Survival in HIV-Infected Patients Who Have Received Zidovudine: Comparison of Combination Therapy with Sequential Monotherapy and Continued Zidovudine Monotherapy

Graham, Neil M.H.; Hoover, Donald R.; Park, L. P.; Stein, Daniel S.; Phair, John P.; Mellors, John W.; Detels, Roger; Saah, A. J.

doi:10.7326/0003-4819-124-12-199606150-00002

Cited by 39 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several in vitro studies have indicated that AZT ϩ ddI act synergistically to inhibit HIV reverse transcriptase [Schinazi et al, 1990;Dornsife et al, 1991], and subsequent clinical studies have shown that this drug combination provides enhanced protection against HIV disease progression and maternal-fetal transmission of HIV when compared with administration of AZT alone [Graham et al, 1996]. At the same time that AZT-ddI potentiates therapeutic/prophylactic efficacy, however, the use of a second NRTI with Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3′‐azido‐3′‐deoxythymidine and 2′,3′‐dideoxyinosine†

Meng

O’Neill

et al. 2002

Environ and Mol Mutagen

View full text Add to dashboard Cite

Combinations of antiretroviral drugs that include nucleoside reverse transcriptase inhibitors (NRTIs) are superior to single-agent regimens in treating or preventing HIV infection, but the potential long-term health hazards of these treatments in humans are uncertain. In earlier studies, our group found that coexposure of TK6 human lymphoblastoid cells to 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), the first two NRTIs approved by the FDA as antiretroviral drugs, produced multiplicative synergistic enhancement of DNA incorporation of AZT and mutagenic responses in both the HPRT and TK reporter genes, as compared with single-drug exposures (Meng Q et al. [2000a]: Proc Natl Acad Sci USA 97:12667-12671). The purpose of the current study was to characterize the mutational specificity of equimolar mixtures of 100 microM or 300 microM AZT + ddI at the HPRT and TK loci of exposed cells vs. unexposed control cells, and to compare the resulting mutational spectra data to those previously found in cells exposed to AZT alone (Sussman H et al. [1999]: Mutat Res 429:249-259; Meng Q et al. [2000b]: Toxicol Sci 54:322-329). Molecular analyses of HPRT mutant clones were performed by reverse transcription-mediated production of cDNA, PCR amplification, and cDNA sequencing to define small DNA alterations, followed by multiplex PCR amplification of genomic DNA to define the fractions of deletion events. TK mutants with complete gene deletions were distinguished by Southern blot analysis. The observed HPRT mutational categories included point mutations, microinsertions/microdeletions, splicing-error mutations, and macrodeletions including partial and complete gene deletions. The only significant difference or shift in the mutational spectra for NRTI-treated cells vs. control cells was the increase in the frequency of complete TK gene deletions following exposures (for 3 days) to 300 microM AZT-ddI (P = 0.034, chi-square test of homogeneity); however, statistical analyses comparing the observed mutant fraction values (measured mutant frequency x percent of a class of mutation) between control and NRTI-treated cells for each class of mutation showed that the occurrences of complete gene deletions of both HPRT and TK were significantly elevated over background values (0.34 x 10(-6) in HPRT and 6.0 x 10(-6) in TK) at exposure levels of 100 microM AZT-ddI (i.e., 1.94 x 10(-6) in HPRT and 18.6 x 10(-6) in TK) and 300 microM AZT-ddI (i.e., 5.6 x 10(-6) in HPRT and 34.6 x 10(-6) in TK) (P < 0.05, Mann-Whitney U-statistic). These treatment-related increases in complete gene deletions were consistent with the spectra data for AZT alone (ibid.) and with the known mode of action of AZT and ddI as DNA chain terminators. In addition, cotreatments of ddI with AZT led to substantial absolute increases in the mutant fraction of other classes of mutations, unlike cells exposed solely to AZT [e.g., the frequency of point mutations among HPRT mutants was significantly increased by 130 and 323% over the background value (4.25 x ...

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3′‐azido‐3′‐deoxythymidine and 2′,3′‐dideoxyinosine†

Meng

O’Neill

et al. 2002

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…Subsequently, widespread treatment with zidovudine (AZT) reduced the incidence of HIV dementia dramatically [68]. With the later introduction of combination therapy and PI-based highly active antiretroviral therapies (HAART), further improvement was seen [59,69]. The incidence of most HIV-related opportunistic infections, including those affecting the CNS, dropped markedly.…”

Section: Hiv Associated With Dementiamentioning

confidence: 99%

Human Immunodeficiency Virus and the Central Nervous System

Mirza

Rathore

2012

Seminars in Pediatric Neurology

View full text Add to dashboard Cite

The pandemic of HIV/AIDS continues to grow daily. Incident cases among women, intravenous drug users and ethnic minorities comprise the fastest growing segment of the HIV-infected population, and the number of HIV-infected individuals over the age of 50 is growing rapidly. Today, the central nervous system and the immune system are seen as main targets of HIV infection. Significant progress in the knowledge and treatment of AIDS has been obtained in recent years. The neurological manifestations directly related to HIV are acute viral meningitis, chronic meningitis, HIV-associated dementia (HAD), vacuolar myelopathy, and involvement of the peripheral nervous system.

show abstract

“…La mayor parte de los estudios señalan que la profilaxis anti-NPC disminuye el riesgo de muerte, oscilando esta reducción entre el 21% y el 52% (8,9,15,54). Destaca el artí-culo de Chaisson RE et al (9) por ser uno de los pocos trabajos en donde se analiza el efecto de la adherencia a los tratamientos sobre la mortalidad.…”

Section: Efecto Del Tratamiento Antirretroviral Y De La Profilaxis Anunclassified

“…Al igual que otros autores (13,48,(54)(55)(56)(57), se ha observado una disminución del riesgo de muerte en los pacientes a los que se les modificó la medicación antirretroviral durante su evolución, aunque estadísticamente no significativo. Esta circunstancia podría estar relacionada con varios factores: a) la existencia de otras variables de difícil control que influyan sobre la supervivencia, como puedan ser aquellas que intervengan en la decisión del médico a la hora de modificar el tratamiento (57); b) el que más de un tercio de la cohorte esté constituida inicialmente por sujetos con sida, mientras que p.…”

Section: Efecto De Modificar El Tratamiento Antirretroviral Sobre La unclassified

“…ej., en el trabajo de Graham NMH y cols. (54), donde sí se observa una reducción significativa en el riesgo de muerte para los sujetos que cambiaron a DDI/DDC o combinaron estos fármacos con la ZDV, ningún paciente tenía sida; c) el que se haya valorado conjuntamente al DDI y DDC, tanto en monoterapia como en biterapia, señalándose en diferentes ensayos clínicos un menor efecto del DDC (48,56); y d) el fracaso terapéutico es más probable en los sujetos previamente tratados con ZDV debido a la aparición de resistencias (55).…”

Section: Efecto De Modificar El Tratamiento Antirretroviral Sobre La unclassified

See 1 more Smart Citation

Estudio de la mortalidad y supervivencia en una cohorte de 1.115 pacientes con infección VIH (1989-97)

Rebollo

García

Castilla³

et al. 2004

An. Med. Interna (Madrid)

View full text Add to dashboard Cite

INTRODUCCIÓNSon muchos los estudios de supervivencia sobre los casos de sida diagnosticados durante las dos primeras décadas desde el inicio de esta epidemia. Sin embargo, la población objeto de estudio es en su mayoría homo/bisexual (1-15). En nuestro país, donde el colectivo más afectado por el VIH son los consumidores de drogas inyectadas (CDI) (16), son escasos los trabajos realizados sobre una muestra amplia de pacientes (17). Por otro lado, las modificaciones que han ido surgiendo en los criterios diagnósticos y ampliación de las enfermedades asociadas al sida, hacen necesario considerar el tipo de evento 11 [0212-7199 (2004) RESUMENFundamento: Analizar la supervivencia y mortalidad por VIH/sida entre 1989 y 1997, y evaluar el impacto que sobre ellas han tenido el tratamiento antirretroviral y la profilaxis frente al Pneumocystis carinii (anti-NPC).Pacientes y métodos: Estudio de una cohorte retrospectiva de 1.115 pacientes (331 con sida) seguidos en una Unidad hospitalaria de VIH en Madrid entre enero de 1989 y mayo de 1997. Se analizó tasa anual de mortalidad y el efecto en la misma del régimen de tratamiento antirretroviral. La regresión de Cox fue utilizada en los estudios de supervivencia para analizar su evolución, la influencia de los distintos eventos oportunistas, el efecto de la adherencia a los tratamientos y del cambio de tratamiento antirretroviral durante el seguimiento.Resultados: La tasa de mortalidad fue de 13,7 por 100 personas-año en 1994 y descendió hasta 4,2 en el primer semestre del 1997 (p=0,001). La monoterapia se asoció a una disminución de la mortalidad del 53% [IC95=34%-65%], la biterapia del 68% [IC95=38%-84%], la triple terapia del 86% [IC95=40-96%] y la profilaxis anti-NPC del 49% [IC95=29%-64%]. En los pacientes con CD4>100/mm 3 la supervivencia mejoró a lo largo del tiempo (p=0,002). En los pacientes con sida, el buen cumplimiento del tratamiento antirretroviral y de la profilaxis anti-NPC se asociaron con una disminución del riesgo de muerte (RR=0,88; IC95=0,63-1,22 y RR=0,72; IC95=0,55-0,95 respectivamente).Conclusiones: La profilaxis anti-NPC y el tratamiento antirretroviral, en especial la terapia combinada, han contribuido a disminuir la mortalidad por sida en los últimos años. El grado de adherencia a los tratamientos se relaciona con el riesgo de morir y la supervivencia. (RR=0.88;.Conclusions: In recent years PCP-prophylaxis and antiretroviral treatment (especially combined therapy) have contributed to a decrease in AIDS-related mortality. Adherence to treatments relates to risk of death and survival.

show abstract

Survival in HIV-Infected Patients Who Have Received Zidovudine: Comparison of Combination Therapy with Sequential Monotherapy and Continued Zidovudine Monotherapy

Cited by 39 publications

References 0 publications

Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3′‐azido‐3′‐deoxythymidine and 2′,3′‐dideoxyinosine†

Molecular analysis of mutations at the HPRT and TK loci of human lymphoblastoid cells after combined treatments with 3′‐azido‐3′‐deoxythymidine and 2′,3′‐dideoxyinosine†

Human Immunodeficiency Virus and the Central Nervous System

Estudio de la mortalidad y supervivencia en una cohorte de 1.115 pacientes con infección VIH (1989-97)

Contact Info

Product

Resources

About