Reverse transcriptase inhibitors in HIV infection

Nucleosides, nucleotides, peptidomimetics, and reverse transcriptase inhibitors in HIV infection therapy 98CCC449. 

Andrade RA, Evans RT, Hamill RJ, Zerai T, Giordano TP. Clinical evidence of interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors in HIV-infected patients with... 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

So far, five different protease inhibitors have been approved by the FDA for the treatment of HIV infection [3, 4]. Clinical trials in which protease inhibitors were evaluated in monotherapy demonstrated the potency of this class of inhibitors (decrease in HIV RNA levels, increase in CD4 cell counts). Treatment regimens were subsequently broadened to include reverse transcriptase inhibitors in combination with protease inhibitors. The result of these clinical trials has led to a list of guidelines with recommendations for the optimal treatment options. Prolonged control of the infection with combination therapy (highly active antiretroviral therapy, HAART ) could be shown. 

Study Design Treatment, randomized, open label, active control, parallel assignment, safety/efficacy study Official Title A Phase III, Randomized, Open-Label Study of Lopina-vir/Ritonavir Tablets 800/200mg Once-Daily Versus 400/100mg Twice-Daily When Co-administered With Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects Primary Outcome Measures ... 

After oral administration, abacavir is rapidly absorbed, and its bioavailability is about 83%. Food does not interfere with its absorption, and it is metabolized by alcohol dehydrogenase to 5 -carboxylic acid derivative and to S -glucuronidc by glucuronidation. Abacavir does not affect the cytochrome P-450 system. In combination with other antiretroviral drugs, abacavir is indicated for the treatment of HIV-1 infection. It is more potent than other nucleoside reverse transcriptase inhibitors in reducing HIV plasma concentration and increasing CD4+ count. 

Clinical use Zidovudine continues to be the most frequently used reverse transcriptase inhibitor in combination drug regimens (HAART). It is of value also in prophylaxis against HIV infection through accidental needlesticks and in prophylaxis against vertical transmission from mother to neonate. 

Nevirapine (NVP), a nonnucleoside reverse transcriptase inhibitor, is widely used for the treatment of human immunodeficiency virus (HIV) infections. It is the main option for the first-line treatment of HIV-1, together with two nucleoside reverse transcriptase inhibitors, in countries with limited resources. NVP is associated with two serious clinically restrictive side effects skin reactions and hepatotoxicity. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in HIV-infected patients taking NVP (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2008). For this reason, NVP is given a black box warning for hepatotoxicity, and concern has been raised over NVP-based treatment. 

The most recent advance in treating HIV infections has been to simultaneously attack the virus on a second front using a protease inhibitor. Recall from Section 27.10 that proteases are enzymes that catalyze the hydrolysis of proteins at specific points. When HIV uses a cell s DNA to synthesize its own proteins, the initial product is a long polypeptide that contains several different proteins joined together. To be useful, the individual proteins must be separated from the aggregate by protease-catalyzed hydrolysis of peptide bonds. Protease inhibitors prevent this hydrolysis and, in combination with reverse transcriptase inhibitors, slow the reproduction of HIV. Dramatic reductions in the viral load in HIV-infected patients have been achieved with this approach. 

Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C (2006) Proteolytic processing of SDF-lalpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Nad Acad Sci USA 103(50) 19182-19187 von Giesen HJ, Roller H, Theisen A, Arendt G (2002) Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HlV-1-infected patients. J Acquir Immune Defic Syndr 29(4) 363-367... 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

The nonnucleoside reverse transcriptase inhibitors (NNRTIs), used in the treatment of AIDS, provide interesting examples of clinically relevant noncompetitive inhibitors. The causative agent of AIDS, HIV, belongs to a virus family that relies on an RNA-based genetic system. Replication of the vims requires reverse transcription of the viral genomic RNA into DNA, which is then incorporated into the genome of the infected host cell. Reverse transcription is catalyzed by a virally encoded nucleic acid polymerase, known as reverse transcriptase (RT). This enzyme is critical for viral replication inhibition of HIV RT is therefore an effective mechanism for abrogating infection in patients. 

AIDS is associated with aberrant lymphocyte production and it has been proposed that Li+ may have a potential role in reversing this. Additionally, 3 -azido-3"deoxythymidine (AZT, zidovudine), an effective inhibitor of viral reverse transcriptase that reduces mortality in AIDS patients, induces hematopoietic suppression in patients resulting in anemia, neutropenia, and overall bone-marrow failure [220]. In murine AIDS, the coadministration of Li+ effectively moderates this toxicity of AZT in vivo [221,222]. There are several case reports where Li+ has been administered to help reduce the hematopoietic suppression in HIV-infected patients taking AZT (for example, see ref. 223). To date, the use of Li+ has been limited to a few weeks of treatment, and varying degrees of success have been achieved nevertheless the outlook in this field is quite hopeful. 

Inhibiting viral replication with combination of potent antiretroviral therapy has been the most clinically successful strategy in the treatment of HIV infection. There have been three primary groups of drugs used nucleoside and nonnucleoside reverse transcriptase inhibitors and protease inhibitors (Pis) (Table 40-5). 

Data from Panel on Clinical Practices for the Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. 2006, http/AMM/vAIDSinfo.NIH.gov Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of nucleoside- and nudeotide-andogue reverse-transcriptase inhibitors and its relationship to dinical toxdties. din Infect Dis 2004 38 743-753 and produd information for agents... 

Isoniazid Daily for 9 months0 In HIV-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors, protease inhibitors, or nonnucleoside reverse transcriptase inhibitors A (II) A (II)... 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used to treat HIV-infected patients that causes mild to severe skin rash and even Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in a substantial proportion (16%) of patients. Nevirapine also induces hepatotoxicity. These adverse clinical symptoms may also occur in non-HIV subjects taking the drug as postoperative prophylaxis [15]. 

Drugs are also used to inhibit the enzymatic reactions of foreign pathogens that enter the human body. An example is the use of reverse transcriptase inhibitor and protease inhibitor for combating the human immunodeficiency virus (HIV), as shown in Exhibit 2.12. Some new inhibitors are used to block HIV from attaching to the human cell, CD4, thus stopping replication and infection of other cells, as presented in Exhibit 2.13. 

HIV infection In combination with other antiretroviral agents (such as nonnucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Other major untoward reactions are the result of rifampin s ability to induce hepatic cytochrome P-450 enzymes, leading to an increased metabolism of many drugs this action has especially complicated the treatment of tuberculosis in HIV-infected patients whose regimen includes protease inhibitors and nonnucleoside reverse transcriptase. Since rifabutin has relatively little of these effects, it is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. 

Single agents are seldom used to treat HIV infection. Instead, multidrug therapy is used to counteract the rapid mutation rate of HIV and to minimize drug toxicity. Highly active antiretroviral therapy (HAART) uses combinations of reverse transcriptase inhibitors and protease inhibitors (Table 51.1). In this system, drugs working by different mechanisms produce a sequential blockade of steps required for viral reproduction. It is... 

Emtricitabine is a nucleoside reverse transcriptase inhibitor, launched for the treatment of HIV infection. It is also currently in phase III for the treatment of hepatitis B virus (HBV) infection (Fig. 35) [98]. 

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