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• W2902684383 abstract "The aim of combined antiretroviral therapy (cART) in HIV-infected patients is viral load suppression below the limit of assay detection, also known as undetectable viral load, attainable only if an appropriate cART regimen is administered and adhered to [1]. Virological failure is defined as a viral load more than 200 copies/ml at 24 weeks of initiating ART or as having two consecutive detectable viremia more than 50 copies/ml after initial viral load suppression [1]. Although the two most common causes of virological failure are suboptimal adherence to treatment and viral resistance, less frequent causes have been described. We report a case of an HIV-infected patient with virological failure, probably mediated by at least two mechanisms secondary to human T-lymphotropic virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL). A 45-year-old black male patient from Guinea was seen at the HIV outpatient clinic for management of HIV and chronic hepatitis B virus (HBV) coinfection diagnosed in 2003. At the time of first consultation, the patient was asymptomatic and was receiving a combination of emtricitabine/tenofovir disoproxil fumarate, atazanavir, and ritonavir since 2010. HIV and HBV viral loads were, respectively, at 13 400 copies/ml (4.13 log copies/ml) and 3057 316 IU/ml, suggesting poor adherence to treatment. HIV drug resistance testing (genotyping) was performed and showed a wild type HIV. The ART regimen was simplified to emtricitabine/tenofovir alafenamide and dolutegravir to increase adherence. On subsequent consultations, HIV viral load remained persistently between 20 000 and 40 000 copies/ml despite the patient's claim of good adherence, but a drastic decrease of HBV viral load (3 logs) was noted. Direct observed therapy (DOT) was initiated and another genotype was performed with the same result. Therapeutic drug monitoring showed therapeutic levels of dolutegravir. High dose boosted darunavir was added to the ART regimen, whereas the patient was still under DOT. Six months after antiretroviral switch, HBV viral load became undetectable, proving correct adherence and drug absorption but HIV viral load remained stable. Subsequently, the patient developed a diffuse papulovesicular rash with a blood absolute lymphocyte count of 26 290/μl and a CD4+ T-cell count of 21 000/μl. Skin biopsy showed an exocytosis of intraepidermal lymphocytes possibly linked to an underlying lymphoma and bone marrow biopsy showed an infiltration by a suspect population of T lymphocytes. PET scan showed supradiaphragmatic and subdiaphragmatic hypermetabolic lymph nodes and splenic involvement. Splenectomy led to the diagnosis of ATL, leukemic subtype. The patient was found to be positive for HTLV-1 (serology and PCR). He was treated with intrathecal chemotherapy and a systemic regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, together with zidovudine and IFN-α as anti-HTLV-1 agents. HIV viral load became finally undetectable several months later once ATL was controlled. Several mechanisms, some of which related to the diagnosis of HTLV-1-associated ATL, may explain HIV virological failure in our patient. Overexpression of efflux transporters is one of these potential mechanisms. P-glycoprotein (P-gp) is a product of the multidrug resistance (MDR-1) gene and acts as a unidirectional drug efflux pump resulting in decreased accumulation of drugs, such as chemotherapy agents and ART, within cells [2,3]. The MDR-1 gene can be found in several subclasses of lymphocytes [2]. P-gp is naturally present in CD4+ lymphocytes and given the patient's extremely elevated CD4+ T-cell count, an overexpression of the MDR-1 gene probably induced an overproduction of P-gp and ultimately a reduced amount of ART drugs reaching their target site. A similar poor response to treatment and poor outcome has been described in HIV patients with non-Hodgkin lymphoma and P-gp overexpression [4]. To confirm this hypothesis, an immunohistochemical analysis for P-gp expression, using C494 mAb specific for the MDR-1 isoform of P-gp on a histological sample from the patient's spleen, showed 70% of malignant cells positive for P-gp (Fig. 1). Moreover, HTLV-1 itself promotes the transcription and replication of HIV-1 [5], among others, via protein Tax-1 which may contribute to persistent viral replication [6]. It has been reported that around 20% of HIV-infected patients are coinfected with HTLV-1; however, this may be underestimated due to lack of systematic testing for HTLV-1 [7]. As such, we hypothesize that coinfection with HTLV-1 contributed to our patient's virological failure.Fig. 1: Immunohistochemical detection of P-glycoprotein on surface of 70% of malignant lymphocytes of the spleen (×400).P-glycoprotein acts as a unidirectional drug efflux pump resulting in decreased accumulation of drugs, such as chemotherapy agents and antiretroviral therapy, within cells.An unexplained HIV virologic failure may mask a severe hematologic complication in HIV-infected patients. Several molecular and genetic mechanisms, some of them being not fully identified, may be at the root of virological failure. Clinicians must be aware of such underlying mechanisms such as overexpression of drug efflux transporters. New strategies aiming to overcome these mechanisms including the overexpression of MDR-1 and P-gp should be evaluated. Acknowledgements Conflicts of interest There are no conflicts of interest." @default.
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• W2902684383 date "2019-01-02" @default.
• W2902684383 modified "2023-10-18" @default.
• W2902684383 title "HIV virological failure in a patient with human T-lymphotropic virus type 1-associated leukemia" @default.
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• W2902684383 doi "https://doi.org/10.1097/qad.0000000000002013" @default.
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