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Antiretroviral Drugs

From the Mayo Clinic and Foundation, Rochester, Minnesota.

Address for correspondence: Zelalem Temesgen, MD, AAHIVS, Mayo Clinic and Foundation, Division of Infectious Diseases, 200 First Street SW, Rochester, MN 55905; e-mail: temesgen.zelalem{at}mayo.edu.

	ABSTRACT

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
The first antiretroviral drug to be licensed, zidovudine, became available in 1987. Until December 1995, the antiretroviral drugs available and approved for clinical use in the United States consisted of only 5 individual drugs belonging to a single class of antiretroviral agents, nucleoside analog reverse transcriptase inhibitors. Since then, numerous other antiretroviral drugs and classes of antiretroviral drugs have been introduced. Additional drugs and newer classes of antiretrovirals are in various stages of development. Currently, there are 22 Food and Drug Administration (FDA)-approved antiretroviral agents categorized in 4 classes of drugs: nucleoside/nucleotide analog reverse transcriptase inhibitors, nonnucleoside analog reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. The authors review the general characteristics of each class of antiretroviral drugs, including mechanism of action, pharmacologic properties, adverse effects, and drug interactions. A synopsis of current antiretroviral treatment guidelines is also provided.

Key Words: antiretrovirals • HIV • nucleoside analog reverse transcriptase inhibitors • nonnucleoside reverse transcriptase inhibitors • protease inhibitors • fusion inhibitors

	THE REPLICATION CYCLE OF HIV

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
A working knowledge of the HIV replication cycle is essential for understanding the mechanism of action of antiretrovirals.³ Figure 1 depicts a simplified schema of the HIV life cycle. The human immunodeficiency virus is an enveloped virus that contains 2 copies of viral genomic RNA in its core. In addition to the copies of RNA, the viral core also contains enzymes required for HIV replication—reverse transcriptase, integrase, and protease. The first step in the HIV replication cycle is the interaction between the envelope proteins of the virus and specific host-cell surface receptors (eg, CD4 receptor) of the host cell. In the second step, the virus binds to the chemokine coreceptors CXCR4 and CCR5, resulting in conformational changes in the envelope proteins. This ultimately results in the "fusion" of the viral envelope and the host cytoplasmic membrane. Fusion creates a pore through which the viral capsid enters the cell. Following entry into the cell, the viral reverse transcriptase enzyme catalyzes the conversion of viral RNA into DNA. This viral DNA enters the nucleus and becomes inserted into the chromosomal DNA of the host cell (integration). This process is facilitated by the viral enzyme integrase. Expression of the viral genes leads to production of precursor viral proteins. These proteins and viral RNA are assembled at the cell surface into new viral particles and leave the host cell by a process called budding. During the process of budding, they acquire the outer layer and envelope. At this stage, the protease enzyme cleaves the precursor viral proteins into their mature products. If this final phase of the replication cycle does not take place, the released viral particles are noninfectious and not competent to initiate the replication cycle in other susceptible cells.

View larger version (57K): [in this window] [in a new window]   Figure 1. Simplified schema of HIV-1 life cycle. The interaction between the envelope proteins of the virus and CD4 receptor and coreceptors of the host cell leads to the binding of the viral envelope and the host cytoplasmic membrane. The viral reverse transcriptase enzyme catalyzes the conversion of viral RNA into DNA. The proviral DNA enters the nucleus and becomes integrated into the chromosomal DNA of the host cell. This process is catalyzed by the viral enzyme integrase. Expression of the viral genes leads to production of viral RNA and proteins. The protease enzyme cleaves the precursor gag and gag-pol proteins into functional mature products. Viral proteins as well as viral RNA are assembled at the cell surface into new viral particles and leave the host cell by a process called budding. During the process of budding, they acquire the outer layer and envelope. Source: Temesgen Z. HIV infection. In: Habermann TJ, ed. Mayo Clinic Internal Medicine Review 2006-2007. 7th ed. Rochester, Minn: Mayo Clinic Scientific Press; 2006:465-491. Used with permission of the Mayo Foundation for Medical Education and Research.

At present, 4 classes of antiretroviral drugs have received FDA approval: nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), nonnucleoside analog reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors. Numerous investigational drug candidates both within existing classes as well as within new classes that exploit our understanding of the HIV replication cycle are in various stages of preclinical and clinical development. Among those that are in the final stages of clinical development are integrase and CCR5 inhibitors.

	NUCLEOSIDE/NUCLEOTIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORS

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
Nucleoside analog reverse transcriptase inhibitors are the first antiretroviral drugs to be approved for the treatment of HIV. The prototype drug in this class, zidovudine, was approved in 1987. The designation nucleoside analog refers to the structural similarity of these drugs to the building blocks of nucleic acids (RNA, DNA) from which they differ by the replacement of the hydroxy (-OH) group in the 3' position by another group that is unable to form the 5' to 3' phosphodiester linkage essential for DNA elongation. Thus, NRTIs interfere with reverse transcriptase activity by competing with the natural substrates and incorporating into viral DNA to act as chain terminators in the synthesis of proviral DNA.⁴ To exert their antiviral activity, NRTIs must first be intracellularly phosphorylated to their active 5' triphosphate forms by cellular kinases.⁵ Tenofovir is the only nucleotide analog reverse transcriptase inhibitor to date. Because it already contains a phosphate molecule in its structure, it only requires phosphorylation by cellular enzymes to its diphosphate form for its antiviral activity. Currently, there are 8 individual NRTIs and 5 coformulated products approved for the treatment of HIV. The production of one of the earlier NRTIs, zalcitabine, has been discontinued; it is no longer used in clinical practice because of its weak antiviral activity and unfavorable pharmacokinetic and toxicity profile.

General characteristics of NRTIs are shown in Table II. Kidneys are the primary route for elimination of all NRTIs. Thus, dose adjustment is required in renal insufficiency for all NRTIs with the exception of abacavir.

Table III lists major adverse reactions associated with NRTIs. One notable classwide adverse effect is mitochondrial toxicity, which is responsible for the clinical syndromes of lactic acidosis with hepatic steatosis, peripheral neuropathy, and lipoatrophy. Although this toxicity is a classwide toxicity, stavudine (d4T), didanosine (ddI), and zalcitabine (ddC) are the drugs most frequently associated with it. Lamivudine (3TC), abacavir (ABC), tenofovir (TDF), and emtricitabine (FTC) are the NNRTIs with low mitochondrial toxicity potential.

Select drug interactions associated with NRTIs are detailed in Table IV.

	NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
Nonnucleoside reverse transcriptase inhibitors bind directly and noncompetitively to the enzyme reverse transcriptase.^6,7 Although these drugs differ structurally from each other, they all share the same mechanism of action, binding to a site on the reverse transcriptase enzyme that is distinct from the substrate (dNTP) binding site and blocking DNA polymerase activity by causing a conformational change and disrupting the catalytic site of the enzyme.⁸ Unlike nucleoside analogs, NNRTIs do not require phosphorylation to become active and are not incorporated into viral DNA. They also have no activity against HIV-2.⁹ There are 3 NNRTIs approved for the treatment of HIV at the present time: nevirapine, delavirdine, and efavirenz. Similar to zalcitabine, delavirdine is rarely used in clinical practice because of its relatively low potency and large pill burden.

Drug interactions are important considerations with NNRTIs.¹⁰ Nevirapine (NVP) and efavirenz (EFV) are inducers of the hepatic cytochrome CYP3A4. Delavirdine, on the other hand, inhibits CYP3A4.¹¹ Efavirenz also inhibits CYP2C9 and CYP2C19, albeit to a lesser extent. Both NVP and EFV are metabolized by CYP2B6 as well as CYP3A4. Through this complex interaction with the P450 enzyme system, NNRTIs may change the metabolism of and thus lower (nevirapine, efavirenz) or increase (delavirdine) the plasma levels of coadministered drugs that are metabolized by the cytochrome P450 system. Similarly, drugs that induce or inhibit cytochrome P450 activity may have an effect on the plasma concentrations of NNRTIs. Nonnucleoside reverse transcriptase inhibitors do not require dose adjustment in case of renal insufficiency as their primary route of elimination is hepatic.

The most common side effect associated with all NNRTIs is rash. Rash usually occurs within the first 6 weeks of initiation of therapy and has been noted in up to 35% of patients receiving nevirapine.^12,13 Nevirapine is also associated with hepatotoxicity, particularly in women with CD4 counts higher than 250 cells/mm³ and men with CD4 counts above 400 cells/mm³.^14,15 The risk of hepatotoxicity is greatest in the first 6 weeks of therapy. However, it may occur at any time during treatment and in some cases may not be reversible with discontinuation of therapy. Rash was observed in approximately half of the patients with symptomatic hepatotoxicity.

Efavirenz, on the other hand, has been commonly associated with central nervous system (CNS) side effects, ranging from dizziness to hallucinations, insomnia, nightmares, and worsening of psychiatric illnesses.¹⁶ These CNS side effects are more common during the first 2 weeks of therapy and usually resolve by 24 weeks. Efavirenz also causes fetal malformations in pregnant monkeys and neural tube defects in children of pregnant women who received it.^17,18 The risk of hepatotoxicity appears to be less with efavirenz as compared to nevirapine.¹⁹

The general characteristics of currently approved NNRTIs are listed in Table V. Table VI lists selected drug interactions associated with NNRTIs.

	PROTEASE INHIBITORS

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
HIV-1 protease is a complex enzyme composed of 2 identical halves (ie, a symmetrical dimer) with an active site located at the base of the cleft.²⁰ It is responsible for the cleavage of the large viral precursor polypeptide chains into smaller, functional proteins, thus allowing maturation of the HIV virion. This process takes place in the final stages of the HIV life cycle. Inhibition of the protease enzyme results in the release of structurally disorganized and noninfectious viral particles.²¹ There are 10 PIs currently approved for clinical use. The availability of fosamprenavir, with an improved pharmacokinetic profile compared to its active metabolite amprenavir, has led to the manufacturer ceasing production of amprenavir. At the present time, fosamprenavir is the only amprenavir product available for adult dosing. Full-dose ritonavir is no longer used for its antiviral effects. Its current utility is solely to enhance the pharmacokinetics of other protease inhibitors given concurrently.

Drug interactions are important considerations with the use of PIs. Protease inhibitors are substrates for the cytochrome P450 system (primarily CYP3A4) and are themselves, to varying degrees, inhibitors of this system, with ritonavir being the most potent inhibitor. Some PIs, such as lopinavir and tipranavir, are also inducers of CYP3A4. This leads to a significant number of interactions with drugs that are inducers, inhibitors, or substrates of this system. The inhibitory effect of protease inhibitors on each other's metabolism has led to the evaluation of specific combinations that provide an advantageous pharmacokinetic profile, may delay or prevent the onset of resistance, and allow for dose reductions, more convenient dosing regimens, and less toxicity.^22-24 All currently licensed protease inhibitors are commonly prescribed as boosted agents with the exception of nelfinavir, which is not well and reliably augmented by ritonavir. In fact, 3 protease inhibitors—lopinavir, tipranavir, and darunavir—require coadministration with ritonavir to achieve effective serum concentrations. Lopinavir is currently available as a coformulated product, with each tablet containing 200 mg of lopinavir and 50 mg of ritonavir.

General characteristics of currently available protease inhibitors are listed in Table VII. Table VIII lists major adverse reactions associated with PIs. Select drugs that should not be coadministered with PIs are detailed in Table IX. Select drugs that require monitoring or dose adjustment when coadministered with PIs are shown in Table X.

	FUSION INHIBITORS

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
The HIV membrane consists of 2 glycoproteins, gp120 and gp41.^25,26 In each envelope structure, gp120 molecules make up the cap, and the stalk is formed by gp41 anchored in the viral lipid bilayer. Upon binding of gp120 to CD4 and chemokine receptors, a critical conformational change occurs in the structure of gp41. The 2 different peptide motifs of gp41, heptad repeat (HR) 1 and 2, unite to form a 6-helix bundle hairpin structure, which then pulls the membranes of the virus and cell closer, resulting in membrane fusion. Enfuvirtide (also known as T-20) is the first, and thus far the only, fusion inhibitor to be approved by the FDA. It is a linear 36-amino acid peptide homologous to a segment of the HR2 region of gp41. It binds to the HR1 region of gp41 and blocks the formation of the 6-helix bundle necessary for fusion. Enfuvirtide is indicated for the treatment of HIV-1 infection in treatment-experienced patients. It is not active against HIV-2. Enfuvirtide is not orally bioavailable. Therefore, it has to be administered as a subcutaneous injection. Its bioavailability after a subcutaneous injection is 84%. It is metabolized by hydrolysis and does not inhibit cytochrome P450 isoenzymes. Enfuvirtide's postsubcutaneous administration elimination half-life is 3.8 hours. Thus, injections are administered twice daily. Injection site reactions (ISRs) are the most common adverse events reported with the use of enfuvirtide. Their manifestation includes erythema, induration, ecchymosis, nodules, or cysts and may present with symptoms of pruritus, pain, or discomfort. A needle-free drug delivery system that may decrease the impact of ISRs is under investigation. Bacterial pneumonia (both gram positive and gram negative) has been observed in patients taking enfuvirtide. Rare cases of systemic hypersensitivity reactions to enfuvirtide have also been reported. These presented with rash, fever, nausea/vomiting, chills, rig-ors, hypotension, and elevated liver enzymes.²⁷

	GUIDELINES ON THE USE OF ANTIRETROVIRAL THERAPY FOR HIV INFECTION

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
There is a general consensus for treating patients with symptoms ascribed to HIV infection. Current Department of Health and Human Services (DHHS) guidelines recommend antiretroviral therapy for all patients with a history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count.²⁸ Opinions on when to start antiretroviral therapy in asymptomatic patients have varied widely, ranging from the "treat early, treat hard" approach of the early HAART years with an emphasis on HIV-1 RNA values to the current, more conservative guidelines delaying therapy until a certain threshold of CD4 cell counts has been reached. Current recommendations of when to start treatment of HIV are based on estimates of the risks of developing AIDS or death. These estimates were made through analysis of data obtained from observational cohorts of HIV-infected persons. The CD4 cell count appears to be a much more important prognostic indicator of disease progression than viral load, but an HIV-1 RNA (viral load) value of >100 000 copies/mL was also independently associated with a greater likelihood of disease progression. For example, the 3-year probability of disease progression for those patients with a CD4 cell count between 100 and 199 cells/mm³ is 9.3% compared to a probability of 3.4% for those with CD4 cell counts >350 cells/mm³. This risk increases to 12% and 4.4%, respectively, if the viral load is >100 000 copies/mL. Current DHHS guidelines recommend initiating antiretroviral therapy in otherwise asymptomatic patients with <200 CD4+ T cells/mm³. The evidence for initiating therapy in asymptomatic HIV-infected persons with a CD4+ T cell count of 200 to 350 cells/mm³ is less strong. However, many HIV clinicians prescribe antiretroviral therapy for such patients. The evidence for initiating antiretroviral therapy for those who have CD4 cell counts above 350 cells/mm³ but also have viral loads >100 000 copies/mL is even less compelling. Many clinicians defer therapy in these patients. It should be emphasized that patients must actively participate in all these decisions, understand the benefits and risks of treatment, and make an informed commitment to a complex long-term treatment.

The latest (October 10, 2006) DHHS-recommended preferred regimens for first-line antiretroviral therapy are listed in Table XI. These regimens attained "preferred" status because they have clinical trial data support for their efficacy, durability of effect, tolerability, and ease of use. The regimens are either NNRTI based or PI based with a backbone of 2 NRTI drugs. Efavirenz is the preferred NNRTI, whereas lopinavir/ritonavir, fosamprenavir/ritonavir, and atazanavir/ritonavir are the preferred PIs. Zidovudine or tenofovir plus lamivudine or emtricitabine make up the preferred nucleoside backbone. In general, in patients with adequate kidney function, coformulated NRTI products are preferred over single-drug formulations for reasons of reduced pill burden and simplicity of regimen.

	SUMMARY

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
Currently, there are 22 antiretroviral agents available for clinical use. Several others are in various stages of basic and clinical development. Understanding how these drugs work, what their potential adverse effects are, and how they interact with each other as well as other concomitantly administered drugs is critical to a successful treatment outcome.

	ACKNOWLEDGEMENTS

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 
Financial disclosure: Dr Temesgen has received research and educational grants and has served on advisory boards for Abbott Pharmaceuticals, Gilead Sciences, Bristol Myers Squibb, Merck, and Tibotec.

	REFERENCES

TOP ABSTRACT THE REPLICATION CYCLE OF... NUCLEOSIDE/NUCLEOTIDE ANALOG... NONNUCLEOSIDE REVERSE... PROTEASE INHIBITORS FUSION INHIBITORS GUIDELINES ON THE USE... SUMMARY ACKNOWLEDGEMENTS REFERENCES

 

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