Therapeutic Drug Monitoring in Human Immunodeficiency Virus Acquired Immunodeficiency

Steven J. Soldin, PhD, ABCC, FACB

Contents

1. Introduction

2. Role of Therapeutic Drug Monitoring in Patients with AIDS

3. Conclusion

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), and it is estimated that 42 million people are infected with HIV. Four classes of drugs are used today to treat people with AIDS; nucleoside reverse transcriptase (NRTIs), non-NRTIs (NNRTIs), protease inhibitors (PIs), and entry blockers (EIs). Evidence is accumulating that both PIs and NNRTIs are good candidates for therapeutic drug monitoring (TDM). However, there is little evidence suggesting that TDM of NRTIs would be helpful other than to assess compliance/adherence to the drug regime. There is no commercially available immunoassay for routine monitoring of antiretrovirals in serum. The current methods for TDM of these drugs include high-performance liquid chromatography (HPLC) and tandem mass spectrometry. Tandem mass spectrometry is a superior technique to HPLC for analysis of these antiretrovirals.

Key Words: HIV; AIDS; nonnucleoside reverse transcriptase; nucleoside reverse transcriptase; protease inhibitors; entry blockers; HPLC; Tandem-MS.

Human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS). HIV is an RNA virus (i.e., it carries its genetic code in the form of RNA) and falls under the family of retroviruses. Retroviruses use RNA and an enzyme called reverse transcriptase to create DNA and then invade the genome. Worldwide, it is estimated that more than 42 million people are infected with HIV, of which more than 28 million are from Sub-Saharan Africa. In North America, AIDS

Summary

1. INTRODUCTION

From: Handbook of Drug Monitoring Methods Edited by: A. Dasgupta © Humana Press Inc., Totowa, NJ

Table 1

Classes of Drugs Used to Treat HIV/AIDS

Nucleoside Analogues (NRTIs) AZT-Zidovudine (1987) Ddl—Didanosine DdC—Zalcitabine d4T—Stavudine

3TC—Lamivudine (AIDS and hepatitis) ABC—Abacavir TNF—Tenofovir

Nonnucleoside Analogues (NNRTIs)

Nevirapine (1996)

Delavirdine

Efavirenz

Protease Inhibitors (PIs) Saquinavir (1995) Ritonavir Indinavir Nelfinavir Amprenavir Lopinavir Atazanavir Tipranavir

Entry Inhibitors (EIs) T-20 (2003) peptide T

was first reported in the early 1980s, and today there are more than 940,000 people infected with HIV on the continent (1,2). The two forms of HIV are HIV-1 and HIV-2 (3). Disease caused by the latter tends to be less severe, and it is rarely found outside Africa. HIV kills an important kind of lymphocyte, the CD4 T lymphocyte. These cells are critical for the adequate functioning of the immune system. As the CD4 cells decrease in number, the body becomes vulnerable to opportunistic infections (4). When people with HIV and opportunistic infections have low CD4 counts (200cells/mL), they are said to have AIDS (5-9). Therapy for HIV/AIDS requires both virologic control and prevention of opportunistic infections. Four classes of drugs are used today

Table 2

Some Pharmacokinetic Parameters for Antiretroviral

Table 2

Some Pharmacokinetic Parameters for Antiretroviral

Protein Binding

Drug (mg/L)

C max (mg/L)

C min

Half-life (h)

Percentage

Vd (L/Kg)

NRTIs

Didanosine

2.4

0.1

1.5

<5

0.8

Lamivudine

1.8

0.1

6

<5

?

Stavudine

2.0

0.02

1.1

<5

1.0

Zalcitabine

<0.025

Undetectable

2.0

<5

0.5

Zidovudine

1.8

<0.02

1.2

<5

1.4

NNRTIs

Delavirdine

16

3.0

6

99

?

Nevirapine

20

3.0

30

60

1.2

PIs

Indinavir

10

0.1

1.8

?

?

Nelfinavir

4

1.0

5

93

4

Ritonavir

14

1.0

4

98

0.4

Saquinavir

0.5

0.015

12

98

10

to treat people with AIDS (see Table 1): nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (also known as AZT), which was the first NRTI to be introduced in 1987, didanosine (also known as ddl), zalcitabine (also known as ddC), stavudine (also known as d4T), and lamivudine (also known as3TC); the non-NRTI inhibitors (NNRTIs), which include nevirapine, introduced in 1996, delavirdine, and efavirenz; the protease inhibitors (PIs), the first of which saquinavir was introduced in 1995, and include ritonavir, indinavir, nelfinavir, amprenavir, lopinavir and atazanavir, and the entry blockers (EIs) such as T-20 introduced in 2003 and peptide T. Table 2 summarizes some pharmacokinetic parameters for HIV drugs.

Treatment of HIV recommended by the Public Health Service Guidelines (2001) calls for the use of multiple drug regimens using 3-9 drugs and both reverse transcriptase inhibitors and PIs; this approach is referred to as highly active antiretro-viral therapy. Currently, AIDS drug therapy is followed by measuring both CD4 counts and viral loads.

2. ROLE OF THERAPEUTIC DRUG MONITORING IN PATIENTS WITH AIDS

Rationale: Several criteria are necessary for therapeutic drug monitoring (TDM). A good relationship should exist between drug concentration and pharmacologic effect. That is, there should be a concentration range at which the drug is subtherapeutic, a range at which it is therapeutic, and a range at which it is toxic. Also, one should not be able to predict a serum concentration for a given drug dose. A reliable method should be available for drug measurement (10), and a procedure should be available to assess the outcome of highly active antiretroviral therapy. Evidence is accumulating that both the PIs and the NNRTIs meet these requirements (8-16). Outcomes are assessed by two different measures, namely, CD4 counts and viral loads. The NRTIs are active as the intracellular triphosphates, and there is little evidence today to suggest that their measurement would be helpful other than to assess compliance/adherence to the drug regimen. Noncompliance is a serious problem and occurs in 33-60% of the patient population (8-10). Common reasons for missing doses include clinical toxicity, forgetfulness, sleeping through the time of prescribed dose, and being away from home.

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