{"id":3104,"date":"2006-09-10T08:41:18","date_gmt":"2006-09-10T07:41:18","guid":{"rendered":"http:\/\/moomango.co.uk\/htb\/?p=3104"},"modified":"2016-11-22T15:49:53","modified_gmt":"2016-11-22T15:49:53","slug":"maraviroc-results-in-r5x4-mixeddual-tropic-patients-unexpected-safety-data-shows-possible-immunolocical-effect","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/3104","title":{"rendered":"Maraviroc results in R5\/X4 mixed\/dual tropic patients: unexpected safety data shows possible immunolocical effect"},"content":{"rendered":"

Simon Collins, HIV i-Base<\/strong><\/p>\n

Of the three CCR5 inhibitors in development last year, only the Pfizer compound (maraviroc) is showing continued promise as a treatment for both naive and treatment experienced patients.<\/strong> [1, 2]<\/p>\n

The rationale for studying maraviroc (MVC) in patients with dual\/mixed (D\/M)-tropic infections includes the theoretical risk of outgrowth of X4-tropic HIV-1 when a patient with D\/M-tropic HIV-1 is treated with a CCR5 antagonist and because X4-tropic HIV-1 has been associated with more rapid CD4 cell depletion and progression to AIDS.<\/p>\n

Mayers and colleagues presented results from a double-blind placebo controlled study in 190 mixed\/dual tropic patients who were randomised to optimised background regimen (OBT) including at least one sensitive drug, plus either maraviroc once-daily (n=63), maraviroc twice daily (n-61) or placebo (n-60). [3]<\/p>\n

Over 90% patients were PI-experienced, with 50-60% currently using T-20. CD4 count and viral load were <100 cells\/mm3<\/sup> and > 5logs respectively. >95% patients had dual\/mixed tropism. Further baseline characteristics and tropism are detailed in Table 1.<\/p>\n

Table 1: Baseline characteristics and tropism<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
<\/td>\nPlacebo + OBT n=62<\/th>\nMVC QD + OBT n=63<\/th>\nMVC BID + OBT n=61<\/th>\n<\/tr>\n
Mean age (yrs), (range)<\/th>\n44.6 (23-65)<\/td>\n42.7 (16-59)<\/td>\n42.5 (16-62)<\/td>\n<\/tr>\n
Female, n (%)<\/th>\n9 (14.5)<\/td>\n10 (15.9)<\/td>\n6 (9.8)<\/td>\n<\/tr>\n
Race, n (%)<\/th>\n<\/td>\n<\/tr>\n
White<\/td>\n40 (64.5)<\/td>\n46 (73.0)<\/td>\n44 (72.1)<\/td>\n<\/tr>\n
Black<\/td>\n18 (29.0)<\/td>\n17 (27.0)<\/td>\n13 (21.3)<\/td>\n<\/tr>\n
Other<\/td>\n4 (6.5)<\/td>\n0 (0)<\/td>\n4 (6.6)<\/td>\n<\/tr>\n
Tropism, n<\/th>\n<\/td>\n<\/tr>\n
X4<\/td>\n2<\/td>\n2<\/td>\n4<\/td>\n<\/tr>\n
R5<\/td>\n0<\/td>\n1<\/td>\n0<\/td>\n<\/tr>\n
NP\/NR<\/td>\n2<\/td>\n3<\/td>\n5<\/td>\n<\/tr>\n
D\/M<\/td>\n58<\/td>\n57<\/td>\n52<\/td>\n<\/tr>\n
CD4 (cells\/mm3<\/sup>)<\/th>\n<\/td>\n<\/tr>\n
Mean<\/td>\n99<\/td>\n85<\/td>\n96<\/td>\n<\/tr>\n
Median<\/td>\n42<\/td>\n40<\/td>\n43<\/td>\n<\/tr>\n
(min, max)<\/td>\n(2, 650)<\/td>\n(1, 442)<\/td>\n(0, 615)<\/td>\n<\/tr>\n
HIV-1 RNA (log10<\/sub> copies\/mL)<\/th>\n<\/td>\n<\/tr>\n
Mean<\/td>\n5.01<\/td>\n5.03<\/td>\n5.10<\/td>\n<\/tr>\n
Median<\/td>\n5.10<\/td>\n5.10<\/td>\n5.17<\/td>\n<\/tr>\n
(min, max)<\/td>\n(3.65, 6.15)<\/td>\n(3.42, 5.94)<\/td>\n(3.61, 6.67)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

After 24 weeks, the mean decrease in viral load was similar between the maraviroc and placebo arms, but there was a statistically significant increase in CD4 counts in the maraviroc groups compared to placebo, which are detailed in Table 2.<\/p>\n

Table 2: Virologic and immunologic responses at week 24<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
All treated patients with D\/M-tropic HIV-1<\/th>\nPlacebo + OBT n=58<\/th>\nMVC QD + OBT n=57<\/th>\nMVC BID + OBT n=52<\/th>\n<\/tr>\n
Mean decrease in HIV-1 RNA (log10<\/sub> c\/mL)*<\/td>\n-0.97<\/td>\n-0.91<\/td>\n-1.20<\/td>\n<\/tr>\n
Treatment diff (MVC – OBT) in HIV-1 RNA decrease (log10<\/sub> c\/mL) (97.5% CI)<\/td>\n–<\/td>\n+0.06 (-0.53, +0.64)<\/td>\n-0.23 (-0.83, +0.360<\/td>\n<\/tr>\n
RNA <400 c\/mL (%)<\/td>\n24.1<\/td>\n24.6<\/td>\n30.8<\/td>\n<\/tr>\n
RNA <50 c\/mL (%)<\/td>\n15.5<\/td>\n21.1<\/td>\n26.9<\/td>\n<\/tr>\n
Mean decrease in RNA in pts using T-20** (log10<\/sub> c\/mL)<\/td>\n-0.89<\/td>\n-1.26<\/td>\n-1.44<\/td>\n<\/tr>\n
Mean CD4 change (cells\/mm3<\/sup>)<\/td>\n+36 (n=58)<\/td>\n+60 (n=57)<\/td>\n+62 (n=52)<\/td>\n<\/tr>\n
Pts with only X4-tropic HIV-1 detectable at time of virologic failure<\/th>\n<\/td>\n<\/tr>\n
Mean CD4 change (cells\/mm3<\/sup>)<\/td>\n-104 (n=2)<\/td>\n+48 (n=12)<\/td>\n+33 (n=12)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

There were 13 category C events: MVC QD (7), MVC BID (3), placebo (3). None of the 7 deaths in the study (MVC QD (2), MVC\u00a0BID (2), placebo (3) were considered MVC-related.<\/p>\n

The study concluded that over 24 weeks, in treatment-experienced patients with D\/M-tropic HIV-1 and advanced disease, maraviroc + OBT was generally well tolerated. There were no cases of hepatotoxicity, lymphoma or adenocarcinoma. Although the treatment arms did not demonstrate superior reductions in HIV-1 RNA compared with placebo, maraviroc + OBT was associated with greater increases in CD4 cell count than placebo + OBT.<\/p>\n

Patients receiving maraviroc + OBT were more likely to fail with X4-tropic HIV-1 than those receiving placebo + OBT. However, patients treated with maraviroc and X4-tropic virus at treatment failure had increases in CD4 cell count consistent with the overall maraviroc-treated population<\/p>\n

Comment<\/h3>\n

While virological response in this study was similar to placebo, this was expected in dual-tropic patients. More significant is the lack of HIV progression in this group, which was the main safety concern.<\/strong><\/p>\n

The safety from short-term exposure to a CCR5 inhibitor in patients with mixed tropism at baseline, may also indicate a lower dependence on a tropism test prior to treatment, especially as the current test is relatively insensitive and expensive.<\/strong><\/p>\n

The CD4 increase in the maraviroc arm was unexpected and deserves further investigation.<\/strong><\/p>\n

References:<\/p>\n

    \n
  1. GSK closes Phase 3 studies of its CCR5 inhibitor aplaviroc and terminates development programme. HIV Treatment Bulletin, Nov\/Dec 2005.
    \nhttp:\/\/www.i-base.info\/htb\/3106<\/a><\/li>\n
  2. Schering discontinues Phase II studies of vicriviroc in treatment naive patients. HIV Treatment Bulletin, Nov\/Dec 2005.
    \n    http:\/\/www.i-base.info\/htb\/3111<\/a><\/li>\n
  3. Mayer H, van der Ryst E, Saag M et al. Safety and efficacy of maraviroc, a novel CCR5 antagonist, when used in combination with optimised background therapy for the treatment of antiretroviral-experienced subjects infected with dual\/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. IAS Toronto, 2006. Abstract late breaker THLB0215.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Simon Collins, HIV i-Base Of the three CCR5 inhibitors in development last year, only the Pfizer compound (maraviroc) is showing continued promise as a treatment for both naive and treatment experienced patients. [1, 2] The rationale for studying maraviroc (MVC) …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3],"tags":[151],"class_list":["post-3104","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","tag-aids-16th-toronto-2006"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/3104","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=3104"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/3104\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=3104"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=3104"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=3104"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}