Antiretroviral agents

Labs C04 ceil count 190 ceiis/mm (nadir 60 celis/mm, viral load SO copteVhiL, glucose 168 mg/dL (fasting), triglycerides 450 mg(dL (fasting). 

HIV is a human retrovirus that infects lymphocytes and other cells with the CD4 surface protein. Infection eventually leads to lymphopenia and CD4 T-cell depletion. The time from onset of HIV infection to development of AIDS varies from months to years. 

There are two enzymes, reverse transcriptase (RT) and protease, within the HIV life cycle to which therapy is directed 

Later in the life cycle during the process of budding, the enzyme HIV protease cleaves the polyproteins in the core, converting the immature viral particles into infectious virions. Protease inhibitors (Pis) inhibit the viral protease enzyme to prevent cleavage of the polyproteins so that 

Initial regimens usually consist of two NRTIs plus either a potent PI or NNRTI. Frequent changes in therapy are required over time due to adverse effects, lack of response, or both. As a general rule, NRTIs do not require dose adjustments when combined with other ARVs. However, Pis and NNRTIs tend to have complex metabolisms and in combination affect each other s levels and potency. Drug resistance occurs with all available agents, and resistance to one agent will often confer resistance to the entire class (Table 59-1). 

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Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

For the treatment of AIDS, TDF is now available in three commercial preparations, as such (Viread ), in combmation with emtricitabine (Truvada ) and m combination with emtricitabme and efavirenz (Atripla ). The latter represents a three-drugs-in-once combination piU, which has become available for the treatment of AIDS since July 2006. The different milestones mat marked the development and ultimate commercialization of Atripla (m 2006) smce the original identification of adefovir as an antiretroviral agent (m 1986) have been previously reviewed (De Clercq 2006, 2007a-c). 

St Clair MH, Millard J, Rooney J, Tisdale M, Party N, Sadler BM, Blum MR, Painter G (1996) In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral Res 29 53-56... 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

ART, antiretroviral therapy HIV, human immunodeficiency vims Ol, opportunistic infection. (Adapted from the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, April 7, 2005.)... 

TABLE 84-5. Summary of Currently Available Antiretroviral Agents... 

Panel on Clinical Practices for Treatment of HIV Infection Convened by the Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. 2006. Available at http //aidsinfo.nih.gov Public Health Service Task Force. Recommendations for use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. October 12,2006. (http //aidsinfo.nih.gov) Smith DE, Walker BD, Cooper DA, et al. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence AIDS 2004 18 709-718. 

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. October 26, 2006. (http //aidsinfo.nih.gov)... 

Department of Health and Human Services (2009) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. December 1, 1-161. 

Centers for Disease Control and Prevention. (1998). Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 47(RR-5), 1-82. 

Balzarini J, Holy A, Jindrich J, Dvorakova H, Hao Z, Snoeck R, Herdewijn P, Johns DG, De Clercq E. 9-[(2RS,)-3-Fluoro-2-phosphonylmcthoxypropyl] derivatives of purines a class of highly selective antiretroviral agents in vitro and in vivo. Proc Natl Acad Sci USA 1991 88 4961-4965. 

B. J. Aungst, N. H. Nguyen, N. J. Taylor, D. S. Bindra. Formulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agent. J. Pharm. Sci. 2002, 91, 1390-1395. 

The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross resistant with antiretroviral agents with which the patient has been treated previously. 

Current recommendations for treating HIV infection advocate a minimum of three antiretroviral agents. The typical regimen consists of two NtRTIs and either a ritonavir-boosted PI or NNRTI. The dual NtRTI backbone should include tenofovir plus emtricitabine (coformulated as Truvada) or zidovudine plus lamivudine (coformulated as Combivir). Abacavir plus lamivudine is an alternative. Recommended initial NtRTIs include atazana-vir-ritonavir, lopinavir-ritonavir, or fosamprenavir-ritonavir. Efavirenz is the recommended NNRTI except for women who plan to become pregnant or who do not have adequate contraception. 

Significant drug interactions can occur with many antiretroviral agents ... 

Slish, J.C. et al. 2006. Update on the pharmacokinetic aspects of antiretroviral agents Implications in therapeutic drug monitoring. Curr Pharm Des. 12 1129. 

Panel on Clinical Practices for Treatment of HIV Infection, Guidelines for Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, Available at http //www.AIDSinfo.nih.gov, Revision July 15,2005, Accessed August 23, 2005. 

Zidovudine, azidothymidine, AZT (Retrovir, Combivir) Antiretroviral agent Inhibits HIV replication by blocking reverse transcriptase... 

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