New antiretroviral drugs in development which may
have antiviral activity against resistant viruses in salvage situations
ABT-378--From Abbott. Very potent in early studies in treatment naive. Has potential in salvage situations when person has PI resistance. Need more
study data to confirm this. Additional data is expected to be reported very soon.
Adefovir--this drug from Gilead Sciences was the first nucleotide developed and is in the latter stages before FDA review for accelerated approval. The modest antiviral activity of this drug (0.60 log reduction) may increase when the M184V 3TC-related mutation is present to as much as 0.90 log. Adefovir appears to retain antiviral activity against virus with NRTI resistance. Preliminary data suggests adefovir resistance is hard to develop. As well adefovir is once a day. However, the drug can cause a kidney related side effect manifested by kidney related lab abnormalities. Dose reduction and discontinuation of the drug may be necessary if these side effects develop. In a recent report of preliminary data from a study Gilead reported the incidence of this side effect was reduced when adefovir dose was reduced from 120 mg once daily to 60 mg once daily. You can read more about resistance, efficacy, and the incidence of the kidney side effects in the current NATAP Reports newsletter (click here to be linked to this article).
PMPA -- is the second nucleotide developed by Gilead. It's more potent than adefovir, once daily, and so far the kidney related side effects have not emerged in studies but it is too soon to conclude they will not occur. PMPA is being studied at lower doses than possible due to caution regarding the potential development of kidney related side effects. Higher doses will be explored as long as kidney related side effects are not observed. The potency of PMPA will likely increase to a level similar to protease inhibitors if higher doses can be reached. The drug is in the middle stages of development. Expanded access may be available by mid 2000. Cross resistance with protease inhibitors is not expected.
AG 1459--new NNRTI from Agouron. In vitro data shows it to have antiviral activity against viruses with NNRTI resistance. Clinical studies to explore its use in naive and NNRTI resistance about to begin. (see NATAP web site to read about two new Agouron drugs and HE2000).
AG 1776-- new PI from Agouron.. In vitro data suggests it also may have antiviral activity against PI resistant virus. Clinical studies are now being designed.
T-20--new fusion inhibitor that has shown nice antiviral activity. Log reductions of 1-1.5 in small one month study. Since its a new class of drug persons resistant to current classes (NRTIs, NNRTIs, and PIs) should not be cross-resistant. Study in salvage situation starting now. Presents a nice opportunity for persons needing to piece together salvage regimen. T-20 will have to be used in combination with other drugs as it appears resistance can and does develop.
DOTC--new NRTI. Early in vitro data shows this to be potent NRTI and has antiviral activity against viruses with AZT and 3TC resistance. Clinical studies are being planned now. It will be tested in individuals with NRTI experience and resistance, and in individuals who are treatment naive. (see NATAP web site for most recent report on DOTC at May Salvage Therapy Workshop).
FDDA--new NRTI which also shows it may have antiviral activity against NRTI resistance virus. Cousin to ddI so it may have synergy with hydroxyurea. This will be tested. In early studies it appears more tolerable and has less side effects than ddI.DAPD--new NRTI which also may have antiviral activity against NRTI resistant virus. Studies being designed.
DuPont NNRTIs--Dupont has new NNRTI which may be able to suppress virus resistant to efavirenz and other NNRTI resistant virus. (see web site for report from Human Retrovirus Conference).
Tiprnavir--new PI from Upjohn. Ealy in vitro and in human data shows it has antiviral activity against protease inhibitor resistant virus. Studies are being planned now to begin soon.
BMS-232632--new once a day PI from Bristol Myers. Studies in PI naive have started. In vitro data showed this drug had antiviral activity against PI resistant virus. Studies in this population are supposed to start soon.
Fusion inhibitors--a number of research efforts are looking at developing fusion inhibitors. Generaly it appears clinical studies for particular drugs are 1-2 years away.
Integrase inhibitors-- this class of potential drugs is being researched by a number of research groups but progress seems to be very slow. I am uncertain if and when drug candidates will be available for clinical studies. It could happen 1-2 yrs from now but depends on luck of candidate emerging.
HE2000-- (see NATAP web site for article). Small clinical study ongoing in So Africa and about to begin at several US sites. Human data from So Africa site should be available at ICAAC in late September. Animal dats showed antiviral activity but its premature to assume anything.
Glaxo Wellcome and Upjohn also have NNRTIs in development which may have antiviral activity against NNRTI resistant virus. A few additional second generation PIs are in development but do not have data yet to report.
As you may know, indinavir+ritonavir, and amprenavir+200 mg ritonavir may be successful components of a salvage regimen. On this web page is preliminary PK data on amprenavir+ritonavir. Several studies, in particular the Mike Youle study presented most recently at the Toronto Salvage Therapy Workshop, have shown good data on using ritonavir+indinavir in salvage situations. You can read several articles about indinavir+ritonavir on this web site. In particular, the current NATAP Reports has recent information about this combination (click here to be connected to the indinavir+ritonavir article in April '99 NATAP Reports).
It's been suggested by a number of studies and resarchers/doctors that a person follow their viral loads every 4-7 weeks; and, If a person is on their first PI regimen and viral load rebound is detected, it's advised that you consider changing or modifying your regimen immediately. Staying on a PI or NNRTI with detectable viral load permits mutations to accumulate. The more mutations that accumulate the less likely a person is to respond to the next PI. Several studies have shown that by switching your PI quickly after detecting viral load rebound you are more likely to respond to second PI therapy.