The FDDA study has been stopped subsequent to ICAAC because 1 study participant died. They had elevated billirubin and LFTs. The person was reportedly over drinking, vomiting and taking extra doses of meds. Several other study participants with elevated bilirubinand possibly LFTs have been hospitalized for observation.

1. DOTC
2. FDDA
3. T-20
4. ABT-378
5. PMPA
6. Tipranavir -- this is a new protease inhibitor . At the Resistance Workshop in June 1999 researchers reported results from an in vitro preliminary study showing that tipranavir was active against virus resistant to protease inhibitors. A detailed report on tipranavir is on the NATAP web site in the Resistance Workshop Reports contained in the Conference Reports section.

Or BCH-10652 is a nucleoside analogue. Following is preliminary data from a double-blind, placebo-controlled phase I/II trial od dOTC monotherapy to assess safety, antiviral activity and pharmacokinetics over 7 day period in HIV-infected individuals. Treatment naives with CD4 >200, viral load 5,000-100,000 copies/ml were randomized to receive dOTC or placebo (8:2) at 3 different dOTC doses.

* Roche Amplicor Assay
** the 8th person went undetectable.

Authors said all dOTC dose were well tolerated with no significant lab or clinical parameter changes. More detailed reports to follow.

Or lodenosine is a reverse transcriptase inhibitor which although similar to ddI it will have oral formulation without need for buffers and antacids to maintain integrity of active component. FDDA has relatively long halflife (20 hrs). The study authors said and prior data suggests FDDA may have have little cross-resistance with other NRTIs such as AZT, ddI or ddC. HIV with multi-nucleoside drug resistant mutation remain sensitive to FDDA. This is in vitro and preliminary and will have to be confirmed in clinical studies. FDDA will likely be explored as a once daily regimen in the future. This study reports interim data analysis of 3 FDDA doses in combination with d4T+indinavir at week 12 compared to 3TC+d4T+indinavir. Study will continue for 48 weeks. Its expected that hydroxyurea and fddA will have same synergy as hydrea and ddI but study hasn't been conducted yet. Differences between these arms could emerge given more follow-up.

Adverse Events

Grade 3/4 Adverse Events in >1% of Patients

Discontinuations

FDDA 100 mg -- 7.1% (n=5)

FDDA 200 mg -- 10% (n=6)

FDDA 300 mg -- 13% (n=8)

3TC -- 21% (n=4)

Or Tenofovir is a nucleotide with a unique preliminary resistance profile. It should be effective against resistant virus. In this study participants had HIV-RNA between 400 and 100,000 copies/ml on stable therapy for >8 weeks and were randomized to receive 75, 150 or 300 mg PMPA or placebo. Participants were permitted to change regimen after 4 weeks. Twenty percent in each arm did so.

Interim VL Changes

4.4% on PMPA (7/160) discontinued, investigators called it well tolerated. It’s promising that after 6 months PMPA treatment there were few who developed kidney related lab abnormalities as is associated with adefovir. The manufacturer of PMPA will have to decide whether to explore higher dosing of PMPA.

ABT-378 (see separate more detailed report on ABT-378 on web site)

is a protease inhibior that will be combined in one capsule with small amount of ritonavir because RTV greatly enhances ABT-378 blood levels making it more potent and effective. Two studies were reported at ICAAC--in treatment naive and people who failed one PI but were NNRTI naive. In the naive study participants received 400/100 or 400/200 of ABT-378/ritonavir in combination with d4T/3TC. After 36 weeks of therapy 95% had <400 copies/ml and (on-treatment analysis) 89% (24/27) had <50 copies/ml. 

In the treatment experienced group at week 36 78% (47/60) had <400 copies/ml. The baseline median viral load was low at 10,000 copies/ml and the study did not examine people who failed 2 or more protease inhibitors. Such a study is ongoing or planned to start soon. Investigators said treatments were well tolerated in that to date only 2 people discontinued for AEs related to ABT-378. A small compassionate access program just started offering ABT-378 to individuals who have low CD4s and need it to compose a viable salvage regimen. A broader program will begin in early 2000.

This is a fusion inhibitor that is administered twice daily by subcutaneous injection. It is a new class of drugs and it’s not expected to have cross-resistance with currently available classes. So it is expected to be of help to individuals with resistance to currently available drugs. Studies are proceeding but their may be a shortage of drug if and when it is approved by the FDA for commercial distribution. There may not be enough drug available to meet demand because this type of drug has never been manufactured before and gearing up will be difficult and limited by manufacturing. In this study people with extensive experience with prior treatment received a regimen including T-20. Participants had received T-20 during previous studies. Participants received 50 mg T-20 BID by self-administered subcutaneous injections in combination with drugs selected on the basis of genotypic resistance testing. Prior to receiving T-20 in this study (n=55) patients had used a median of 11 prior drugs and 93% has used drugs from all 3 classes. Median baseline VL was 80,000 copies/ml and CD4s of 70. Percentage of patients with genotypic mutations associated with NRTIs and NNRTIs was 87% and with protease inhibitors was 93%. At 16 weeks no one discontinued due to T-20 toxicity and 60% (33/55) had VL reductions >1 log and/or <400 copies/ml; 36% (20/55) had <400 copies/ml.