Edited and Published by Jules Levin Executive Director/Founder NA TAP 580 BROADWAY, SUITE 1010, NEW YORK, NY, 10012 1 - 8 8 8 - 2 6 - N ATA P (212) 219-0106 fax (212) 219-8473 [email protected] h t t p : / / w w w. n a t a p . o r g IN THIS ISSUE: Tipranavir Tipranavir . .1 HIV Entry Inhibitors . .1 Tipranavir: new protease inhibitor is effective in large stud- CCR5 Inhibitors: GW873140 . .4 ies for patients with extensive resistance to currently avail- Entry Inhibitor Drugs in Human Studies . .4 able protease inhibitors UK-427,857 CCR5 Inhibitor . .7 Schering D 690 CCR5 Inhibitor; TNX-355 . .9 An Expanded Access Program started November 30, 2004 Attachment Inhibitors . .11 < h t t p s : / / w w w.tpv-eap.com>, which will provide access to Fuzeon . .12 tipranavir now through your doctor for patients who need it. You New HIV Antiretroviral Drugs in Development . .15 can also call 1-888-524-8675 for more information about the TMC-125 . .15 EAP. It’s recommended to take tipranavir along with at least one TMC-114 . .15 additional new drug, to which a patient is fully sensitive. Fuzeon, Reverset . .16 a new entry inhibitor drug, is an option to consider and is being HIV Maturation Inhibitor PA-457 . .17 made available by Roche for individuals who are unable to SPD754 . .17 access it. You can find out more by speaking to your doctor. GW695634 . .18 Double PI Regimens: Reyataz/ritonavir . .18 s 630 patients with extensive treatment-experience resistance to 908/Ritonavir . .22 protease inhibitors were randomized to tipranavir or another Saquinavir/ritonavir . .27 boosted PI regimen in RESIST 1 Study Kaletra Report . .28 Sustiva . .31 s Patients were highly treatment experienced: median of 12 prior Triple PI Regimins . .32 antiretroviral HIV medications: 6 NRTIs, 2 NNRTIs, 4 protease ART Hepatotoxicity . .33 inhibitors; patients had an average of 15 baseline protease muta- 6th Lipodystrophy Workshop: heart disease, lipoatrophy . .34 tions Insulin Resistance/Diabetes and HIV; Aging & HIV . .35 Reyataz & Glucose Metabolism . .37 s 41.5% of patients taking tipranavir vs 22.3% taking other PI Trizivir + Tenofovir Compared to Combivir + Efavirenz . .38 regimens had at least 1 log reduction in viral load (p<0.0001) FDAApproves Two Once Daily 1 Pill New Nuke Regimens 39 (Intent-To-Treat: non-completer=failure analysis, most stringent). Tenofovir+ FTC Once Daily Compared to w/Combivir . .39 HIV Superinfection & Response to HAART . .40 s 34.7% of patients taking tipranavir vs 16.5% taking other PI HIV Drug Resistance Found in 1 of 7 Treatment Naives . .41 regimens had <400 copies/ml (ITT: non-completer=failure analy- Transmitted HIV Drug Resistance & Response to HAART . .41 sis) Depression, HAART & Women . .42 Prevalence & Late Diagnosis of HIV in Black Men in NYC 42 continued on the next page... Safety & Tolerabiltiy of Vaginal Tenofovir-Microbicide . .43 New HIV Drug Class: ‘Entry Inhibitors’ Which Block HIV from Entering CD4 Cell Perhaps the greatest hope in the foreseeable future of HIV administered by infusions at least one week apart perhaps two. treatment is the development of entry inhibitors. There are 4 promising orally administered entry inhibitors being studied in The three steps required for HIV to enter cells: attachment, bind- patients. ing to a co-receptor (CCR5, CXCR4), fusion of HIV into cell (CD4 cell). The currently available classes of drugs work to prevent the This report explains how entry inhibitors work. Below are process of HIV reproducing itself and infecting new cells after extensive reports reviewing the current status of 5 new entry HIV enters the CD4 cell: nucleosides (AZT, d4T, abacavir, teno- inhibitor drugs in active development: UK-427,857 CCR5 fovir, 3TC, FTC, ddI) and non-nucleosides (efavirenz, nevirapine, inhibitor (Pfizer), BMS’ attachment inhibitor program, SCH-D delavirdine), and protease inhibitors (Reyataz, Kaletra, Crixivan, CCR5 inhibitor (Schering-Plough), GW873140 CCR5 inhibitor Saquinavir, Fosamprenavir, Viracept). (GlaxoSmithKline), and TNX-355 (Tanox) attachment inhibitor administered by infusion every week or two. These drugs are orally administered, except for the Tanox drug, which is continued on the page 3... Visit the NATAP website at http://www.natap.org s If also taking Fuzeon, 47% taking TPV/r vs 21.9% taking ies of tipranavir. RESIST 1 and RESIST 2 are the large phase other PI regimens had <400 cp/ml III studies conducted by Boerhinger Ingleheim examining the antiviral activity and safety of tipranavir. The 24-week results s 25.1% of patients taking tipranavir vs 10% of patients taking of RESIST-1, which is the US based study, was reported at other PI regimens had <50 copies/ml. If also taking Fuzeon: ICAAC (October 04), and RESIST-2 results were reported at 32.8% taking TPV/r vs 14.3% taking other PI regimens had the European HIV Conference in Glasgow November 2004. <50 c/ml Tipranavir is dosed at 500 mg twice daily along with 200 mg of ritonavir also twice daily to boost tipranavir levels. s Viral load reduction at week 24: -0.88 for patients taking TPV/r vs -0.28 for patients taking other PI regimens. About R E S I S T study participants were randomized to receive 36% of patients in the study were taking Fuzeon. tipranavir (500/200) or other boosted PI regimens, and all par- ticipants also received 2 nukes which could be selected by s TPV/r treatment response was improved with use of other using resistance testing. The baseline characteristics were active ARV drugs in the optimized background regimen. comparable for study participants who received tipranavir or the other PI regimen: 90% men; 75% white, 21% black; 8% 24 week results were reported just weeks ago for the first time had hepatitis; average CD4 count was 120; average viral load from the 2 large phase III trials of tipranavir, the new ritonavir- was 66,000 copies/ml; and on average each patient already boosted protease inhibitor developed for patients with resist- had 15 protease inhibitor drug mutations. Patients had a phe- ance to currently available protease inhibitors. The RESIST-1 notype resistance test (Virco assay) before starting the study & 2 Studies examined the performance of tipranavir in over and were in general sensitive to tipranavir, but highly resistant 1400 highly treatment-experienced patients in the USA and to other protease inhibitors: on average study participants had internationally. These studies found tipranavir is effective for 77-fold resistance to Kaletra (LPV/r), 39-fold resistance to many patients with extensive resistance to currently available indinavir, 27-fold resistance to saquinavir, and 12-fold resist- protease inhibitors. ance to amprenavir. Study participants had on average 12 prior antiretroviral HIV 36% of the study participants in RESIST-1 also were taking medications (6 nukes, 2 NNRTIs, and 4 protease inhibitors), Fuzeon, but some patients had been on Fuzeon for a period and had an average of 15 protease inhibitor drug mutations of time before starting the study. Other patients started prior to entering the study. The two RESIST studies had simi- Fuzeon for the first time when they started tipranavir in this lar results so I’ll report here the results from RESIST-1 which study; these patients were more likely to see a better viral was conducted in the USA. response because the patients who had previously started Fuzeon may have already developed resistance to Fuzeon. Although patients in this study had extensive resistance to available protease inhibitors ranging from 12-fold to 77-fold, Results the average viral load reduction was -1.5 log copies/ml at Viral Load Response week 4, a potent response. Unfortunately, by week 24 the viral The study protocol defined a treatment response as 1 log or load on average increased for some patients. At week 24, the more viral load reduction from baseline to week 24. You can average viral load reduction was -.88 log copies/ml. However, see in the table below that patients who received tipranavir --a very important point-- patients who also took Fuzeon, the (TPV/r) did much better than patients who received other pro- new entry inhibitor, along with tipranavir had a better tease inhibitors: they had a better reduction in viral load, and response: 35% of all patients receiving tipranavir in this study were more likely to achieve an undetectable viral load. achieved <400 copies/ml HIV viral load at week 24, but for Patients who also took Fuzeon along with tipranavir had bet- patients who also took Fuzeon 47% had <400 copies/ml HIV ter success in achieving undetectable viral load (47% had viral load. This demonstrates a very important point: when <400 copies/ml and 33% had <50 copies/ml). starting a new regimen, it is crucial to achieving success to start simultaneously at least 2 new drugs to which the patient (ITT analysis) is fully sensitive. This will provide the best opportunity to achieve a good viral load response and for the response to be TPV/r Other PIs durable. % with Treatment Response 41% 22% (1 log viral load reduction) Tipranavir is expected to receive FDA approval around March/April 2005. If a person needs immediate access to Median viral load reduction tipranavir, the Expanded Access Program has started and a Week 4 -1.5 log 0.5 log patient can gain access to it through their doctor. As well, Week 24 -0.88 -0.28 Roche is making Fuzeon available to take along with tipranavir in this study if a patient needs availability. This way Proportion with Undetectable Viral Load a patient can start with two new drugs and this should help in <400 copies/ml 35% 16% achieving the best viral load reductions that hopefully can also TPV+Fuzeon 47% 22% be durable.