Superiority of Protease Inhibitors over Nonnucleoside Reverse-Transcriptase Inhibitors when Highly Active Antiretroviral Therapy Is Resumed after Treatment Interruption

ABSTRACT Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.

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Clinical Evidence of Interaction Between Itraconazole and Nonnucleoside Reverse Transcriptase Inhibitors in HIV-Infected Patients with Disseminated Histoplasmosis

Annals of Pharmacotherapy ◽

10.1345/aph.1l624 ◽

2009 ◽

Vol 43 (5) ◽

pp. 908-913 ◽

Cited By ~ 12

Author(s):

Roberto A Andrade ◽

Richard T Evans ◽

Richard J Hamill ◽

Teddy Zerai ◽

Thomas P Giordano

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Clinical Data ◽

Highly Active Antiretroviral Therapy ◽

Small Sample Size ◽

Small Sample ◽

Reverse Transcriptase Inhibitors ◽

Blood Concentrations ◽

Nonnucleoside Reverse Transcriptase Inhibitors ◽

Disseminated Histoplasmosis

Background Itraconazole is the preferred drug for chronic maintenance therapy in HIV-infected patients with disseminated histoplasmosis. Unfortunately, few clinical data exist confirming a presumed interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Objective To determine whether serum itraconazole concentrations are affected by the type of antiretroviral therapy (NNRTI or protease inhibitor [PI]) being taken concomitantly. Methods This retrospective cohort identified patients on antiretroviral therapy and itraconazole for disseminated histoplasmosis between January 2003 and December 2006 at a large HIV clinic in Houston, TX. Available laboratory values were abstracted from medical records. Results Thirteen itraconazole concentrations from 10 patients were avaitable for analysis: 7 patients were on concomitant Pls, 4 on concomitant NNRTIs, and 2 on antiretroviral regimens containing both Pls and NNRTIs. Six of the itraconazole concentrations during concomitant PI treatment were therapeutic (>1.0 μg/mL). in contrast with none in patients taking an NNRTI. All patients taking concomitant NNRTIs had undetectable serum itraconazole concentrations (<0.05 μg/mL). Two patients switched from NNRTI-based to PI-based antiretroviral regimens and subsequently reached therapeutic itraconazole concentrations. Although limited by small sample size, this study provides the largest clinical data among HIV-infected patients demonstrating that coadministration of an NNRTI and itraconazole results in significant decreases in itraconazole blood concentrations, likely by inducing the CYP3A4 enzyme system. Conclusions Itraconazole concentrations should be monitored in patients taking concomitant NNRTIs. PI-based highly active antiretroviral therapy (HAART) may be preferred over NNRTI-based HAART when itraconazole is used to treat HIV-infected patients with disseminated histoplasmosis.

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Long-Term Effect of Different Classes of Highly Active Antiretroviral Therapy on Transaminases

Journal of Laboratory Physicians ◽

10.4103/0974-2727.59705 ◽

2009 ◽

Vol 1 (02) ◽

pp. 077-081

Author(s):

Ebele J Ikekpeazu ◽

Emeka E Neboh ◽

Ignatius C Maduka ◽

Odutola Odetunde ◽

Uche Ifejimalu

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Highly Active Antiretroviral Therapy ◽

Teaching Hospitals ◽

Reverse Transcriptase Inhibitors ◽

Hiv Patients ◽

Nucleoside Reverse Transcriptase Inhibitors ◽

Highly Active ◽

Long Term Effect ◽

Negative Controls

ABSTRACT AIM: The current use of highly active antiretroviral therapy (HAART) for HIV/AIDS patients has increased the recognition of their hepatotoxic effects. The present study is aimed at evaluating the level of aspartate transaminase (AST) and alanine transaminase (ALT) in HIV patients on different classes of HAART, for various durations, which causes its toxicity Materials and Methods: The AST and ALT levels were estimated in a total of 340 subjects, of which 290 were HIV positive subjects drawn from patients attending the HIV clinic in two Teaching Hospitals, in Nigeria. 240 of the HIV patients were divided into 3 equal groups of 80 each and placed on non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI), and protease inhibitors (PI), respectively, and were monitored for different periods of time (3, 6, 12, and >12 months). 50 of the HIV patients, yet to be placed on anti-retroviral therapy and 50 apparently healthy HIV-negative subjects served as the positive and negative controls, respectively. Results: A significant increase in enzyme levels was noted at three and six months in the NNRTI group, and at only three months in the NRTI and PI groups, when compared with the controls. However, increased ALT was observed at six months in those on PI. The increased ALT and AST levels noted in the NNRTI group were significant when compared to those on NRTI and PI over a three- and six-month duration. Conclusion: Liver enzyme activities were generally raised in the first three months of HAART, and further in the NNRTI group, after which they progressively fell to the normal level, with time. The highest degree was observed with NNRTIbased HAART.

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Significant Toxicities Associated with Antiretroviral Therapy

Journal of Pharmacy Practice ◽

10.1106/2uu8-8jjd-uhru-c14r ◽

2000 ◽

Vol 13 (6) ◽

pp. 457-474

Author(s):

Tina J. Kanmaz ◽

Nancy J. Lee

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Highly Active Antiretroviral Therapy ◽

Standard Of Care ◽

Mitochondrial Toxicity ◽

Reverse Transcriptase Inhibitors ◽

Short Term ◽

Nucleoside Reverse Transcriptase Inhibitors ◽

Highly Active

Use of at least three potent antiretroviral agents has become the standard of care in the management of HIV infection. The potential toxicities associated with highly active antiretroviral therapy (HAART) however, may limit a patient’s ability to adhere to and tolerate these agents. Although a comprehensive discussion of all toxicities associated with HAART is beyond the scope of this article, selected short-term and long-term significant toxicities will be reviewed. Short-term toxicities that will be discussed include abacavir-induced hypersensitivity reactions, efavirenz-associated central nervous system side effects and rash associated with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitor (PI) amprenavir. Several long-term toxicities associated with the nucleoside reverse transcriptase inhibitors (NRTIs) are hypothesized to be due to mitochondrial toxicity. These toxicities include myositis and lactic acidosis with hepatic steatosis, pancreatitis and peripheral neuropathy. Some experts also hypothesize that mitochondrial toxicity is responsible for the lipodystrophy syndrome, which includes hyperglycemia, abnormal fat redistribution and dyslipidemia. Finally, indinavir-associated nephrolithiasis, which may present with either short term or long term use will be discussed. This article will provide the practicing pharmacist with a review of these significant toxicities, the implicated agents, incidence, usual clinical presentation, and recommendations for management.

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