icon_folder.gif   Conference Reports for NATAP  
  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois, December 16-19
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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.
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.