Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed the safety and efficacy and evaluated the adherence to lopinavir/ritonavir (LPV/r) dosed QD or BID in antiretroviral-naive, HIV-1-infected subjects through 96 weeks of treatment. A randomized, open-label, multicenter comparative study was conducted. A total of 190 antiretroviral-naive subjects with plasma HIV-1 RNA above 1000 copies/ml and any CD4(+) T cell count were enrolled. Subjects were randomized (3:2) to LPV/r 800/200 mg QD (n = 115) or 400/100 mg BID (n = 75). Subjects received TDF 300 mg and FTC 200 mg QD. Adherence to LPV/r through 96 weeks was measured using MEMS((R)) monitors. Median baseline VL and CD4(+) T cell count were 4.8 log(10) copies/ml and 216 cells/mm(3), respectively. Prior to week 96, 37% (QD) and 39% (BID) of subjects discontinued, primarily due either to adverse events (17% QD, 9% BID) or to loss to follow-up or nonadherence (12% QD, 17% BID). The proportion of subjects with VL <50 copies/ml [57% QD, 53% BID; p = 0.582 (ITT NC = F)], change in CD4 count (244 cells/mm(3) QD, 264 cells/mm(3) BID; p = 0.513), and evolution of resistance did not differ between groups through 96 weeks. Diarrhea (17% QD, 5% BID, p = 0.014) was the most common moderate or severe, study drug-related adverse event. Adherence to LPV/r was higher for the QD group than the BID group and declined over time in both groups. Time to loss of virologic response was significantly associated with adherence to LPV/r in both groups. LPV/r QD resulted in virologic response similar to LPV/r BID through 96 weeks in antiretroviral-naive subjects. Adherence was significantly higher in the QD group.
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PMID:A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. 1816 8

The HIV-1 reverse transcriptase (RT) resistance mutations K65R and M184V occur individually and in combination, and can contribute to decreased treatment responses in patients. In order to understand how these mutations interact with one another to confer drug resistance, the susceptibilities and underlying resistance mechanisms of these mutants to nucleoside RT inhibitors (NRTIs) were determined. Virus carrying K65R have reduced susceptibility to most NRTIs, but retain full susceptibility to zidovudine (AZT). M184V mutants have reduced susceptibility to lamivudine (3TC), emtricitabine (FTC) and didanosine (ddl), and contribute to reduced susceptibility to abacavir; however, they remain fully susceptible to tenofovir (TFV), AZT and stavudine (d4T). In cell culture, the K65R+M184V virus showed slightly increased susceptibility to TFV, AZT and d4T compared with K65R alone, but showed further decreases in susceptibility to 3TC, FTC, ddl and abacavir. There are two major biochemical mechanisms of resistance: altered NRTI binding/incorporation and altered NRTI excision after incorporation. For most NRTIs, the primary mechanism of resistance by K65R, M184V and K65R+M184V mutant RTs is to disrupt the NRTI-binding/incorporation steps. In the case of AZT, however, decreased binding/incorporation by K65R and K65R+M184V was counteracted by decreased AZT excision resulting in wild-type susceptibility. For TFV, decreased excision by K65R and K65R+M184V may partially counteract the K65R-driven decrease in incorporation relative to wild-type resulting in only low levels of TFV resistance. The K65R-mediated effect on decreasing NRTI excision was stronger than for M184V. These studies show that both mechanisms of resistance (binding/incorporation and excision) must be considered when defining resistance mechanisms.
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PMID:The balance between NRTI discrimination and excision drives the susceptibility of HIV-1 RT mutants K65R, M184V and K65r+M184V. 1832 Sep 35

Preexposure prophylaxis (PrEP) with antiretroviral drugs constitutes a promising strategy for HIV prevention. Potent PrEP regimens with reverse transcriptase inhibitors can prevent detectable SHIV infection in a repeated low-dose macaque model that resembles human transmission, supporting plans to quickly move this approach into human trials. However, the possibility remains that extremely low levels of virus replication could nonetheless occur during PrEP and seed viral reservoirs in tissues. Therefore, seemingly protected macaques may harbor occult virus that may be initially contained by cytotoxic T cells, but could emerge later. To explore this possibility, we studied whether CD8(+) cells suppress viremia in four rhesus macaques apparently protected by daily or intermittent Truvada (FTC and tenofovir) during 14 low-dose, rectal SHIV(SF162P3) challenges and during a subsequent drug washout period. CD8(+) cells were efficiently ablated with antibodies in these and two additional control macaques that were previously infected but had reached undetectable virus set points. During 4 weeks of follow-up, all four macaques remained free of plasma viremia and provirus in blood lymphocytes. In contrast, plasma viremia resurged to 10(6) to 10(7) copies per milliliter within 2 weeks in both control macaques. Thus, these results indicate that the undetectable viremia in the PrEP-protected macaques was not due to CD8(+) cells that were containing a low-level infection. Rather, the PrEP treatment created conditions in which infection was prevented, eliminated, or controlled by unknown mechanisms. These data provide important information for PrEP usage to prevent HIV transmission, and fully support the continued pursuit of PrEP prevention measures in humans.
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PMID:Short communication: no evidence of occult SHIV infection as demonstrated by CD8+ cell depletion after chemoprophylaxis-induced protection from mucosal infection in rhesus macaques. 1837 May 90

Highly active antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. Increasingly, fixed-dose antiretroviral combinations with equal or greater potency than traditional antiretrovirals, along with fewer side effects, reduced toxicity, and simplified dosing convenience are being utilized. Tenofovir-emtricitabine (TDF-FTC) represents one of the more recent fixed-dose combinations. In combination with either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, TDF-FTC is a preferred choice in recent treatment guidelines on the basis of demonstrated potency in randomized clinical trials, one-pill-a-day dosing convenience, and relatively low toxicity. In addition, the drug is active against hepatitis B virus. Caution must be exercised in patients with renal insufficiency, or when the drug is used with certain other drugs. This manuscript reviews the use of TDF-FTC in the treatment of HIV.
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PMID:Review of tenofovir-emtricitabine. 1851 68

Unique viral variants and resistance mutations may occur in the genital tract of HIV-2 ARV-naive infected women. We sequenced and phylogenetically analyzed protease (PR), reverse transcriptase (RT), and envelope (ENV) from PBMC and genital tract samples from four ARV-naive women in Senegal. HIV-2 protease polymorphisms that predict HIV-1 protease inhibitor (PI) resistance were common. Two subjects had protease mutations (T77I and I64V) in genital tract samples that were not found in PBMCs. One subject had the HIV-2 reverse transcriptase M184I mutation in CVL DNA (but not PBMCs) that is known to confer 3TC/FTC resistance in HIV-2. In another subject, the reverse transcriptase A62V mutation was also found in CVL-RNA but not PBMCs. We found no significant difference in ENV variants between PBMCs and the genital tract. HIV-2 RT and PR mutations in the genital tract of ARV-naive females may have implications for transmitted HIV-2 resistance and ARV therapy.
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PMID:HIV type 2 protease, reverse transcriptase, and envelope viral variation in the PBMC and genital tract of ARV-naive women in Senegal. 1854 24

A new solid-phase extraction (SPE) method has been developed and validated on a liquid chromatography (LC) coupled with a mass spectrometer for the determination of plasma concentrations of tenofovir (TNF) and emtricitabine (FTC) in HIV infected patients. Chromatographic separation was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an Atlantis 4.6 mm x 150 mm, reversed phase analytical column. Detection of TNF, FTC, and internal standard (IS) was achieved by electrospray ionization mass spectrometry (ESI-MS) in the positive ion mode. Calibration ranged from 15.6 to 4000 ng/mL for TNF and 11.7 to 3000 ng/mL for FTC. Plasma was analyzed, and the limit of quantitation was 15.6 ng/mL for TNF and 11.7 ng/mL for FTC; limit of detection was 2 ng/mL for TNF and 1.5 ng/mL for FTC. Mean recovery of TNF, FTC, and IS were 46.5% [relative standard deviation (RSD): 8.8%] and 88.8% (RSD: 1.0%), and 81.7% (RSD: 3.1%), respectively. The method did not show any significant interference with antiretrovirals or other concomitant drugs administered to patients, and no significant "matrix effects" were observed. The method was applied for the determination of antiretroviral plasma concentration of HIV-positive patients treated with FTC and/or TNF, in combination with various other antiretrovirals.
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PMID:A new assay based on solid-phase extraction procedure with LC-MS to measure plasmatic concentrations of tenofovir and emtricitabine in HIV infected patients. 1864 74

Efflux proteins have been shown to greatly affect the uptake of antiretroviral drugs by cells and to prevent their access to the HIV-1 replication site. The active efflux of these drugs might produce subtherapeutic drug levels and favor resistant viral strains and the emergence of sanctuary sites. This study has been performed to investigate whether emtricitabine (FTC) is a substrate and/or inhibitor of MRP1 in human peripheral blood mononuclear cells (PBMCs, HIV-1 target site). Moreover, we have reported the impact of FTC combined with protease inhibitors (PIs) (ritonavir, atazanavir, lopinavir) on Pgp and MRP1 expression and function, and on PI accumulation. Following a 72-h incubation with antiretroviral regimen, Pgp and MRP1 expression and function were assessed on lymphocytes; and intracellular drug concentrations were measured by LC-MS/MS. FTC concentrations were determined following incubation with or without specific efflux proteins inhibitors. FTC inhibitor properties were measured using 2 different MRP substrates. Quantitative real-time PCR showed that PBMCs express high levels of both Pgp and MRP1 mRNA copy number whereas MRP2 and MRP3 were not detectable. Our findings indicate a decrease in MRP1 function after exposure to FTC. MK571 (specific MRP inhibitor) significantly increases FTC accumulation in PBMCs. FTC increases intracellular calcein and [(3)H]-vincristine accumulation. Emtricitabine has both inhibitor and substrate characteristics with MRP1 in PBMCs in vitro, and does not interact with PI accumulation.
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PMID:Emtricitabine: Inhibitor and substrate of multidrug resistance associated protein. 1869 33

Recent findings suggest bidirectional antagonisms between the K65R mutation and thymidine analogue mutations in human immunodeficiency virus type 1 (HIV-1)-infected, treatment-experienced patients, yet little is known about HIV-2 in this regard. This study addressed the effects of innate polymorphisms in HIV-2 on emergent resistance to nucleoside/nucleotide analogues. Emergent drug resistance profiles in HIV-2 subtypes A (n = 3) and B (n = 1) were compared to those of HIV-1 subtypes B and C. Drug resistance was evaluated with cord blood mononuclear cells (CBMCs) and MT2 cells, using selective pressure with tenofovir (TFV), zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), or various dual-drug combinations. Resistance was evaluated using conventional and ultrasensitive sequencing approaches. In agreement with our previous findings, dual-drug combinations of TFV, ddI, ABC, d4T, ZDV, and 3TC preferentially selected for K65R in HIV-1 subtype C isolates. In HIV-1 subtype B, TFV-3TC and ZDV-3TC selected for M184I and D67N, respectively. In contrast, selections with all four HIV-2 cultures favored the development of M184I in dual-drug combinations that included either 3TC or FTC. Since HIV-2 cultures did not develop K65R, an ultrasensitive allele-specific real-time PCR assay was developed to distinguish the presence of 65R from wild-type K65 after 16 cycles with a discriminatory ability of 0.1% against a population of wild-type virus. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and show that polymorphisms may influence the development of the resistance pathways that are likely to emerge.
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PMID:Nucleoside and nucleotide analogs select in culture for different patterns of drug resistance in human immunodeficiency virus types 1 and 2. 1906 92

The huge improvement in the therapeutic arsenal for HIV infection has led to HIV becoming a chronic disease. Like us, our patients are aging and their life expectancy is close to that of the general population. Consequently, we need safe, easily administered drugs with interactions that can be controlled and the least possible impact on highly prevalent comorbidities such as atherosclerosis or coinfection with hepatotropic viruses. Drugs should fit the patient's lifestyle without affecting quality of life and, above all, be free of effects leading to stigma, such as lipoatrophy, a major concern for most recently diagnosed patients. The choice of the two nucleoside analogue reverse transcriptase inhibitors used at the start of antiretroviral therapy should be based on careful evaluation of the abundant data accumulated on all these determining factors which are heralding a new era in the control of HIV infection. Thus, in this scenario, thymidine analogues have been relegated to alternative use. Fixeddose combinations of tenofovir and emtricitabine (TDF/FTC) or abacavir and lamivudine (ABC/3TC) are the backbone of choice when initiating antiretroviral therapy. Direct comparative data are still scarce but suggest similar virological efficacy, with highly preliminary data suggesting some disadvantages associated with the use of ABC/3TC. After excluding patients at risk of hypersensitivity to ABC, both combinations are well tolerated, but TDF/FTC is associated with a better lipid profile. Recent data from the Data Collection on Adverse Events of Anti-HIV drugs (DAD) study show an unexpected association of ABC with increased cardiovascular risk and thus more detailed studies are required.
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PMID:[Are all analogue combinations equal?]. 1919 37

Standard antiretroviral therapy (ART) consists of a combination of three active drugs. The selection of these drugs varies considerably according to the clinical scenario. The "gold standard" in patients initiating ART is tenofovir (TDF)/emtricitabine (FTC)/efavirenz. TDF/FTC is also considered a combination of choice when, for various reasons, ART is initiated with a boosted protease inhibitor. Abacavir and lamivudine (ABC/3TC) is also considered a combination of choice in most clinical practice guidelines. HLA-B*5701 determination minimizes the possibility of hypersensitivity of ABC and is a positive datum for the use of ABC/3TC. However, negative findings from the data collection on Adverse Events of Anti-HIV drugs (DAD) and ACTG5202 studies on this combination should be bourne in mind. TDF can also be a good choice for substituting another nucleoside analogue to avoid or reverse certain toxicities in patients with good virological control. Substituting thymidine analogues for TDF improves lipid profile and produces partial recuperation of subcutaneous fat. Because of the profile of resistance to TDF, this drug continues to be active in most patients with one, or even several, therapeutic failures. TDF plays and especially important role in patients coinfected with hepatotrophic viruses. In summary, TDF is a widely used drug in clinical practice due to its excellent combination of effectiveness, durability and tolerability, in addition to its ease of administration in a single daily dose, whether in its individual formation (Viread), or associated with FTC (Truvada), or with FTC and efavirenz (Atripla).
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PMID:[Current role of tenofovir in clinical medicine]. 1933 72


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