Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection

Quercia, Romina; Perno, Carlo Federico; Koteff, Justin; Moore, Katy H. P.; McCoig, Cynthia; Clair, Marty St.; Kuritzkes, Daniel R.

doi:10.1097/qai.0000000000001660

Cited by 76 publications

(46 citation statements)

References 98 publications

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“…Randomized trials of lamivudine monotherapy in adults and children with hepatitis B 65 – 67 and of other current-generation NRTIs in non-HIV-infected individuals 68 , 69 have safety profiles that are similar to placebo treatment. However, lamivudine, although less toxic than its predecessors, is associated with development of rare adverse events such as lactic acidosis, hepatomegaly and steatosis, particularly when used in combination with other more toxic anti-retroviral drugs administered to sicker HIV patients in earlier eras, and in children 70 . Regulatory agency labels for NRTIs contain warnings of lactic acidosis, although it should be noted that currently-approved anti-diabetic medications such as metformin also carry these warnings.…”

Section: Discussionmentioning

confidence: 99%

Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

et al. 2020

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Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.

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Section: Discussionmentioning

confidence: 99%

Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

et al. 2020

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“…Nausea, vomiting, diarrhea, headache and/or rash often occur in HIV-positive individuals taking HIV-reverse transcriptase inhibitors ( Table 2 ) [ 147 , 220 , 221 ]. Moreover, the long-term use of these drugs has been reported to cause neutropenia, anemia, myopathy, and liver or kidney malfunction ( Table 2 ) [ 147 , 220 , 221 ].…”

Section: Mmp-9 Inhibitorsmentioning

confidence: 99%

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

Barillari

2020

IJMS

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In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient’s health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.

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“…The oral drug Lamivudine (3TC) is a cytidine analogue containing an oxathiolane ring with an unnatural (−)-β- L -stereochemical configuration, making it a poor substrate for host DNA polymerases. 26 This prodrug, which can be taken orally and has low toxicity, is converted by cellular enzymes, first to a monophosphate, then to the active triphosphate form, Lam-TP. Emtricitabine (Emtriva, FTC) has a similar structure to Lamivudine but with a fluorine at the 5-position of the cytosine.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

et al. 2020

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SARS-CoV-2 is responsible for the current COVID-19 pandemic. On the basis of our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues (the triphosphates of Sofosbuvir, Alovudine, and AZT) inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). We also demonstrated that a library of additional nucleotide analogues terminate RNA synthesis catalyzed by the SARS-CoV-2 RdRp, a well-established drug target for COVID-19. Here, we used polymerase extension experiments to demonstrate that the active triphosphate form of Sofosbuvir (an FDA-approved hepatitis C drug) is incorporated by SARS-CoV-2 RdRp and blocks further incorporation. Using the molecular insight gained from the previous studies, we selected the active triphosphate forms of six other antiviral agents, Alovudine, Tenofovir alafenamide, AZT, Abacavir, Lamivudine, and Emtricitabine, for evaluation as inhibitors of the SARS-CoV-2 RdRp and demonstrated the ability of these viral polymerase inhibitors to be incorporated by SARS-CoV-2 RdRp, where they terminate further polymerase extension with varying efficiency. These results provide a molecular basis for inhibition of the SARS-CoV-2 RdRp by these nucleotide analogues. If sufficient efficacy of some of these FDA-approved drugs in inhibiting viral replication in cell culture is established, they may be explored as potential COVID-19 therapeutics.

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Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 76 publications

References 98 publications

Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

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