re: vertex
I'm glad that Vertex finally applied for expanded access, because this drug has been in trials for a long time. Phase I clinical trials started 6 years ago, and Phase III trials started in January 1997. Many of the reports so far have included a small number of patients, with variable results, and differing side effects. I hope they present larger studies. They must have data for larger trials, if they are applying for an NDA soon. Most of the information below is old news.
Initially Vertex claimed a unique resistance pattern, and the 150V mutation is not found in other PI's. However that is the first mutation, other mutations follow that are similar to those found in other protease inhibitors. In ACTG 347, PI and 3TC na‹ve patients received either ZDV/3TC/AMP or AMP monotherapy. Resistance data showed that 4/19 AMP monotherapy recipients had the I50V mutation, while 16/19 had mutations associated with cross-resistance to other protease inhibitors at L10, M46, K20, V82, and I84. Four of eight monotherapy failures PBMC isolates show cross resistance to other PI's consistent with genotypes. The mutation that occurs with Viracept failure, D30n? is found only with Viracept. Sometimes the 90 mutation arises later, and this mutation can occur with Saquinavir failure. But Viracept does have the best resistance profile of the PI's, with few if any mutations common to other protease inhibitors.
"These data do not support the earlier contention that AMP might not display cross-resistance with all other available protease inhibitors of this class due to a unique resistance pattern. "As with other triple therapy failure that include a PI, viral rebound is not always due to PI resistance, but more likely to 3TC resistance. However this is an early event, and AMP resistance would be expected to follow. "
atp.org.uk Protease Inhibitor Resistance
Combining Three Hot Drugs Is Not So Hot (This isn't a new study, actually none are. )
It is not thought that AMP will be that useful for salvage, at least when combined with abacavir or Sustiva, as all three show cross -resistance. The open label NIH 2007 trial enrolled 101 participants with 20 weeks of detectable viral loads. Initially a small group (n=11) who had failed Indinavir, were given Amprenavir and Abacavir. Two showed a 2 log drop, but it only lasted for 6-8 weeks. One patient's VL declined for 28 weeks. After Sustiva was added, 5/9 patients showed at least 1 log drop. However, Sustiva activated liver metabolism, and reduced Amprenavir Cmax by 46% and trough levels by 59%. Even though Sustiva levels decreased AMP greatly, the dosage of AMP was not increased because AMP already has a high pill burden: 8 large pills, twice a day. Only 5% of NNRTI-experienced patients and 24% of NNRTI-na‹ve <copies at 8 weeks. Many of the patients were cross resistant to Sustiva, the main force behind the combination.
atp.org.uk
"For all the participants, previously developed cross-resistance apparently presented a major challenge to both the Abacavir and Amprenavir. And whether Efavirenz was effective or not in a patient, it lowered Amprenavir levels, making this protease inhibitor still more problematic."
"This regimen was also complicated by the three drugs' overlapping side effects: 47% of participants suffered skin rash or irritation, 59% had digestive complaints and central nervous system side effects were evident in 67%. Such side effects could cover up a relatively rare systemic syndrome that leads to a potentially life-threatening hypersensitivity to abacavir. However, Dr. Falloon stressed that this syndrome has only occurred upon discontinuing and then reintroducing the drug."
I don't think this particular salvage combo sounds too hot.
According to a brief report by Jules Levin yesterday, AMP's resistance profile suggests that it may have effectiveness for those who failed previous protease therapy (I don't believe it, only if it is a combination of many drugs-Mega HAART, just my opinion, unless he knows about some new studies) Studies of combining amprenavir with a second PI show promising data. The initial results of
studying these double protease combinations are available in the May edition of
our newsletter, NATAP Reports. I think those were treatment na‹ve patients. One year data is expected to be reported in November at an AIDS conference in Glascow.
Amprenavir has not yet been studied with RTV, but RTV may reduce the amount of
amprenavir needed and may increase amprenavir antiviral activity by increasing
its blood levels. Amprenavir with IDV, NFV, or SQV were studied and have
appeal.
In preliminary PK studies:
Indinavir increased (Cmax- 16-31%; AUC- 22-64%) amprenavir blood levels.
Amprenavir increased nelfinavir Cmin by 100%.
These PK interactions may allow effective salvage regimens, using the right drugs. The above combination shows as expected, AMP and Abacavir and Sustiva are not effective in heavily pretreated patients, especially if they have had NNRTI exposure.
Patients experiencing early virologic rebound during amprenavir combination with ZDV/3TC (n=7) showed no mutations in some cases (3/7), 3TC resistance alone (3/7) and both NA and PI mutations (1/7, mutants in protease at codons 5 0, 54, 84 each as minorities). In amprenavir monotherapy (n=19) patients with rebounding viral load, 4/19 had the I50V mutation, as well as 16/19 having other mutations typical of PIs (including at codons 10, 20, 46, 82 and 84) [abs 71 & 86].
It is not thought it will be useful for salvage therapy, as Amprenavir shows similar cross resistance patterns as crixivan and ritonavir. At one point, Vertex was emphasizing how well it crosses the blood brain barrier. Lately, they have been emphasizing how great AMP is at immune reconstitution, because in a study presented recently, the CD4 cells increased +200 from a baseline of 756. Such a high baseline indicates they were in good shape to begin, immunologically.
A newer theory is that a large number of CD4 cells may be harmful, because it just provides more target cells. What is needed are more specific anti-HIV CTLs. atp.org.uk
Rapid, large increases in CD4 cell counts in response to combination therapy may not be all good
"Large increases in target cell numbers as a consequence of immune reconstitution, while reducing risk of opportunistic infections, also increases the probability of treatment failure. As Dr McClean explains "Since HIV is an obligate parasite, it has no intrinsic growth rate. The viral reproduction rate is strongly dependent on the number of target cells available in which it can reproduce and therefore increases as a result of immune reconstitution. " This hypothesis was supported by the observation, again in study ACTG 343, that virological failure was, indeed, more likely in those patients experiencing a large CD4 cell rise [abs 74]. Improvement in HIV specific CTL in concert with rises in CD4+ lymphocyte populations may well offset this effect, but has yet to be reported with PI-containing regimens in chronic infection (although this was reported in hydroxyurea containing regimens - see below)."
"Specific induction of anti-HIV CTL responses may be needed to give additional suppression of HIV in the face of increasing target cell availability. A late breaker presentation at Geneva reported the preliminary efficacy of immune stimulation with a killed gp-120 depleted whole HIV preparation (Remune) as immunotherapy in patients receiving combination therapy [Geneva abs.31227]. This study contained a control arm of adjuvant only, and at week 20 the Remune receiving arm demonstrated strong lymphocyte proliferative responses to a variety of HIV antigens which were not seen in the control arm (more details in the Geneva reports starting in the next issue of ATP's DocFax).
Ironically, Vertex is stressing how well AMP is at rebuilding or building immune reconstitution, but they are only referring to an increase in CD4 cells, and according to this theory, would be more likely to lead to viral failure, due to the increase in target cells available to be infected.
Vertex does not mention an increase in anti_HIV CTLs.
Hot off the press, not, yesterday it was
22 Sep 1998 20:09:33 -0500
[AEGIS] Research teams agree that HAART may help fight PML
In a letter published last week in the New England Journal of Medicine, a
team of Italian researchers report promising results observed in patients
with progressive multifocal leukoencephalopathy (PML) who were receiving
highly active antiretroviral therapy (HAART).
PML is a viral infection of the brain which can cause debilitating symptoms
in infected patients, including partial paralysis, speech problems and loss
of vision. Until recently, no satisfactory treatment of PML was available
and most patients with the condition died. However, it now seems that
combination therapy with protease inhibitors (HAART) may offer hope to
patients with PML.
Doctor Paula Cinque and colleagues at the San Raffaele Hospital in Milan
initiated HAART in 10 patients with symptoms of PML within 90 days of their
onset; none of the patients had previously used protease inhibitors. PML
diagnosis was confirmed by the presence of JC virus DNA in the
cerebrospinal fluid of each patient. Under treatment, "neurologic symptoms
improved substantially in six patients, remained stable in three and
worsened in one." In addition, half of the patients showed no sign of JC
virus DNA in their cerebrospinal fluid after at least 112 days of
treatment. As well, nine patients had undetectable HIV viral load and a
median CD4+ increase of 43 cells after 180 days.
This team's findings were supported by researchers at the University of
North Carolina School of Medicine, site of the ACTG 243 study that showed
double nucleoside analogue and cytarabine therapy to be ineffective against
PML. In a letter published in response to the Milanese team's report, Dr
Colin Hall and colleagues affirmed that "control of HIV should be the aim
in HIV-infected patients presenting with progressive multifocal
leukoencephalopathy."
N Engl J Med 1998;39:848-849.
Both letters referred to in this article may be viewed at the Web site of
the New England Journal at:
nejm.org |
