Conference Highlights - Advances in Antiretroviral Therapy Volume 11 Issue 3 May/June 2003 Advances in Antiretroviral Therapy Mary A. Albrecht, MD, Timothy J. Wilkin, MD, Eoin P. G. Coakley, MD, and Scott M. Hammer, MD As witnessed in previous years, Entry Inhibitors isolates in vitro, including non-B sub- antiretroviral therapy was a dominant types. Phase 1 safety studies in HIV- theme of the 10th Conference on CCR5 Antagonists. AK-602 is a CCR5 seronegative individuals showed no Retroviruses and Opportunistic Infect- inhibitor in preclinical development. In obvious toxicities (including QTc inter- ions, with important information for vitro studies suggest that it preferential- val prolongation) and that it was well- clinicians presented in the areas of ly blocks the HIV-CCR5 interaction and tolerated at a range of doses given for new antiretroviral agents, management has less effect on the interaction of up to 12 days. The IC50 for HIV replica- of treatment-naive and -experienced CCR5 and chemokines such as RANTES tion is 0.2 nM, and the IC50 for binding patients, treatment strategies (particu- and MIP-1β (Abstracts 10 and 564a). It of MIP-1β is 3 to 7 nM. Pharmacokinetic larly treatment interruptions), and drug suppresses HIV replication and is orally studies in humans showed good absorp- resistance. This review will highlight the bioavailable in the SCID-Hu mouse tion, with a terminal half-life of 17 major findings presented at the confer- model. Although CCR5 ∆32 homozygos- hours with repeated doses. ence from studies performed in the ity appears to have no untoward effects developed world. One important new in humans, CCR5 inhibitors, such as CXCR4 Antagonist. AMD070 is an orally aspect of this year’s meeting, however, SCH-C and TAK-779, that affect bioavailable CXCR4 inhibitor active in was the reporting of experiences with chemokine-CCR5 interactions are, in vitro against a wide variety of X4 virus- antiretroviral agents in the developing fact, being studied in organ transplant es and R5/X4 dual tropic viruses (EC 1- world. These reports will not be sum- 50 recipients as possible immune modula- 10 nM), but not R5 viruses (Abstract marized here, but readers may visit tors. This immune modulation is proba- 563). It is being developed by Anormed, the conference Web site for more infor- bly not a desirable quality when treating whose development of AMD-3100 was mation concerning these sessions HIV infection, suggesting that CCR5 stopped because of suboptimal efficacy (www.retroconference.org). inhibitors that do not affect chemokine- but did establish proof of concept for CCR5 binding may be preferable to targeting CXCR4. AMD070 appears to Investigational Antiretroviral those that do. AK-602 has potent activi- be either additive to or synergistic with Agents ty against a wide panel of primary R5 other antiretrovirals and does not inter- and multidrug-resistant isolates (50% act with any other chemokine receptor inhibitory concentration [IC ] 0.2-0.6 Results of select studies on investiga- 50 tested. Phase 1 studies are planned. tional antiretroviral agents are summa- nM). rized in Table 1. TAK-220 is a CCR5 inhibitor that is orally bioavailable, unlike manufacturer Monoclonal Antibody to CD4. TNX-355 is Ta keda Chemical Industries’ previous a human monoclonal antibody (IgG4) to CCR5 inhibitor, TAK-779 (Abstracts 11 CD4 formerly known as Hu5A8 Dr Albrecht is Assistant Professor of and 562). The authors did not present (Abstract 13). It does not prevent attach- Medicine in the Division of Infectious the structure of the new compound but ment of HIV to CD4 but does prevent Diseases at Beth Israel Deaconess did say that it was not similar to TAK- subsequent interactions. No immuno- Medical Center, Harvard Medical School, 779. TAK-220 appears to bind specifi- suppressive effects were noted in previ- Boston, Mass. Dr Wilkin is Instructor of cally to CCR5 (not CCR1, CCR3, or other ous studies with peripheral blood lym- Medicine in the Division of International chemokine receptors). It is active in phocytes or rhesus macaques. In this Medicine and Infectious Diseases at vitro against primary R5 viruses, includ- study, HIV-infected individuals on stable Weill Medical College of Cornell ing those resistant to other available antiretroviral therapy or no antiretrovi- University, New York, NY. Dr Coakley is drugs (50% effective concentration ral therapy, and with plasma HIV-1 RNA Assistant Professor at Tufts University [EC50] 1.1 nM and 90% effective con- levels of greater than 5000 copies/mL School of Medicine and Attending centration [EC90] 13 nM), and appears and CD4+ counts of greater than 100 Physician in the Division of Geographic synergistic with other antiretrovirals cells/µL, were given a single dose of the Medicine and Infectious Diseases at against wild-type R5 virus. agent at increasing amounts with suc- New England Medical Center, Boston, UK-427,857 is a CCR5 inhibitor that cessive cohorts. The mean baseline Mass. Dr Hammer is Professor of has entered phase 1 studies. Studies CD4+ count and plasma HIV-1 RNA Medicine at Columbia University College suggest that it is specific for CCR5-virus levels were 354 cells/µL and 4.78 log10 of Physicians and Surgeons and Chief of interactions and, consistent with the copies/mL, respectively. Mean drops in the Division of Infectious Diseases at mechanism, is not active against X4 plasma HIV-1 RNA of 1.48 log10 and Columbia Presbyterian Medical Center viruses (Abstracts 12, 546a, and 547). It 1.09 log10 were achieved at the 2 highest in New York, NY. is active against a broad range of viral doses (10 mg/kg and 25 mg/kg), respec- 97 International AIDS Society–USA Topics in HIV Medicine Table 1. New Antiretroviral Agents Drug Abstract Mechanism Development Results Name Nos. Stage AK-602 10, 564a Entry inhibitor (CCR5) Preclinical IC50 0.2-0.6 nM TAK-220 11, 562 Entry inhibitor (CCR5) Preclinical EC50 1.1 nM UK-427,857 12, 546a, 547 Entry inhibitor (CCR5) Preclinical; phase 1 IC50 0.2 nM studies in HIV- seronegative subjects AMD070 563 Entry inhibitor Preclinical EC50 1-10 nM (CXCR4) TNX-355 13 Fusion inhibitor Phase 1 studies in 1.09-1.5 log10 copies/mL (human monoclonal HIV-infected subjects drop in plasma HIV-1 RNA antibody) levels after single dose T-1249 14lb Fusion inhibitor Phase 2 studies in 1.1 log10 copies/mL drop in HIV-infected subjects plasma HIV-1 RNA levels after 11 days as functional monotherapy1 Racivir 552 Nucleoside reverse Phase 2 studies in 2.1-2.6 log10 copies/mL transcriptase inhibitor HIV-infected subjects drop in plasma HIV-1 RNA levels after 28 days (given with stavudine/efavirenz) V-165 9, 556 Integrase inhibitor Preclinical EC50 8.9 µM (inhibits initial interac- tion of integrase and DNA) PA-457 14 Gag processing Preclinical Not available inhibitor (inhibits pro- cessing of p24 capsid protein) RO-033-4649 7 Protease inhibitor Preclinical IC50 17 nM for wild-type viruses; IC50 100 nM for highly PI-resistant viruses TMC114 8, 549, 553 Protease inhibitor Phase 2 studies in 1.1-1.5 log10 copies/mL boosted with low- HIV-infected subjects reduction in plasma HIV-1 dose ritonavir RNA levels after 14 days as functional monotherapy2 1This study substituted T-1249 for enfuvirtide (T-20) as the sole change in a failing antiretroviral regimen. Better efficacy was seen with a shorter time on the failing regimen containing enfuvirtide. 2Participants were multiple-PI-experienced, and their PI-containing regimen was failing; the median baseline plasma HIV-1 RNA was 4.3 log10 copies/mL. TMC114/ritonavir was substituted for the failing PI or PIs as the sole change in antiretroviral therapy for 14 days. IC50 indicates 50% inhibitory concentration; EC50, 50% effective concentration. 98 Conference Highlights - Advances in Antiretroviral Therapy Volume 11 Issue 3 May/June 2003 tively. The nadir plasma HIV-1 RNA level overlap in their resistance profiles imen for at least 12 weeks prior to study was achieved at days 14 and 21, respec- (Abstract 140). V-165 has a different entry. Subjects were randomized either tively. These days coincided with the resistance pattern than these agents to continue lamivudine therapy duration of antibody coating of CD4, and is active against isolates resistant to (n=146) or to switch to emtricitabine giving further support for the proposed the diketoacids. It is also active against (n=294) within their current antiretro- mechanism of action. No CD4+ cell nonnucleoside reverse transcriptase viral drug regimen. Subjects who main- depletion was noted; in fact, CD4+ cell inhibitor (NNRTI)-, nucleoside reverse tained plasma HIV-1 RNA suppression count increases were seen for the 3 transcriptase inhibitor (nRTI)-, and of less than 400 copies/mL at week 48 highest dose groups (3, 10, and 25 fusion inhibitor-resistant viruses and is of the FTC 303 study were then offered mg/kg). No resistance has been created synergistic with zidovudine and nelfi- the option of participating in a rollover to date. navir versus wild-type virus. The in vitro extension study, FTC 350, which evalu- potency (EC50 8.9 µM) is comparable to ated the use of emtricitabine 200 mg Fusion Inhibitor. Miralles and colleagues that for the Merck integrase inhibitor, once daily. The baseline median plasma presented interim results of a study L-870,810. HIV-1 RNA level and CD4+ cell count evaluating T-1249 in patients in whom a were 1.7 log10 copies/mL and 484 regimen containing enfuvirtide (T-20) Gag Processing Inhibitor cells/µL, respectively. was failing (Abstract 14lb). T-1249 is a At week 48, 77% of the subjects fusion inhibitor similar to enfuvirtide PA-457. PA-457 appears to target a new (n=227) randomized to emtricitabine given by subcutaneous injection once point in the HIV-1 life cycle: Gag pro- therapy achieved suppression of plasma daily.