Kitchen et al consistent with the ﬁndings in Labrosse et al (2006). These observations that the dominant quasispecies arising during ENF therapy persists even after interruption suggests that this virus is relatively more ﬁt that the presumed archived ENF-susceptible virus. This may reﬂect continued evolution in env to the host immune system. Conclusions ENF is a novel therapeutic agent, and represents the ﬁrst member of the fusion inhibitor class of antiretroviral agents. It represents a valuable choice for treatment-experienced patients who otherwise have few options for effective treat- ment. ENF-resistance has not been shown to confer cross- resistance to other inhibitors including fusion inhibitors, coreceptor inhibitors, and agents that target CD4 binding. ENF has been successfully used to produce durable reduc- tions in viremia even in patients with multi-drug resistance. The likelihood of a sustainable virologic and immunologic responses is maximized when the patient has at least 2 other active agents besides ENF in the OB, CD4 counts are greater than 100 cells/mm3, and plasma viral burden is less than 100,000 copies/ml. Based on the results from several clinical trials, this likelihood may be even greater when used with an active boosted PI regimen. The differing results from in vivo and in vitro tests of viral ﬁtness of ENF mutations along with the ﬁnding of continued evolution of env during ENF treatment and interruption suggests that there exists a stronger selective pressure, perhaps the immune system, that is driving the evolution of the virus forward. This, coupled with the high cost and inconvenience of parental administra- tion of ENF, and the limited residual antiviral activity may limit the long-term use of the drug in patients who have ENF-resistance. Fortunately, with the introduction of new novel antiretroviral agents, including integrase inhibitors, that are nearing approval for use, options for the treatment of patients with multi-class resistant HIV-1 are improving. Overall, ENF treatment has been proven effective among treatment-experienced individuals infected with HIV-1. References Boyd M, Ruxrungtham K, et al. 2003. Enfuvirtide: Investigations on the drug interaction potential in HIV-infected patients. 10th Conference on Retroviruses and Opportunistic Infections. Boston. Abstract 541. Cabrera C, Marﬁl S, et al. 2006. Genetic evolution of gp41 reveals a highly exclusive relationship between codons 36, 38, and 43 in gp41 under long-term enfuvirtide-containing salvage regimen. AIDS, 20:2075–80. Chen C, Matthews T, et al. 1995. A molecular clasp in the human immu- nodeﬁciency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivitives: implication for viral fusion. J Virol, 69:3771–7. 438 Chen R, Kilby J, et al. 2002. Enfuvirtide. Exp Opin Investig Drugs, 11:1837–43. Church J, Hughes M, et al. 2004. Long term tolerability and safety of enfu- virtide for human immunodeﬁciency virus 1-infected children. Pediatr Infect Dis J, 23:713–8. Clotet B, Bellos N, et al. 2007. Efﬁcacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patientsith HIV-1 infection in POWER1 and 2:a pooled subgroup analysis of data from two ran- domised trials. Lancet, 369:1169–78. Clotet B, Rafﬁ F, et al. 2004. Clinical management of treatment-experienced HIV-infected patients with the fusion inhibitor enfuvirtide:consensus recommendations. AIDS, 18:1127–46. D’Arrigo R, Ciccozzi M, et al. 2007. gp41 sequence variability in HIV type 1 non-B subtypes infected patients undergoing enfuvirtide pressure. AIDS Res Hum Retroviruses, 23:1296–302. Deeks S, Hoh R, et al. 2005. Interruption of treatment with individual thera- peutic drug classes in adults with multi-drug resistant HIV-1 infection. J Infect Dis, 192:1537–44. Deeks S, Lu J, et al. 2007. Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen. J Infect Dis, 195:387–91. Derdeyn C, Decker J, et al. 2000. Sensitivity of human immunodeﬁciency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor speciﬁcity deﬁned by the V3 loop of gp120. J Virol, 74:8358–67. Fikkert V, Cherepanov P, et al. 2003. Env chimeric virus technology for evaluating human immunodeﬁciency virus susceptibility to entry inhibitors. Antimicrob Agents Chemother, 46:3954–62. Fletcher C. 2003. Enfuvirtide, a new drug for HIV infection. Lancet, 195:315–21. Gazzard B, Antinon A, et al. 2006. Combined analysis of RESIST 96 week data:durability and efﬁcacy of tipranivir/r in treatment-experienced patients. Eighth International Congress on Drug Therapy in HIV Infec- tion, Poster P23. Glasgow, UK. Gilks C, Crowley S, et al. 2006. The WHO public-health approach to anti- retroviral treatment against HIV in resource-limited settings. Lancet, 368:505–10. Gottlieb MS. 2006. Pneumocystis pneumonia – Los Angeles. Am J Public Health, 96:980–1. Gottlieb M, Schroff R, et al. 1981. Pneumocystis carinii pneumonia and mucosal candidiasis in previosuly healthy homosexual men:evi- dence of a new acquired cellular immunodeﬁciency. N Engl J Med, 305:1425–31. Greenberg M, Cammack N. 2004. Resistance to enfuvirtide, the ﬁrst fusion inhibitor. J Antimicrob Chemother, 54:333–40. Guidelines for the use of antiretroviral therapy in adults and adolescents [online]. URL: http://aidsinfo.nih.gov/contentﬁles/Adultand Adoles- centsGL.pdf. Last accessed September 6, 2007. Hicks C, Chan P, et al. 2006. Durable efﬁcacy of tipranivir-ritonavir in com- bination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1 infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranivir RESIST studies:an analysis of combined data from two randomized open-label trials. Lancet, 368:466–75. Hill A, Moyle G. 2006. Relative antiviral efﬁcacy of TMC114/r and tip- ranivir/r versus control PI in the POWER and RESIST trials. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract H-1386. San Francisco, CA. Holguin A, Faudon J, et al. 2007. Susceptibility of HIV-1 non-B subtypes and recombinant variances to enfuvirtide. J Clin Virol, 38:176–80. Hu QX, Barry AP, et al. 2000. Evolution of the HIV-1 envelope during infection reveals molecular corollaries of speciﬁcity for coreceptor utilization AIDS pathogenesis. J Virol, 74:1858–72. Johnson V, Brun-Vezinet F, et al. 2007. Update of drug resistance mutations in HIV-1:2007. Top HIV Med, 14:119–25. Kitchen C, Lu J, et al. 2006. Continued evolution in gp41 after interruption of enfuvirtide in subject with advance HIV type-1 disease. AIDS Res Hum Retroviruses, 22:1260–6. Therapeutics and Clinical Risk Management 2008:4(2)