 |
|
|
| |
Antiretroviral Therapy: Part 2.- FTC, Interferon, TMC-114 (new PI)
Reported for NATAP by Grame Moyle, MD, Ass. Dir. of HIV Research at Chelsea &
Westminster Hospital, UK, London
|
| |
| |
New drugs
There was not much new drug information in the poster section on new drugs
although elsewhere at the conference we heard encouraging news on azazanavir,
tipranavir as PIs and TMC-125 as an NNRTI.
FTC
The poster section had news of FTC a new once daily (QD) nucleoside analog.
FTC is remarkably similar to 3TC a drug that is also set to be used once
daily. They share the same resistance mutation (184V) albeit that once study
suggested that FTC may select this mutation slightly more slowly, they are
both well tolerated and have similar activity clinical against HIV and
hepatitis B. There are no combination formulations in development at present
with FTC (unlike with 3TC where we have both Combivir' and Trizivir'). It is
therefore hard to see an advantage to FTC although it may be used in the
future if combination tablets became available for once daily use such as
with ddI, d4T extended release or perhaps efavirenz or tenofovir. Long-term
72 week safety data with this agent was reported from extension data from one
of their phase II studies known as FTC-350 (Van Der Horst C, et al. abstract
1932). The available data included 214 patients who received FTC for the full
72 weeks. Most reported adverse effects were mild or moderate in nature and
not always clearly drug related or specifically related to FTC. The reported
values are low relative to many trials of similar length. The incidence of
drug-related severe or worse events was 5% and <1%, respectively. Most of the
events were gastrointestinal in nature, mainly nausea or diarrhoea. The
incidence of Grade 3 or 4 laboratory abnormalities was 18% and 15%,
respectively, mainly asymptomatic and transient elevations in the muscle
enzyme CPK. Efficacy data from a second FTC study (FTC-303) comparing FTC or
3TC used in combination with d4T plus an NNRTI in 234 treatment naive South
African patients (99 males and 135 females) reported efficacy data through 48
weeks (Zeier M, et al. abstract 1933). No efficacy differences were seen
between the choice of FTC and 3TC. The authors provided a novel analysis by
gender. Viral failure (VL never <400 or rebounded to above 400 copies/ml on
2 consecutive occasions) was observed in 14% of males and 10% of females,
with CD4 counts rises of 203 and 182 cells/mm3, respectively. Adverse events
rates leading to treatment interruption or discontinuation occurred similarly
in men (12%) and women (11%) although more men stay in the study, only 4%
being lost to follow-up or discontinued for personal/other reasons relative
to 14% of women. Of note, approximately 3% of women in the study withdrew due
to pregnancy. It is encouraging to see women responding similarly to men
virologically, but this is not the first study to suggest that somewhat
smaller rises in CD4 may be observed in women.
TMC-114: new PI
TibotecVirco have a number of interesting compounds, both PIs and NNRTIs is
early phase development. Data on one of the NNRTIs was presented during one
of the oral sessions. The new PI made the poster session. They reported on a
randomized, double-blind, placebo-controlled, dose-ranging trial of single
oral doses of their lead PI TMC-114. These types of studies, done in small
numbers of HIV negative volunteers are used to understand the pharmacology of
the drug to help plan studies in HIV infected persons so that they don't
start with insufficient doses that might allow for resistance or too high a
dose that might cause toxicity. They evaluated two groups of 9 healthy
volunteers each given active in 6 cases and placebo in 3. The sue of placebo
help identify which reported problems related to 'background' health
problems or the excipients that make up the inactive parts of the tablets.
The doses evaluated were 100, 200, 400, 800, 1200 or 1600 mg. The drug was
very well tolerated so further evaluation of 2400, 3200 and 4000 mg was
performed. The drug achieved levels that would be expected to be active
against HIV, including forms resistant to many currently available compounds
at 800mg or more and the elimination half-life of about 10 hours suggests the
feasibility of twice or perhaps once daily dosing (Van Der Geest R, et al;
abstract 1934). The most common side effects were diarrhea, and tingling
fingers or lips (also described with ritonavir and amprenavir) in the
occasional volunteer. The drugs now will go through multiple dosing in
volunteers then on to studies in persons with HIV.
Interferon: HIV antiviral
Interferon alpha has activity against HIV in vitro and was investigated in
the 'bad old days' when few drugs were available. Some limited activity was
reported in clinical trials but interest waned as new drugs emerged and
because of the inconvenience of daily injections. New forms of intereferon
alpha with polyethylene glycol (PEG) chemical groups attached are now
available as treatments for Hepatitis B and C (brands are PEG-Intron from
Schering Plough, and Pegasys by Roche Laboratories). These preparations allow
for once weekly dosing, have better activity against the hepatitidies and may
have some tolerability advantage over the previous forms. Several small
studies reported that these preparations have clear anti-HIV activity,
reducing HIV viral load by 0.5 log or more on average, sustained over 3 or
more months (Moreno L, et al; abstract 1937, Rodriguez A, et al; abstract
1938). These effects were often observed in individuals with detectable virus
despite HAART regimens underlining that as interferon alpha dose not affect
HIV via the same mechanisms as approved HIV drugs it retains activity despite
resistance to these drugs being present. Changes in CD4 were not significant
over the short term follow-up reported. Known side effect if pegylated
interferon alpha include fever, myalgia, and flu-like symptoms. The data
certainly justify further investigation of interferon alpha as part of a
salvage therapy for HIV but also provide strong reassurance for those with
HIV starting on pegylated interferon for Hepatitis that it won't harm the
management of their HIV infection and might just do it some good. Editorial
note: we do not have clear evidence yet that potential interactions between
ribavirin and certain NRTIs (3TC, AZT, d4T, ddI) won't have detrimental
effects. So far in studies we have not seen any evidence of clinical
detrimental effects but ongoing lab studies and larger clinical studies have
not presented results yet.
|
|
| |
|
|
|
|
|
