Treatment of Human Immunodeficiency Virus Infection with Saquinavir, Zidovudine, and Zalcitabine

Collier, Ann C.; Coombs, Robert W.; Schoenfeld, David; Bassett, Roland L.; Timpone, Joseph; Baruch, Alice; Jones, Mitchell L.; Facey, Karen; Whitacre, Caroline C.; McAuliffe, Vincent J.; Friedman, Harvey M.; Merigan, Thomas C.; Reichman, Richard C.; Hooper, Carol J.; Corey, Lawrence

doi:10.1056/nejm199604183341602

Cited by 687 publications

(251 citation statements)

References 39 publications

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“…In one such trial, despite similar levels of viral suppression, therapy with AZT and the protease inhibitor saquinavir results in superior rises in CD4 T cell counts, after 8 and 16 weeks therapy when compared to non protease inhibitor therapy with AZT and DDC. 104 In addition, recent reports describe improvements in CD4 counts despite unsuppressed viral replication in patients treated with protease inhibitor based combination antiretroviral salvage regimens. 105 ± 107 A second line of evidence which suggests that protease inhibitors directly affect T cell homeostasis is the observation that in patients treated with protease inhibitor based therapy, CD8 T cell numbers rise in a manner which is greater than that seen with non protease inhibitor based regimens.…”

Section: Discussionmentioning

confidence: 99%

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

et al. 1999

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T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P50.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBL's from HIV negative patients, and apoptosis sensitive PBL's from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

et al. 1999

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“…cell count, and viral load advantage associated with drug regimens that include protease inhibitors, although no exact figure is known. [162][163][164][165][166] We assumed that protease inhibitors lengthen life in persons with asymptomatic HIV by a factor of 1.5. Thus, we assumed that mean time from HIV infection to development of AIDS is 9.8 years with no protease inhibitors 167 and 14.7 years with protease inhibitors, and mean time from development of AIDS to death is 2.1 years with no protease inhibitors 167,168 and 3.15 years with protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

HIV transmission and the cost-effectiveness of methadone maintenance

Zaric¹,

Barnett²,

Brandeau³

2000

Am J Public Health

195

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OBJECTIVES: This study determined the cost-effectiveness of expanding methadone maintenance treatment for heroin addiction, particularly its effect on the HIV epidemic. METHODS: We developed a dynamic epidemic model to study the effects of increased methadone maintenance capacity on health care costs and survival, measured as quality-adjusted life-years (QALYs). We considered communities with HIV prevalence among injection drug users of 5% and 40%. RESULTS: Additional methadone maintenance capacity costs $8200 per QALY gained in the high-prevalence community and $10,900 per QALY gained in the low-prevalence community. More than half of the benefits are gained by individuals who do not inject drugs. Even if the benefits realized by treated and untreated injection drug users are ignored, methadone maintenance expansion costs between $14,100 and $15,200 per QALY gained. Additional capacity remains cost-effective even if it is twice as expensive and half as effective as current methadone maintenance slots. CONCLUSIONS: Expansion of methadone maintenance is cost-effective on the basis of commonly accepted criteria for medical interventions. Barriers to methadone maintenance deny injection drug users access to a cost-effective intervention that generates significant health benefits for the general population.

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“…In one such instance, HIV-infected subjects were randomized in a clinical trial to receive therapy with three drugs, including one protease inhibitor (saquinivir, zidovudine, and zalitabine) or two drugs. One of the two drug regimens included a protease inhibitor (zidovudine and saquinivir), and the other two-drug regimen had no protease inhibitors (zidovudine and zalitabine) [1]. Two-hundred and eighty subjects completed 24 weeks of treatment.…”

Section: The Role Of Hiv Protease Inhibitors During Treatment Of Hiv mentioning

confidence: 99%

HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo

et al. 2007

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HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8 + T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

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Treatment of Human Immunodeficiency Virus Infection with Saquinavir, Zidovudine, and Zalcitabine

Cited by 687 publications

References 39 publications

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

HIV transmission and the cost-effectiveness of methadone maintenance

HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo

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