) has been demonstrated to play a role in multidrug resistance in the therapy of solid tumours, haematological malignancies and Plasmodium falciparum infection. HIV‐1 protease inhibitors (PIs) have been described to be substrates of P‐gp. In vitro and in vivo studies performed in mice have demonstrated that P‐gp may affect the oral bioavailability and intracellular accumulation of PIs. P‐gps have been detected on peripheral CD4 blood cells in HIV‐1‐infected, but antiretroviral‐naive patients.

Method

We quantified P‐gp expression and performed functional tests of P‐gp activity in the CD4 cells in HIV‐1‐infected patients, with and without virological failure, treated with PIs, and in healthy patients (control group).

Result

Out of the 18 HIV‐infected patients studied, P‐gp expression and function were found in the CD4 cells of six patients (four of 10 without, and two of eight with virological failure). Out of the 43 healthy patients studied, P‐gp expression and function were found in the CD4 cells of 11 patients (26%). We found P‐gp in peripheral CD4 cells of patients treated with PIs, with and without virological failure, within the same frequency than in antiretroviral naive patients or than in non HIV‐infected patients.

Conclusions

P‐gp expression in peripheral CD4 blood cells does not seem to be enhanced by PI treatment and does not seem to be linked particularly to virological failures. These facts do not preclude of the role of P‐gp on PI absorption or efficacy in other compartments of the body such as gut, lymph nodes or brain in HIV‐1 PI‐treated patients.

     

HIV耐药的临床和基础研究进展

文章主要关注以下方面内容:艾滋病病毒Ⅰ型(HIV-1)持续存在、储存和消除等方面的策略研究;HIV-1侵入抑制剂的耐药研究(包括通过对比使用CCR5拮抗剂治疗前的基因型和表现型来确定HIV-1的核心接受位点);反转录酶抑制剂在聚合酶领域的耐药研究(包括乙型肝炎病毒和HIV-1对拉米夫定的耐药,HIV-1 B和C亚型在K65Rw位点突变);反转录酶抑制剂在联结和RNase H领域的耐药研究[包括突变在对依非韦仑和etravirine(一种新药)应答方面的作用];对丙型肝炎病毒和HIV-1蛋白酶抑制剂的耐药研究;对整合酶抑制剂雷特格韦(Raltegravir)的耐药研究;全球耐药流行情况(包括对资源匮乏地区二线抗病毒药物耐药反应的预测模型);少数耐药变异株的作用(包括这些变异株在预防艾滋病母婴传播中的作用)。     

Remembering Professor Walter A. Scott

Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and colleagues who knew him as a dedicated and unassuming scholar, and a lively scientist with a great sense of humor.     

Receipt and timing of HIV drug resistance testing in six U.S. jurisdictions

The Department of Health and Human Services recommends drug resistance testing at linkage to HIV care. Because receipt and timing of testing are not well characterized, we examined testing patterns among persons with diagnosed HIV who are linked to care. Using surveillance data in six jurisdictions for persons aged ≥13 years with HIV infection diagnosed in 2013, we assessed the proportion receiving testing, and among these, the proportion receiving testing at linkage. Multivariable log-binomial regression modeling estimated associations between selected characteristics and receipt of testing (1) overall, and (2) at linkage among those tested. Of 9,408 persons linked to care, 66% received resistance testing, among whom 68% received testing at linkage. Less testing was observed among male persons who inject drugs (PWID), compared with men who have sex with men (adjusted prevalence ratio [aPR]: 0.88; 95% confidence interval [CI]: 0.81–0.97) and persons living in areas with population <500,000 compared with those in areas with population ≥2,500,000 (aPR: 0.88; CI: 0.84–0.93). In certain jurisdictions, testing was lower for persons with initial CD4 counts ≥500?cells/mm³, compared with those with CD4 counts <200?cells/mm³ (aPR range: 0.80–0.85). Of those tested, testing at linkage was lower among male PWID (aPR: 0.85; CI: 0.75–0.95) and, in some jurisdictions, persons with CD4 counts ≥500?cells/mm³ (aPR range: 0.63–0.73). Two-thirds of persons with diagnosed HIV who were linked to care received resistance testing, and most received testing at linkage as recommended. Improving receipt and timing of testing among male PWID, persons in less populous settings, and in all jurisdictions, regardless of CD4 count, may improve care outcomes.     

Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy

Objectives

Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV‐infected patients failing RAL‐containing regimens.

Methods

Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF.

Results

At the time of VF, RAL‐resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi‐species. In addition, RAL‐resistance mutations were detected in HIV DNA in all patients.

Conclusions

Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second‐generation integrase inhibitors. Moreover, RAL‐resistance mutations can be archived early in PBMC.     

抗HIV-1药物的研发特点及进展

目前高效抗逆转录病毒联合疗法在HIV的治疗中取得了很好的疗效,在国内外得到广泛应用。目前已有6类30余种抗逆转录病毒药物应用于抗病毒治疗,主要包括核苷类逆转录酶抑制剂、非核苷类逆转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂、膜融合抑制剂和CCR5辅助受体拮抗剂,分别作用于HIV复制的不同环节。此外,还有许多其他新型药物正处于研发和临床试验阶段。     

Inflammatory profile associated with insulin resistance in non-overweight versus overweight people living with HIV in Pune,Western India

BackgroundPeople living with HIV have greater diabetes (T2DM) than the general population despite lower prevalence of overweight/obesity. Both insulin resistance (IR), a T2DM precursor, and HIV are independently associated with chronic inflammation. Inflammation may be a pathophysiological link explaining IR in people living with HIV who are not overweight but is not well understood.AimsTo study the association between inflammation and IR in non-overweight and overweight people living with HIV.MethodsIn a cohort of adult people living with HIV with undetectable viral load in Pune, India, we measured fasting insulin, glucose, and 9 inflammatory markers. IR was defined as HOMA-IR ≥2, and non-overweight as BMI ≤23 kg/m². We used modified Poisson regression to evaluate the association between inflammatory markers and IR in overweight and non-overweight.ResultsOf 288 participants, 66% (n = 189) were non-overweight. Among non-overweight, prevalence of IR was 34% (n = 65). Each doubling of MCP-1 and leptin was associated with IR on univariate analysis (prevalence ratio (PR) 1.29, 95%CI 1.07–1.53, p < 0.01; PR 1.13 95%CI 1.01–1.26, p = 0.03). Leptin remained associated with IR after adjustment for age, MCP-1, gender, cholesterol, and waist circumference (adjusted PR 1.20 95%CI 1.06–1.36, p < 0.01). Among overweight, prevalence of IR was 69% and no markers were associated with IR.ConclusionsOne in 3 non-overweight people living with HIV in India with controlled viremia have IR. Leptin was associated with IR among non-overweight people living with HIV and may provide insight into the pathophysiology of metabolic disease in this population.     

Clinical management of HIV drug resistance

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.