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About the Antiretroviral Drug Profiles
Back to Drug Profiles
Introduction
Organization
Drug Names
Drug Classes
Background
Clinical Use
Related Resources
DHHS Guidelines
When to Start Treatment
Risks and Benefits of Therapy at CD4 > 350
ARV Therapy for Treatment Naive patients
Advantages and Disadvantages of Components of Initial Therapy
Not Recommended as Initial Therapy
Should Not be Offered at Any Time
Adverse Events of ARVs
Interactions Database
Stanford Resistance Figures/Notes
Introduction
Where it has succeeded, antiretroviral therapy has altered the nature of HIV disease, transforming an almost uniformly fatal illness into a chronic but apparently stable condition. How effective treatment can be made available to the great majority of people with HIV/AIDS is an urgent issue of global significance. Even where such treatment is available, however, its use is complicated by a number of factors, including side effects, drug-drug interactions, and the selection of drug-resistant virus.

These discussions present some of the practical issues associated with the clinical use of antiretroviral drugs for the treatment of HIV-1 infection. Not all information used in clinical decision making fits comfortably into the tables of a pocket guide or a database. These narratives include information that may be useful in the formulation of treatment strategies when complete, quantitative data are not available.

The information presented is not intended to substitute for a thorough familiarity with the official labeling (package insert) of each drug. These discussions are not treatment recommendations or guidelines. Some of the information discussed may involve dosing or treatment strategies outside the approved labeling of the drugs or diagnostic tests in question. Such discussions reflect the opinions of the authors, not the views of the drug manufacturer or of any regulatory agency.

Organization
Information is organized in the following categories:
Drug Names
Names used in the United States for each drug or licensed combination of drugs are listed as follows:

The first name listed is the generic name, which, in the United States, is determined prior to licensing by the U.S. Adopted Name Council subject to the approval of the World Health Organization. The generic name remains in the public domain and is used by other companies producing the drug after the patent expires, or in countries where international trade agreements permit production of the drug outside U.S. patent protection.

The second name listed is the brand (proprietary or trademark) name, which is developed by the manufacturer as a marketing consideration, subject to the approval of the Food and Drug Administration (FDA). The brand name remains the property of the manufacturer. Proprietary names widely used outside the United States are also included.

When commonly used, the chemical name, abbreviations based on it, or the manufacturer's designation used in pre-marketing trials of the drug, may be listed following the brand name.

Drug Classes

The class of each drug appears after the name of the drug. There are currently 6 major classes of antiretroviral drugs: nucleoside analogue reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), fusion inhibitor, chemokine coreceptor antagonist (consisting of 2 subclasses: CCR5 antagonist and CXCR4 antagonist), and integrase inhibitor.

NRTIs function by inhibiting the synthesis of DNA by reverse transcriptase, the viral enzyme that copies viral RNA into DNA in newly infected cells. Nucleoside analogues bear a structural resemblance to the natural building blocks of DNA: the nucleosides adenosine and guanosine, thymidine and cytidine. Nucleoside analogues are triphosphorylated within the cell, and some undergo further modifications (didanosine, for example, is converted into its active moiety, 2',3'-dideoxyadenosine-5'-triphosphate). Nucleotide analogues resemble monophosphorylated nucleosides, and therefore require only 2 additional phosphorylations to become active inhibitors of DNA synthesis. Reverse transcriptase fails to distinguish the phosphorylated NRTIs from their natural counterparts, and attempts to use the drugs in the synthesis of viral DNA. When an NRTI is incorporated into a strand of DNA being synthesized, the addition of further nucleotides is prevented, and a full-length copy of the viral DNA is not produced.

NNRTIs also inhibit the synthesis of viral DNA, but rather than act as false nucleotides, the NNRTIs bind to reverse transcriptase in a way that inhibits the enzyme's activity.

PIs bind to the active site of the viral protease enzyme, preventing the processing of viral proteins into functional conformations. Viral particles are still produced when the protease is inhibited, but these particles are not effective at infecting new cells.

Fusion inhibitors prevent HIV from entering target cells. Drugs of this class bind to the HIV envelope protein gp41, which is involved in viral entry. By blocking the interactions between regions of the gp41 molecule, fusion inhibitors interfere with the conformational change (folding) of the envelope molecule required for fusion with the target cell membrane.

Chemokine coreceptor antagonists also prevent the entry of HIV into target cells. They bind to coreceptors (either CCR5 or CXCR4) on the surface of CD4 cells. By doing so, they block a required step in viral entry. In contrast to drugs from other classes, which act on viral enzymes, coreceptor antagonists bind human proteins.

Integrase inhibitors bind a viral enzyme known as integrase and interfere with the incorporation of reverse-transcribed HIV DNA into the chromosomes of host cells.

Background
The drug's availability and use over time are discussed, including date of initial FDA approval, initial evidence of efficacy, formulations available, and variations in dosing since initial approval.
Clinical Use
This section includes factors relevant to selecting each drug as part of an antiretroviral combination regimen, including:

Potential combinations using the drug, and factors favoring or disfavoring their use, including overlapping toxicities and drug interactions;
Evidence and arguments concerning use of the drug in initial ("first-line") regimens, including status in recommendations of the U.S. Department of Health and Human Services (DHHS) treatment guidelines, and concerning use of the drug in subsequent ("salvage") regimens;
Drug characteristics affecting adherence, including common side effects;
Issues related to drug resistance, including:
Implications of resistance to the drug in question for subsequent treatment with other antiretrovirals;
Implications of pre-existing resistance to other antiretrovirals for treatment with the drug in question;
Special uses, if any (for example, prevention of mother-to-child transmission, postexposure prophylaxis, treatment of coinfection with hepatitis B, etc).