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Is the Treatment of HIV with Protease Inhibitors
smashed any hope that an antiretroviral drug could effectively rid the Superior to that of Reverse Transcriptase Inhibitors?
body of HIV. Furthermore, the rate at which the virus mutates and its resistance to any single antiretroviral drug cause an urgency in the production of medications that could effectively suppress the virus to an undetectable level with minimal side effects. Hence, since then many daughter drugs of AZT and drugs that target other areas of the life cycle of the virus have been developed. Currently, there are two types of HIV drugs: reverse transcriptase inhibitors and protease inhibitors. This research paper aims to show the effectiveness of these two types of treatment and to investigate whether the treatment of the virus using protease inhibitors is superior to that using reverse transcriptase Abstract
inhibitors. However, in order to understand how the two different inhibitors of the virus work, it is imperative to understand the structure The development of antiretroviral drugs has revolutionized the treatment and the life cycle of the virus. Hence, the paper first targets the structure of HIV. Currently, there are two categories of antiretroviral drugs and life cycle HIV, tracing how HIV affects the body before introducing available to suppress the replication of the virus: reverse transcriptase the medications that have been developed to suppress the virus. inhibitors and protease inhibitors. This paper aims to determine whether Furthermore, the comparison of the two classes of antiretroviral the treatment of the virus with protease inhibitors is superior to medication is narrowed down to the analysis of two categories: side treatment using reverse transcriptase inhibitors. First, the effects of HIV effects and potential drug interactions. are presented. This encompasses the structure and life cycle of virus. Next, the three classes of antiretroviral drugs are introduced, which are then compared according to their adverse drug reactions and interactions. Lastly, the conclusion evaluates the superiority of the HIV and AIDS are often times used interchangeably. However, protease inhibitors to the reverse transcriptase inhibitors. AIDS is caused by the human immunodeficiency virus (HIV), which affects and weakens the body’s immune system, allowing the body to develop life-threatening infections and cancers. The term AIDS, Introduction
Acquired Immune Deficiency Syndrome, is used to define the most advanced stages of the HIV infection, that is, it applies to people who HIV/AIDS is one of the world’s greatest threats for which there is no have encountered serious complications due to HIV (HIV Infection and cure. The disease, which was initially stereotyped to the gay community, has now wreaked havoc on many underdeveloped and developing nations with an estimate of 3.1 million deaths in 2004 (UNAIDS, 2004). Virus Structure
Despite an increase in the international spending to combat AIDS from 250 million dollars in 1998 to 4.8 billion dollars in 2002, the United HIV is thought to contain two identical copies of single-stranded RNA, Nations reports that the rate of infection still continues to rise (UNAIDS, approximately 9500 nucleotides in length, which may be linked together 2004). In addition, the Joint United Nations Programme on HIV/AIDS, to form a genomic RNA dimer (Human Immunodeficiency Virus: UNAIDS, has estimated the number of people living with HIV/AIDS in Structure and Pictures, n.d.). The two strands of RNA are associated with 2004 to be 39.4 million, which includes the 4.9 million people who a nucleocapsid protein and are found within a bullet-shaped capsid along acquired the disease in 2004 (UNAIDS, 2004). with other viral proteins, such as integrase and reverse transcriptase, In 1987 AZT was the first antiretroviral drug to be approved by which are essential for the maturation of the virus. The capsid is engulfed the FDA and gave great hope for the eradication of the virus (Bartlett, by a layer of matrix protein that is directly attached to the envelope of the 2001). However, the virus quickly developed resistance to the drug and virus. The HIV envelope is a phospholipid bilayer that was derived from the host cell as the virus budded out. Throughout the HIV envelope are where it integrates itself into the cell’s genome using the integrase peg-like structures that consist of three or four gp41 glycoproteins stems enzyme, which was also deposited into the cell during penetration. The capped with three or four gp120 glycoproteins (The Structure and Life of genetic make-up of the cell is now known as a provirus, that is, it is HIV, 2004). These glycoproteins are antireceptors, that is, they are retroviral DNA that has been integrated into the human genome involved in the attachment and fusion of the virus to the host cell. The virus now latently infects the host, that is, it remains HIV Infection: The HIV Life Cycle
dormant in the host cell’s genome until the cell becomes activated. The latency period of the life cycle of HIV, which varies, allows the virus to HIV is a lentivirus, which is a subgroup of retroviruses known for their replicate and multiply when the genome of the host cell is replicated and latency upon infection, persistent presence in the blood of the host, multiplied. Once the cell becomes activated, the virus uses the machinery infection of the nervous system, and the debilitation of the host’s of the cell to produce proteins, which are compiled to make new virons, immune system (Dubin, 2004). Retroviruses contain RNA as their virus particles. This process is implemented when the viral DNA is genetic make up and the reverse transcriptase enzyme, which they use to transcribed back to two strands of RNA, which are transported out of the convert their genome to DNA. HIV interacts with its host cells by nucleus. One strand is called a messenger RNA and the other strand binding to special receptors known as CD4 receptors that are found on represents the viral genome that is packed into new viral particles. Viral white blood cells known as helper T lymphocytes or helper T cells or messenger RNAs, like all other messenger RNAs, are composed of CD4+ cells, which play an integral role in coordinating the body’s regions known as codons that “code” for various proteins. In the case of HIV, the messenger RNA codes for proteins critical to the maturation of Furthermore, the virus may target other cells involved in the the virus: protease, integrase and reverse transcriptase (The Structure and body’s immune system, such as monocytes and macrophages (The Life Cycle of HIV, 2004). Proteases are enzymes that cleave long strands Structure and Life of HIV, 2004). In addition to binding to CD4 of proteins, known as polyproteins, to produce functional proteins. receptors on the host cell using its gp120 glycoproteins, interactions with Hence, the viral protease cleaves the viral proteins to produce functional co-receptors such as CCR5 or CXCR4 are needed for the virus to enter products, which assemble at the cell membrane of the host cell (Gelman, the host cell (Gandhi et al., 1999). The CCR5 co-receptor has been 2004). The final stage of the life cycle of the virus results in the budding shown to be critically involved in the binding of the virus to the host cell, of the viron out of the host cell. This occurs when functional products since individuals’ hemizygous for mutations in the CCR5 region are attach to the cell membrane to allow the formation of the nucleocaspid. resistant to infection by HIV (Pieribone, 2002/2003). Upon binding to The nucleocaspid then merges with the cell membrane and buds off the the receptors and co-receptors, the viral envelope fuses with the cell cells. Ultimately, the infected host helper T cells die and the body’s membrane of the host cell allowing viral penetration to occur, that is, the immune system weakens (Ghandhi et al., 1999). entry of the viral genome and viral proteins (the nucleocapsid of the virus) into the cytoplasm of the cell (Pieribone, 2002/2003). The nucleocapsid is then partially dissolved to release the viral RNA and viral proteins. The viral genome is then transcribed to form double- In 1987, AZT (zidovudine) was the first antiretroviral drug to be stranded DNA using the reverse transcriptase enzyme, which was approved by the FDA (Bartlett, 2001). The success of the treatment of released into the host’s cytoplasm during penetration. The reverse HIV-positive patients with AZT brought forth hope of the complete transcriptase enzyme uses nucleotides, the building blocks of DNA, eradication of the virus, since it was thought that the half-life of infected found in the cell’s cytoplasm to make the double-stranded DNA CD4 cells was 10-14 days, and therefore treatment using antiretroviral (Pieribone, 2002/2003). During this process of transcription various drugs could eliminate the virus in 2-3 years. However, it has been found mutations occur in the viral genome (HIV, n.d.). This process of that the half-life of the infected cells ranges from 6-44 months. This, transcription of the viral genome from RNA to DNA is only possible along with the resistance of the drug, eliminated any hope for the because of the presence of the reverse transcriptase enzyme. Upon eradication of the virus from the body (HIV and AIDS, 2004). Hence, transcription, the double-stranded DNA travels to the nucleus of the cell there is currently no available treatment that will completely eradicate the HIV virus from the body. However, the treatments available aim to HIV’s viral DNA is unable to be integrated into the host cell’s genome drive the viral load, which is the number of virus present in the and ultimately reproduce. In addition, nucleoside RTIs, unlike nucleotide bloodstream, below any detectable limit, while increasing the CD4 cell RTIs, must first be phosphorylated to their active form before they can be incorporated into the viral DNA (Nucleoside/Nucleotide Reverse There are currently 20 approved antiretroviral drugs that belong Transcriptase Inhibitors, n.d.). However, NRTIs cannot completely stop to three different classes of drugs; that is, they target three different areas the reproduction of the virus. Hence, the viruses that continue to of the life cycle of the virus (USDHHS, 2004), as shown in Table 1 reproduce develop resistance to NRTIs due to the production of mutant (below). These three classes include reverse transcriptase inhibitors (RTIs), protease inhibitors (PIs) and fusion inhibitors (FIs). The reverse transcriptase inhibitors are further subdivided into two groups: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
nucleoside/nucleotide reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. This research paper focuses on the In 1996, NNRTIs or “non-nukes” were the second class of reverse transcriptase inhibitors and the protease inhibitors. antiretroviral drugs to be approved for treatment (Bartlett, 2001). There are currently three approved NNRTIs available for treatment of HIV Table 1: Drugs approved for HIV Infection infection (USDHHS, 2004). Like NRTIs, NNRTIs target the reverse Nucleoside/
transcriptase enzyme’s function of producing viral double-stranded Non-nucleoside RT
Protease
Nucleotide
Inhibitors
Inhibitors
Inhibitors
DNA. NNRTIs attach themselves to the enzyme, preventing it from RT Inhibitors
converting the viral RNA into DNA. Hence, once again the virus is unable to reproduce (Non-Nucleoside Reverse Transcriptase Inhibitors, n.d.). NNRTIs have been proven to be a very potent antiretroviral drug. However, resistance to the drugs occurs very easily if they are not taken as prescribed. In addition, the resistance to one NNRTI confers resistance to the entire class of NNRTIs (Non-Nucleoside Reverse Transcriptase Protease Inhibitors (PIs)
In 1996, PIs became the third class of antiretroviral medications Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
to be approved by the FDA (Bartlett, 2001). There are currently 9 available PIs available for the treatment of HIV (USDHHS, 2004). AZT, the first approved antiretroviral drug, is found in this class Compared to the NRTIs and NNRTI, PIs inhibitors target a different of drugs. There are 9 NRTIs available for the treatment of HIV infection stage of the life cycle of the virus. PIs inhibit the function of the protease (USDHHS, 2004). NRTIs are also referred to as nucleoside analogs or enzyme, which is essential to the maturation of new viral particles “nukes.” NRTIs target the stage of the life cycle when the reverse (Gelman, 2004). By binding to the protease enzyme, PIs prevent the transcriptase enzyme is converting the viral RNA to double-stranded enzyme from cleaving the viral proteins to produce the functional DNA, which is later integrated into host cell’s genome and used to create products that assemble to form the new viral particles (How the Protease new viral particles (Bartlett, 2001). NRTIs mimic the nucleotides used by Inhibitors Work, 1996). In addition PIs have been proven to be more the reverse transcriptase to create the double-stranded viral DNA, that is, potent than the nucleoside/nucleotide reverse transcriptase inhibitors they contain faulty versions of the nucleotides. Therefore, when the reverse transcriptase enzyme uses the NRTIs they disrupt the production of the viral DNA and cause early termination of the DNA. Hence, the and pancreas. In addition, when used in combination with PIs, NRTIs cause the loss and redistribution of fat, that is, lipodystrophy (Elion & The current guidelines for the commencement of antiretroviral Boyle, 2002). Furthermore, life threatening reactions are associcated treatment indicate that treatment is imperative for individuals with a CD4 with all NRTIs, whether it be from the allergic reactions associated with cell count below 200. However, treatment is only recommended for a Abacavir or the fatal pancreatitis associated with Didanosone. CD4 cell count above 200 if the viral load is above 55,000 (USDHHS, The long-term side effects of PIs include elevation of blood sugar level with development (or worsening) of diabetes, elevation of Comparative studies have been conducted in order to investigate body fat (triglycerides) and cholesterol and lipodystrophy (Vernochet et the most effective HIV antiretroviral drug in terms of virological efficacy al., 2004). In addition, less common side effects caused by PIs include and tolerability. The results have shown that monotherapy and dual liver toxicity and bone damage. However, six out of nine PIs have not therapies, that is, therapies that involve the use of one or two been labeled with any pertinent “black box warning” (any special antiretroviral drugs, are not as effective as therapies that involve the use warning of problems that may be associated with the use of the drug) by of combination therapies, which target different stages of the life cycle of the FDA (USDHHS, 2004). The side effects of PIs are usually associated the virus (USDHHS, 2004). In addition, when considering the superiority of one class of drug to another, considerations should be given to The long-term side effects of NNRTIs appear to be milder than possible side effects, risk of interactions, possible resistance and dosage those of NRTIs or PIs; including stomach problems, headaches, rashes, dizziness and drowsiness. However, fatal hepatoxicity (liver damage) is associated with the use of Nevirapine. Furthermore, two out of the three Side Effects
NNRTIs available for the treatment of HIV are not associated with any Every drug has its pluses and minuses, and will therefore have its side effects. The side effects can be as mild as nausea or as fatal as liver Drug Interactions
disease. The side effects or adverse drug reactions can be divided into two categories: toxic or allergic. The toxic side effects are caused by the When choosing an antiretroviral drug considerations should be drug itself and are dose dependent. They may result in drowsiness, given to other drugs that are being used by the HIV-positive patient. kidney damage, liver damage or anemia, etc. (Bartlett, 2001). However, Drug interactions can be broadly classified according to those that affect allergic reactions are caused by the immune system’s response to a the pharmacokinetic or pharmacodynamic properties of other drugs foreign substance in the body and are not dose related. They may result (Faragon & Piliero, 2004). The pharmacokinetic drug interactions alter in a high fever or rashes or both (Bartlett, 2001). In general, antiretroviral such properties as the concentration and half-life of the drug, while drugs can cause stomach problems, which include nausea, vomiting, pharmacodynamic interactions alter pharmacological activities of the abdominal pain, or diarrhea; lactic acidosis; lipodystrophy; and other side drug without causing changes in the concentration or other effects that are particular to each drug (Bartlett, 2001). Furthermore, of pharmacokinetic properties (Faragon & Piliero, 2004). Most drug the 50% of HIV patients whose treatments fail, it is estimated that 70- interactions that occur with HIV medications are those that result in the 80% of that group has failed because of the harsh side effects that were change of pharmacokinetic properties of the drugs due to the changes in associated with the drugs (Elion & Boyle, 2002). the rate of absorption, distribution, metabolism or elimination of the The long-term side effects of NRTIs are usually associated with drugs (Faragon & Piliero, 2004). It has been documented that the most the damage the drugs cause to the mitochondrion (organelles that drug interactions are associated with NNRTIs and PIs, since they are provides the cell with energy) of the cells (Bartlett, 2001). This damage metabolized in the same pathway as many other drugs (Margolese, results in the build up of lactic acid, which consequently results in the 2003). NNRTIs and PIs are metabolized in the liver by the CYP3A4 destruction of red and white blood cells, muscle pain, wasting away of isoenzyme in the cytochrome P450 (CYP450) system (USDHHS, 2004). the limbs, fatigue and peripheral neuropathy (numbness). More serious Examples of other drugs that are used for non-HIV treatment but are side effects include destruction of the cells of the liver (lactic acidosis) metabolized in the same pathway include drugs such as lipid-lowering agents, calcium channel blockers, immunosuppressants, anticonvulsants, summarized in Table 2 (below), no one drug alone, whether it be a erectile dysfunction drugs, antifungal drugs, oral contraceptives, and reverse transcriptase inhibitor or a protease inhibitor could effectively methadone (USDHHS, 2004). In addition, herbal medications such as St. treat the virus. This is due to the resistance that mutated forms of the John’s Wort should be avoided with any antiretroviral medication, virus confer to any medication when used independently. Research has shown that the best therapy for HIV is a combination of at least three Unlike NNRTIs and PIs, NRTIs are not metabolized in the drugs (Bartlett, 2001). This combination, referred to as the Highly Active cytochrome P450 (CYP450) system. Hence, NRTIs are only associated Antiretroviral Therapy or ‘HAART,’ was later changed to Potent with minimal drug interactions (Faragon & Piliero, 2004). Drug Antiretroviral Therapy upon the addition of the protease inhibitors in interactions that do occur with NRTIs are usually pharmacodynamic in 1995 (USDHHS, 2004). However, the combination is still commonly nature. Examples include the co-administration of the NRTIs zidovudine and stavudine, which are both thymidine (a nucleotide involved in the making of the double-stranded DNA from the viral RNA) analogs competing for the same site on the growing double-stranded viral DNA (USDHHS, 2004). Some pharmacokinetic interactions that are associated with the use of NRTIs are mainly reported as an increase in Didanosine concentration when co-administered with Tenofovir, which also causes a decrease in the PI Atazanavir. However, the combination of NNRTIs and PIs with other drugs that are metabolized by the CYP3A4 enzyme results in drug interactions. For example, Nevirapine and Efavirenz are inducers of the CYP3A4 enzyme, while Delavirdine is an inhibitor. Hence, the use of Nevirapine and Efavirenz results in the reduced concentration of drugs that are metabolized in the same pathway, while Delavirdine causes an increase in drug level and drug toxicity (Faragon & Piliero, 2004). Like NNRTIs, PIs have many complex drug interactions. However, all PIs are potent inhibitors of the CYP3A4 enzyme and cause an increase in the concentration of other medications co-administered with them (USDHHS, 2004). Hence, PIs increase the adverse drug reactions that are experienced by antiretroviral medications and other medications that have side effects. Therefore, numerous medications must be avoided when taking PIs. In addition, Ritonavir is the most potent inhibitor of the CYP3A4 enzyme, and also an inhibitor of the CYP2D6 enzyme and an inducer of the CYP1A2 and CYP2C9 enzymes, which are other enzymes found in the CYP450 system, as shown in Table 3 (Faragon & Piliero, 2004). An advantage of this property of Ritonavir is its co-administration with other PIs metabolized by CYP3A4 enzyme, in order to ‘boost’ their concentration (Chrisman, 2003). Comparative studies have shown that monotherapy is not an Clinical trials have devised regimens that have proven to be effective treatment for the HIV infection (USDHHS, 2004). As successful in the treatment of the virus. Today there are three different combinations that are recommended to “treatment-naïve” patients (individuals who have never taken antiretroviral medications), which are based on the following combinations: triple References
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