Combination therapy with thymosin α1 and interferon for the treatment of chronic hepatitis C infection: A randomized, placebo-controlled double-blind trial†

Sherman, Kenneth E.; Sjögren, Maria H.; Creager, Robin L.; Damiano, Melissa A.; Freeman, Scott R.; Lewey, Scot; Davis, Dirk R.; Root, Spencer S.; Weber, Fredrick L.; Ishak, Kamal G.; Goodman, Zachary

doi:10.1002/hep.510270430

Cited by 83 publications

(57 citation statements)

References 38 publications

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“…This observation is similar to what was found when IFN was used in combination with 5-fluorouracil (12), all-trans-retinoic acid (25), and thymosin ␣ 1 (26) to treat proliferating carcinomas. Another potential candidate for combination therapy is the cyclic cogenitor of CDV, 1-[({S}-2-hydroxy-2-oxo-1,4,2-dioxophosphorian-5-yl)-methyl-]cytosine dihydrate, which has been shown to be active against herpesvirus infections (7) and HPV (J.…”

supporting

confidence: 85%

Alpha Interferon Augments Cidofovir's Antiviral and Antiproliferative Activities

Johnson

Gangemi

2003

Antimicrob Agents Chemother

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The antiviral and antiproliferative activities of alpha 2a interferon (IFN-␣2a) and cidofovir in human papillomavirus type 16 (HPV-16)-transformed keratinocytes were evaluated. The compounds in combination were more effective than comparable levels of either drug alone. Evaluation of effective drug ratios revealed a synergistic cooperation between IFN-␣2a and cidofovir in inhibiting the proliferation of HPV-infected cells. IFN also has a history of use in the clinical treatment of human papillomavirus (HPV) dermatopathology (21,32,35). An intracellular mechanism by which IFN-␣2a inhibits HPVtransformed-cell proliferation, and presumably HPV-induced papillomas, is through the suppression of viral oncoprotein expression and cytostatic arrest of cell cycling at G 1 , by preserving p53 and retinoblastoma tumor suppressor activity (1, 15). Unfortunately, because of the cytostatic nature of IFN, prolonged therapy is required and treatment is problematic (4, 33) due to drug tolerance or to detrimental side effects (e.g., intolerable flu-like symptoms and loss of drug responsiveness).The activity of cidofovir {CDV; (S)-1-[3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine} against herpesvirus DNA polymerase through inhibition of second-strand synthesis has been reported (13, 34). CDV has also been shown to have some success in the treatment of molluscum contagiosum virus, which also encodes a DNA polymerase (10). CDV applications have achieved modest reductions in the clinical presentation of a variety of HPV-induced tissue proliferations (27-29) and reduced the proliferation of cells transformed by HPV (14), even though this virus lacks a viral DNA polymerase. In contrast to what is found for uninfected cells, CDV is readily phosphorylated to the active triphosphate form in HPV-infected cells and is incorporated into both virus and host cell DNA (14).When used alone, both IFN-␣2a and CDV (5, 9, 19) present significant toxicity concerns. Therapeutic regimens may be improved with combinations in which individual drugs work through distinct antiviral mechanisms. We have observed this potential when suboptimal combinations of IFN and CDV produced a more rapid reduction in cell proliferation and at higher concentrations caused a nearly complete inhibition of transformed cells from which cell growth did not recover after treatment was abated (our preliminary data were presented earlier [Abstr. 17th Int. Conf. Papillomavirus Res., abstr. THER4, 1999]). Moreover, therapies that are cytotoxic, and thus potentially lethal, to virus-infected cells may reduce the likelihood of a resurgence of disease and/or a requirement for prolonged treatment by substantially reducing or eliminating the population of infected cells.This study examined the ability of IFN-␣2a to augment the activity of CDV at concentrations that would impart minimal host toxicity while still being effective against virus-infected cells. Antiproliferative activities of the compounds were evaluated by colony reduction assays. Briefly, primary normal newborn human foresk...

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supporting

confidence: 85%

Alpha Interferon Augments Cidofovir's Antiviral and Antiproliferative Activities

Johnson

Gangemi

2003

Antimicrob Agents Chemother

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“…A timosina alfa 1 é um imunomodulador específico, estimulando células NK, produção de linfócitos CD8 assim como aumento de resposta Th1 das células CD 4. Apesar disso, o uso clínico isolado de timosina tem sido ineficaz contra o VHC, embora sua associação com IFN apresente melhores resultados 33 . Dentre todas as associações testadas até o presente apenas aquela de IFN e ribavirina produziu resultados consistentes em termos de sensível aumento percentual de resposta sustentada.…”

Section: Esquemas Terapêuticosunclassified

Hepatite C

Strauss

2001

Rev. Soc. Bras. Med. Trop.

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Resumo Estima-se que cerca de 3% da população mundial esteja infectada pelo vírus da hepatite C. Todos os que receberam transfusão de sangue ou seus componentes e os usuários de drogas podem estar infectados. Procedimentos odontológicos, médicos, tatuagem ou acupuntura também constituem fatores de risco. A infecção se cronifica em até 85% dos indivíduos, com evolução assintomática durante anos ou décadas e apresentação clínica variada. Para o diagnóstico, a determinação do anti-VHC revela-se muito sensível e a confirmação se faz pela determinação do RNA-VHC no sangue; o estadiamento da doença e a avaliação da atividade inflamatória pela biópsia hepática. O tratamento objetiva deter a progressão da doença hepática através da inibição da replicação viral. Devido à baixa eficácia terapêutica aliada a importantes efeitos colaterais do interferon e da ribavirina, esses medicamentos encontram indicações e contra-indicações específicas. Vários fatores preditivos de resposta ao tratamento, principalmente a carga viral e o genótipo do VHC, mostramse úteis na avaliação dos pacientes. Palavras-chaves: Hepatite C. RNA-VHC. Interferon. Ribavirina.Abstract It has been estimated that 3% of the world population is infected with the hepatitis C virus. Those who are blood product recipients or have been illicit drug users are at risk. Dental and medical procedures as well as tattooing and acupuncture are also risk factors. Chronic infection occurs in up to 85% of infected cases but they may remain without symptoms during years or even decades, and clinical presentation varies. Determination of anti-HCV in sera is a fairly sensitive tool for the diagnosis, and confirmation requires the identification of HCV-RNA. Staging of the liver disease as well as definition of its present activity can be graded by liver biopsy. The aim of treatment is to stop the progression of the hepatic disease by inhibiting viral replication. Due to the low therapeutic efficacy combined with important side-effects, the administration of interferon and ribavirin have specific indications and contraindications. Predictive factors of therapeutic response, particularly viral load and genotypes of HCV, are useful in the evaluation of patients. Key-words: Hepatitis C. RNA-HCV. Interferon. Ribavirin A hepatite C vem sendo estudada há vários anos, mesmo antes da descoberta do vírus causador da doença -o Vírus da Hepatite C (VHC) -há 10 anos. Nesta última década, entretanto, houve avanços significativos no entendimento de sua epidemiologia, modos de transmissão, patogênese, diagnóstico e terapêutica.Sabemos hoje que, a hepatite C compete com a doença hepática alcoólica como a maior causa de doença crônica do fígado, podendo ser a vencedora em várias áreas geográficas. Estima-se que 3 % da população mundial esteja contaminada, sendo relevante o número de pessoas que desconhece o fato de albergar o vírus. Um estudo populacional na cidade de São Paulo mostrou prevalência de 1 a 4% de anti-VHC, variando com a faixa etária 6 . As altas porcentagens de cronicidade da do...

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“…This has been a major concern of hepatogastroenterologists. Unfortunately, both HBV-and HCV-associated forms of chronic hepatitis have thus far responded poorly to current antiviral therapies, including IFN-· [28], lamivudine [42], and thymosin-· [12,68]. Although the pathogeneses of chronic hepatitis B and C are not completely understood, the overwhelming evidence suggests that liver damage in HBV and HCV infections is mediated by host immune responses [3,13,62].…”

mentioning

confidence: 99%

Activation of Th1 Immunity Is a Common Immune Mechanism for the Successful Treatment of Hepatitis B and C: Tetramer Assay and Therapeutic Implications

et al. 2003

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Both chronic hepatitis B and C virus (HBV and HCV) infections respond ineffectively to current antiviral therapies. Recent studies have suggested that treatment outcomes may depend on the development of type 1 T helper (Th1) and Th2 cell responses. Specifically, activation of Th1 immunity may play a major role in successfully treating hepatitis B and C. This model was revisited herein by evaluating immune responses in 36 HBV and 40 HCV patients with or without treatment, in an attempt to find a common immune mechanism for successful treatment. The immune responses in all examined cases were studied by peripheral blood mononuclear cell (PBMC) proliferation and cytokine responses to viral antigens, cytotoxic T lymphocyte (CTL) responses, enzyme-linked immunospot (ELISPOT) assay, and tetramer staining of virus-specific CD8+ T cells. The overall results revealed that all responders among both HBV- and HCV-infected cases displayed significantly higher PBMC proliferation to viral antigens with a predominant Th1 cytokine profile. Furthermore, the Th1-dominant responses were associated with significant enhancement of CTL activities and were correlated with ELISPOT data, while non-responders responded more weakly. During therapy, the numbers of tetramer-staining, virus-specific CD8+ T cells showed greater increases in responders than in non-responders (p = 0.001). The frequencies determined by the tetramer assay were approximately 200-fold higher than data estimated by limiting-dilution analysis. In conclusion, activation of Th1 immunity accompanied by enhancement of CTL activity during therapy is a common immune mechanism for successfully treating hepatitis B and C, and therefore may have important therapeutic implications.

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Combination therapy with thymosin α1 and interferon for the treatment of chronic hepatitis C infection: A randomized, placebo-controlled double-blind trial†

Cited by 83 publications

References 38 publications

Alpha Interferon Augments Cidofovir's Antiviral and Antiproliferative Activities

Alpha Interferon Augments Cidofovir's Antiviral and Antiproliferative Activities

Hepatite C

Activation of Th1 Immunity Is a Common Immune Mechanism for the Successful Treatment of Hepatitis B and C: Tetramer Assay and Therapeutic Implications

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