A Controlled Trial of Zidovudine in Primary Human Immunodeficiency Virus Infection

Loes, Sabine Kinloch de; Hirschel, Bernard; Hoën, Bruno; Cooper, David A.; Tindall, Brett; Carr, Andrew; Saurat, J.‐H.; Clumeck, Nathan; Lazzarin, Adriano; Mathiesen, Lars; Raffi, François; Antúnes, Francisco; Overbeck, Jan von; Lüthy, Ruedi; Glauser, M. P.; Hawkins, David; Baumberger, Christophe; Yerly, Sabine; Perneger, Thomas; Perrin, Luc

doi:10.1056/nejm199508173330702

Cited by 288 publications

(101 citation statements)

References 28 publications

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“…Throughout, the time-dependent covariate L i (j) was assumed to act as both a confounder and a mediator for the treatment effect on survival. This assumption is consistent with the role of disease progression markers, such as updated CD4 cell count in HIV-positive individuals, which (i) is associated with mortality hazard, (ii) affects current decisions regarding treatment initiation, interruption or continuation, and (iii) partly reflects the effects of past treatments (Graham et al, 1992;Kinloch-de Loes et al, 1995).…”

Section: Simulations For a Cohort Study Of Hiv-positive Patientssupporting

confidence: 70%

Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study

Xiao¹,

Abrahamowicz²,

Moodie³

2010

The International Journal of Biostatistics

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Marginal structural models (MSM) provide a powerful tool to control for confounding by a time-dependent covariate without inappropriately adjusting for its role as a variable affected by treatment . In this paper, we demonstrate that it is possible to fit a marginal structural Cox model directly, rather than the typical approach of using pooled logistic regression, using the weighted Cox proportional hazards function that has been implemented in standard software. To evaluate the performance of the marginal structural Cox model directly via inverse probability of treatment weighting, we conducted several simulation studies based on two datagenerating models: one which replicates the simulations of Young et al. (2009) and an additional, more clinically plausible approach which mimics survival data with time-dependent confounders and time-varying treatment. Using the simulations, we illustrate the limitations of the conventional time-dependent Cox model and the MSM fitted via pooled logistic regression. Furthermore, we propose two novel normalized weights with the goal of reducing the MSM estimators' variability. The performance of the normalized weights is evaluated alongside the usual unstabilized and stabilized weights.

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Section: Simulations For a Cohort Study Of Hiv-positive Patientssupporting

confidence: 70%

Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study

Xiao¹,

Abrahamowicz²,

Moodie³

2010

The International Journal of Biostatistics

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“…Initially, patients may experience anorexia, fatigue, myalgias, and insomnia, although these symptoms may resolve spontaneously with continued use. With long-term use, the predominant adverse effect of zidovudine is myelosuppression, specifically neutropenia and anemia, which have been shown to occur in 16 % and 24 % of patients, respectively [32]. Zidovudine is associated with myopathy, lactic acidosis, and hepatic steatosis resulting from mitochondrial toxicity, which we will discuss below.…”

Section: Zidovudine (Zdv Azt)mentioning

confidence: 98%

A Review of the Toxicity of HIV Medications

et al. 2013

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Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

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“…El medicamento solo se empezó a distribuir regularmente a partir de 1994. Si bien algunos estudios indican los efectos beneficiosos del uso de AZT contra la progresión al sida (13)(14)(15)(16), en otros trabajos no se corroboran esos resultados (17)(18)(19). Todavía persiste la polémica sobre si el tratamiento antivírico precoz produce efectos de largo plazo (20,21), pero la monoterapia con AZT ya no se recomienda como tratamiento estándar inicial para la infección por VIH (22).…”

Section: Discussionunclassified

Uso de los servicios de salud y progresión al sida entre personas con infección por VIH en Belo Horizonte (Minas Gerais), Brasil

Acúrcio¹,

Guimarães²

1998

Rev Panam Salud Publica

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A Controlled Trial of Zidovudine in Primary Human Immunodeficiency Virus Infection

Abstract: Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

Cited by 288 publications

References 28 publications

Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study

Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study

A Review of the Toxicity of HIV Medications

Uso de los servicios de salud y progresión al sida entre personas con infección por VIH en Belo Horizonte (Minas Gerais), Brasil

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