Drug Criteria & Outcomes: New Therapies in HIV/AIDS Treatment
Drug Criteria & Outcomes
New Therapies in HIV/AIDS Treatment
By Justin Garmany, PharmD Candidate, Harrison School of Pharmacy, Auburn University, and Richard Cramer, PharmD, Drug Information Coordinator, Department of Pharmacy, Hunstville (AL) Hospital
The human immunodeficiency virus (HIV) is the biological cause of the acquired immunodeficiency syndrome (AIDS), which was first recognized in the United States in 1981. HIV is an RNA retrovirus that violates the natural production course of DNA by producing DNA from RNA by utilization of a reverse transcriptase enzyme embedded in the virus. There are two types of HIV virus, HIV-1 and HIV-2, with HIV-1 being the primary cause of AIDS in the United States. HIV-2 is mostly seen in Western Africa and is less likely to be encountered in the Western world.
Since the first reports of HIV, more than 65 million people worldwide have been infected with HIV; 25 million have lost their lives to AIDS. At the end of 2005, the World Health Organization (WHO) estimated that 38 million people were living with HIV/AIDS worldwide with 64% of cases being from sub-Saharan Africa. In the United States, approximately 1 million persons are living with HIV/AIDS, with an estimated 40,000 new infections occurring annually. Of particular concern is that of the U.S. cases, 164,000-312,000 people are unaware that they are infected and experts suspect that the majority of new infections each year are acquired from these undiagnosed cases.
The HIV Life Cycle
To comprehend current treatment modalities, it is important to understand HIV's complex life cycle. HIV targets cells involved with the immune response, specifically helper T cells (CD4 cells). The virus must first bind and penetrate the cell and it does so by utilization of an outer glycoprotein expressed on the virus that has high affinity for CD4 receptors. There are two types of CD4 coreceptors, CCR5 and CXCR4, which the virus targets for attachment. Viruses that prefer the CCR5 virus (R5 viruses) are generally seen in the majority of sexually transmitted cases and in early disease. Those viruses that preferentially use the CXCR4 receptor (X4 viruses) are usually seen in later stages of the disease. Although viruses can prefer one coreceptor over another, there can be a combination of both R5 and X4 viruses in some cases.
Once HIV attaches and penetrates the CD4 cell it uncoats and begins copying its genetic material. It does this by utilization of an enzyme unique to HIV called reverse transcriptase, which is capable of transcribing its RNA to form DNA. Once reverse transcription occurs, the newly formed viral DNA enters the nucleus and integrates into the host cell genome via another enzyme unique to HIV called integrase. Once integration occurs, the virus is able to establish a chronic infection. Now that the virus has integrated into the host cell genome, the cell produces messenger RNA (mRN) and subsequent viral proteins. The viral proteins then bud from the host cell through the plasma membrane where the virus matures via the HIV protease enzyme, thus forming functional viral proteins to produce a viable and complete new virus.
Treatment Goals and Guidelines
The development of highly reactive antiretroviral therapy (HAART) has greatly changed the clinical course of HIV. People who acquire HIV no longer receive an instant death sentence but can now be managed in a way similar to other chronic diseases. HAART has profoundly reduced morbidity, improved quality of life, and prolonged survival in HIV patients. The goals of therapy are to maintain a high CD4 cell count, reduce the viral load to undetectable levels for as long as possible, and ultimately reduce morbidity and mortality. According to the Department of Health and Human Services (DHHS) guidelines, treatment should be started in the following patients:
- Patient with a history of an AIDS defining illness (i.e., opportunistic infections)
- CD4 T-cell count < 350 cells/mm3 (normal values: 600-1,500 cells/mm3)
- Pregnant patients and those with HIV-associated nephropathy should start therapy regardless of CD4 T-cell counts
- Patients coinfected with hepatitis B (HBV) when treatment is indicated
Available Therapies
Current available therapies for HIV/AIDS include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists, and integrase inhibitors. Of these available agents, the CCR5 antagonists and integrase inhibitors are the newest classes of agents to be introduced to the market. These new drugs, both of which act by a different mechanism of action than other available antiretroviral therapies, are particularly important in the treatment of HIV due to the fast rate of resistance that develops against the traditional agents. It is estimated that 6-16% of newly infected HIV patients will already be resistant to one drug and 3-5% will have reduced susceptibility to drugs from more than one class.
The CCR5 antagonist maraviroc (Selzentry™) was FDA approved on Aug. 6, 2007, for the treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who are infected only with CCR5-tropic HIV-1 and have evidence of viral replication. It is also indicated for treatment-experienced adult patients who have HIV-1 strains resistant to multiple antiretroviral agents. This agent opens up a whole new class of agents to help suppress viral load and prolong treatment in patients with few treatment options remaining due to multiple drug resistance. Maraviroc is currently available in 150 mg and 300 mg tablets and the usual recommended starting dose is 300 mg twice daily. It is recommended by the DHHS guidelines to perform a coreceptor tropism assay whenever the use of a CCR5 inhibitor is under consideration.
Maraviroc like most drugs for HIV/AIDS, has some limit adverse effects. One in particular is a black box warning for drug-induced hepatotoxicity with allergic-type features. It is recommended to consider discontinuation if signs/symptoms of hepatitis or an allergic reaction occur following drug administration. Other commonly reported adverse effects include fever, dizziness, cough, upper respiratory tract infection, rash, and abdominal pain. Maraviroc is a major substrate for CYP3A4 and so caution should be used when concurrently administering strong inducers or inhibitors of this enzyme system. As many of the current therapies for HIV/AIDS are inhibitors and inducers of the CYP3A4 enzyme, dosage adjustment recommendations are available.
Raltegravir (Isentress™) is the first integrase inhibitor, and was approved by the FDA on Oct. 12, 2007, for the treatment of HIV-1 infection in treatment-experienced patients with multi-drug resistance in combination with other antiretroviral agents. Like maraviroc, raltegravir provides another treatment option for patients who have few therapeutic alternatives due to drug resistant virus. Raltegravir is currently available in a 400 mg tablet with the recommended dose of 400 mg twice daily. The most commonly reported adverse effects are headache, fatigue, dizziness, increased blood glucose, lipodystrophy, vomiting, and increased liver enzymes.
Another drug of particular importance is the new second generation NNRTI etravirine (Intelence™) that was FDA approved on Jan. 18, 2008. Etravirine is indicated in conjunction with at least two other antiretroviral agents in treatment-experienced patients. It differs from other NNRTIs in that it possesses activity against HIV-1 strains resistant to others within the NNRTI class. Hepatic enzymes metabolize etravirine; primarily CYP3A4, 2C9, and 2C19, so drug interactions are a concern with this product. The most commonly reported adverse effects are rash, increased LDL-cholesterol and triglycerides, increased blood glucose, nausea, abdominal pain, and hypertension. Etravirine is available in a 100 mg tablet with a typical starting start dose of 200 mg twice daily.
The most recent addition to the PI class is darunavir (Prezista™). It was approved by the FDA on June 23, 2006, for the treatment of HIV-1 infection in combination with ritonavir (Norvir®) and other antiretroviral agents. It is recommended that this drug be limited to treatment-experienced patients or patients resistant to multiple PIs. Ritonavir is another member of the PI class, which is coadministered frequently with other antiretroviral agents to increase their plasma concentrations due to its strong inhibitory effects on the CYP3A4 enzyme. Darunavir is a major substrate for CYP3A4, which does not reach appreciable plasma concentrations without the coadministration of ritonavir.
The most commonly reported adverse effects of darunavir therapy are increased triglycerides, nausea, diarrhea, vomiting, taste disturbances, increased GGT, and weakness. Darunavir is available in a 300 mg tablet with the starting dose being 600 mg of darunavir with 100 mg of ritonavir, both administered twice daily.
Conclusion
Significant progress has been made in the management of HIV/AIDS since its recognition. There are several classes of agents available for treatment and more are likely to follow. However, despite great strides in HIV/AIDS therapy, many problems remain such as viral resistance and the inability to halt disease progression. More research on new agents and treatment strategies are needed to further improve quality of life and survival of patients with HIV/AIDS.
Resources
Fletcher CV, Kakuda TN. Human Immunodeficiency Virus Infection. In: Dipiro JT, Talbert RL, Yee GC, et al, editors. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:2255-2275.
Intelence™ [Package Insert]. Raritan, NJ: Tibotec Therapeutics; January 2008.
Isentress™ [Package Insert]. Whitehouse Station, NJ: Merck & CO., Inc.; October 2007.
Prezista™ [Package Insert]. Raritan, NJ: Tibotec Therapeutics; June 2006.
Selzentry™ [Package Insert]. New York, NY: Pfizer Labs; August 2007.
Merson MH. The HIV-AIDS pandemic at 25 — the global response. N Engl J Med 2006;354:2414-2417.
Sepkowitz KA. One disease, two epidemics — AIDS at 25. N Engl J Med 2006;354:2411-2414.
The human immunodeficiency virus (HIV) is the biological cause of the acquired immunodeficiency syndrome (AIDS), which was first recognized in the United States in 1981.Subscribe Now for Access
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