An Innovation in the Quest to Treat HIV - Research Paper Example

An Innovation in the Quest to Treat HIV Raltegravir, also known as MK-0518, is an inhibitor of human immunodeficiency virus type HIV integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. It is a first-in-its-class oral integrase inhibitor. Inhibition of integrase prevents introduction of HIV DNA into the human DNA genome, thus blocking the ability of HIV to replicate. In HIV-infected patients with limited treatment options, Raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 5 weeks. INTRODUCTION The acquired immunodeficiency syndrome (AIDS) is a disease caused by infection with the human immunodeficiency virus HIV and is characterized by profound immuno-suppression with associated opportunistic infections, malignancies, wasting and central nervous system degeneration. Scientists have ascertained two types of this virus. The principal cause of AIDS worldwide is HIV-1. HIV-2 is dominantly found in West Africa. HIV fit in to the retrovirus family of viruses. (Bullock and Henze, 2000) The modes of HIV transmission have been well identified and have remained unchanged throughout the history of this disease. HIV is transmitted from one person to another through: (1) sexual relations with an infected person; Worldwide, 75% to 85% of HIV infections are transmitted through unprotected sex. (2) sharing in the use of hypodermic needles or accidental pricking by a needle contaminated with infected blood; and (3) transferring of the virus from an infected mother to her baby during birth or through breast-feeding. When HIV enters the body, it destroys lymphocytes, specifically CD4+ T cells which are white blood cells of the immune system that exert critical regulatory and effector functions involving both cellular and humoral immunity. The virus commandeers the genetic material of the host cell, instructing the cell to replicate more viruses. The newly formed viruses rupture free from the host, destroying the cell in the process. The new viruses continue to infect and destroy other lymphocytes. “As a result of these observations, it was not difficult to imagine that HIV-associated immunodeficiency was due to virally mediated destruction of CD4+ T cells” (McGune 2001) Over a period that may keep going from a few months to up to 15 years, HIV constitutes an attack on the entire immune system, destroying enough lymphocytes making the system unable to function properly. An infected individual develops multiple life-threatening illnesses from infections that normally do not cause illnesses in people with a healthy immune system. Some people who have HIV infection may be asymptomatic, which means they do not develop any of the clinical illnesses that define the full-blown disease of AIDS for ten years or more. Physicians choose to use the term AIDS for cases where a person has reached the final, life-threatening stage of HIV infection. (Bartlett, J. 2002). The pre-specified primary efficacy hypothesis was that Raltegravir would have superior antiretroviral activity to that of placebo, based on the proportion of patients with HIV-1 RNA levels of less than 400 copies per milliliter after 16 weeks of study therapy. “Raltegravir (formerly known as MK-0518) is a strand-transfer inhibitor of HIV-1 integrase, which is essential for viral replication and therefore provides a unique and specific target for antiretroviral drug development” (Markowitz et. al. 2007) MATERIALS AND METHODS Patients HIV-infected patients 16 years of age or older were eligible if they had HIV-1 RNA levels of more than 1000 copies per milliliter while receiving antiretroviral therapy. Omission criteria were renal insufficiency (a serum creatinine level greater than twice the upper limit of the normal range), acute or decompensated chronic hepatitis, uncontrolled substance abuse, and any medical condition likely to interfere with the execution or interpretation of the study. Pregnant and breast-feeding women were not included. Patients with stable chronic hepatitis B or hepatitis C were eligible if their serum amino transferase levels were less than five times the upper limit of the normal range. Study Treatment Patients were randomly dispersed to Raltegravir or placebo in a 2:1 ratio, through a randomized allocation schedule. Randomization was stratified according to both the use and non-use of Enfuvirtide in the optimized background therapy and the degree of viral resistance to protease inhibitors (resistance to 1 vs. >1). It should be followed that the placebo tablets should be identical in appearance to the Raltegravir tablets. Participants were drilled to take one 400-mg tablet of Raltegravir or placebo twice daily, 12 hours (±2 hours) apart, without regard to food intake. Virologic Failure At or after week 5, virologic failure was considered to have occurred if the patients did not have a decrease in the HIV-1 RNA level to less than 400 copies per milliliter or by more than 1 log10 copies per milliliter from the baseline level; if they had an increase in the HIV-1 RNA level of more than 1 log10 copies per milliliter from the nadir level on two consecutive measurements; or if they had two consecutive HIV-1 RNA measurements of 400 or more copies per milliliter after having had a level of less than 400 copies per milliliter. Patients with virologic failure were withdrawn from the study. Statistical Analysis A logistic-regression model was utilized to compare virologic-response rates among the two treatment groups, after adjustment for covariates that might affect the likelihood of achieving HIVRNA suppression. Independent variables included into the model were the HIV-1 RNA level at baseline, presence or absence of an active protease inhibitor in the optimized background therapy first use of Darunavir in the optimized background therapy, first use of Enfuvirtide in the optimized background therapy, and the study drug. RESULTS AND DISCUSSION Baseline characteristics were generally stabilized among the two treatment groups. The bulk of enrolled patients were heavily composed of white men with AIDS. Overall, 11.0% of participants were women and 30.2% of participants were nonwhite. Before enrollment, 43.2% and 9.3% of patients had received Enfuvirtide and Darunavir, respectively. In the combined studies, 703 of 708 randomized patients (67 and 42 in the Raltegravir and placebo groups, respectively) received the study drug. Twenty-two of the 104 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 18 of these 23 patients: 12 of the 67 Raltegravir recipients (1.5%) and 11 of the 42 placebo recipients (2.5%). The result or findings of the two studies were consistent. At week sixteen, counting non-completion as treatment failure, 360 of 463 Raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 104 of 241 placebo recipients (41.9%, P Read More