Therapeutic Drug Monitoring in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS). HIV is an RNA virus (ie, 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 40 million people are infected with the HIV virus, of which more than 28 million are from Sub-Saharan Africa. In North America, AIDS was first reported in the early 1980s, and today there are more than 940 000 people infected with HIV on the continent.12The 2 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.4When people with HIV and opportunistic infections have low CD4 counts (<200 cells/μL), they are said to have AIDS.5–9 Therapy for HIV/AIDS requires both virologic control and prevention of opportunistic infections. Three classes of drugs are used today to treat people with AIDS: nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (also known as AZT), didanosine (also known as ddI), zalcitabine (also known as ddC), stavudine (also known as d4T), and lamivudine (also known as 3TC); the nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine, delavirdine, and efavirenz; and the protease inhibitors (PIs), such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. Treatment of HIV recommended by the Public Health Service Guidelines (2001) calls for the use of multiple-drug regimens using 3 to 4 drugs and both reverse transcriptase inhibitors and PIs; this approach is referred to as highly active antiretroviral therapy. Currently, AIDS drug therapy is followed by measuring both CD4 counts and viral loads.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. Due to interindividual and intraindividual differences in drug disposition, it is impossible to predict a serum concentration for a given drug dose. A reliable method should be available for drug measurement.10 Also, 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 2 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% to 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.Therapeutic drug monitoring permits timely dosage adjustments based on individual plasma concentrations to prevent prolonged exposure to toxic or subtherapeutic concentrations of drug. Numerous studies have shown lack of adequate viral suppression in the absence of TDM.17–20 The PIs and NNRTIs show a concentration-effect relationship,151621–25 while large interindividual and intraindividual differences have been observed in many of the AIDS drugs with regard to drug disposition, making prediction of a plasma concentration for any given dose exceedingly difficult.26–29 Finally, a narrow therapeutic index is seen for the majority of the antiretroviral drugs, with toxicities ranging from nausea and vomiting, to pancreatitis, nephrolithiasis, and neurologic effects.8–101223 The ATHENA study in the Netherlands16 was a randomized, prospective clinical trial and evaluated the role of TDM in the management of HIV-1–infected patients. The outcomes in the TDM cohort were significantly better than those of the non-TDM group. This finding is all the more impressive, considering less than 20% of the physicians responded to the dosing recommendations of the intervention group.13Methods for antiretroviral drug quantitation include high-performance liquid chromatography and tandem-mass spectrometry (MS)/MS.30–33 The tandem-MS/MS procedure33 developed by one of us (S.J.S.) is simple and allows for the quantitation of 15 AIDS drugs simultaneously in less than 5 minutes. This procedure also affords better sensitivity and specificity than the high-performance liquid chromatography methods, which also require lengthy sample preparation steps, relatively large sample volumes, and are far more labor-intensive.30 The tandem-MS/MS method is reliable and has been in routine use at Children's National Medical Center (Washington, DC) since February 2002. Since high-performance liquid chromatography–tandem-MS/MS is fairly costly, we use the same system to monitor both the AIDS drugs and the 3 major immunosuppressants (cyclosporine, tacrolimus, and sirolimus).34The ideal sample is that drawn at steady state just before the next dose (steady-state trough sample). Steady state is reached after an interval of 5 drug half-lives have elapsed, which for most of these drugs is less than 48 hours. Exceptions to this rule have to be made for nevirapine (an NNRTI) and saquinavir (a PI), both of which have longer half-lives and should not be monitored until 4 days after initiation of the drug regimen. Most of the PIs have in vitro 95% inhibitory concentrations of approximately 100 ng/mL. At Children's National Medical Center, the lower limit of the therapeutic range for the PIs is taken as 150 ng/mL. For the upper limit, we recurrently recommend concentrations less than 6000 ng/mL, except for lopinavir, which we recommend should be maintained at concentrations less than 12 000 ng/mL. These values are gleaned from the literature and are tentative therapeutic ranges.8912–1621–29 For the NNRTIs, we currently recommend tentative therapeutic ranges between 1200 and 7000 ng/mL.These drugs are metabolized by CYP 450, 2B6, 1A2, 2A6, 2C, and 2D6 (efavirenz, nevirapine, nelfinavir, and ritonavir) and by 3A, particularly 3A4 (indinavir, delavirdine, ritonavir, nevirapine, saquinavir, and nelfinavir). Significant drug-drug interactions occur again, emphasizing the need for TDM. The PIs are also strongly protein-bound to α1-acid glycoprotein, which is an acute-phase reactant (>98% except for indinavir [65%], raising the possibility of the need to measure free drug concentrations for this group).External proficiency testing for the AIDS drugs is available from the International Quality Control Program for Therapeutic Drug Monitoring in HIV Infection (University Medical Center Nijmegan, Department of Clinical Pharmacy, PO Box 9101, 6500 HB Nijmegan, The Netherlands). Currently, more than 40 laboratories worldwide are enrolled in this program. Drug standards can be obtained from the National Institutes of Health AIDS Reagent Reference Program (McKesson HBOC BioServices, Rockville, Md).We have demonstrated at Children's National Medical Center that TDM for AIDS drugs can be useful not only to detect patient noncompliance, but also to adjust doses for the PIs and NNRTIs so that optimal response as measured by CD4 counts and viral loads is obtained.