CROI meeting, Seattle
The drug pipeline starts filling up again
At the World AIDS Conference in Durban, South Africa in 2000, observers looked in vain for reports on new medications for treatment of HIV. ‘‘Perhaps,’’ they said, ‘‘we will have to wait until the meetings in the United States.’’ But there were few new therapies unveiled at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), and the field seemed barren at the 2001 Conference on Retroviruses and Opportunistic Infections (CROI). And so it went until the Ninth CROI in Seattle, Washington, in February.
`‘After a lull for 2 or 3 years,’’ said Brian Gazzard, MD, consultant at Chelsea and Westminster Hospital, London, England, ‘‘the news is really quite exciting.’'
Added Robert Schooley, MD, professor of medicine at the University of Colorado Health Sciences Center, Denver: ‘‘This is the year of the HIV-entry inhibitor. We are seeing a whole host of drugs coming forward to address this step in the virus life cycle.’'
First anti-CCR5 drug
SCH C, the first of a new class of drugs – the CCR5 co-receptor attachment inhibitors – sharply reduced HIV RNA. ‘‘We believe this is proof of principle,’’ said Mark Laughlin, MD, director of clinical pharmacology at Schering-Plough, Inc., Madison, New Jersey. (J. Reynes et al., SCH C: safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. Ninth CROI. Seattle, Washington, February 2002 [abstract 1]). Even when used as monotherapy, SCH-C appeared effective in 10 out of 12 patients, reducing viral loads from 0.5 log10 to 1.5 log10. Numerous other trials will be necessary before SCH-C can be added to the clinicians’ armamentarium, but if the drugs survives those trials, Dr. Laughlin said that he expects that SCH-C will most certainly be combined with other classes of antiretroviral agents to enhance its effectiveness and reduce risk of developing resistance.
In the study, patients received monotherapy at a dose of 25 mg every 12 h. Laughlin acknowledged that because the drug's half-life is about 24 h, it might be possible to provide therapy on a once-a-day basis. The patients in the 10-day trial were on no antiretroviral agents and were required to be treated only with SCH C for 10 days and then were observed over an 18-day period. Laughlin said viral loads rose slightly at the start of the trial and then dropped dramatically.
One as potent as five
`‘Remarkable’’ results using the second generation non-nucleoside reverse transcriptase inhibitor TMC 125, being developed by Tibotec-Virco, were reported by Dutch researchers. (S. Sangkatsing et al., TMC125 monotherapy for 1 week results in a similar initial rate of decline of HIV-1 RNA as therapy with a 5-drug regimen.Ninth CROI. Seattle, Washington, February 2002 [abstract 5]). As monotherapy, the reductions in plasma HIV RNA produced were equivalent to that seen in earlier studies of a potent five-drug cocktail – considered the most effective treatment for lowering viral levels.
Joep Lange, MD, professor of internal medicine at the Academic Medical Center, University of Amsterdam, commented on the results from the 12-person TMC125 study with the 5-drug cocktail. ‘‘Not only were the drops in virus similar in both groups, but there was a remarkable increase in CD4-positive cells as well,’’ Dr. Lange said. ‘‘There was a gain in CD4-positive cells of about 120. We almost never see increases like this.’'
Dr. Gazzard also presented data on TMC125, detailing how the experimental drug could control viral replication even in patients with virus that had developed mutations allowing the pathogen to escape efavirenz or nevirapine therapy. In the week-long study in which TMC125 was substituted for the non-nucleoside reverse transcriptase inhibitor that was failing to keep the virus in check the 16 male patients showed a steady reduction in viral load until the viral level had fallen nearly 1 log10 when the patients’ blood was tested on day 8 of the trial. Twelve of the patients showed multiple mutations to NNRTIs in genotype testing.
Twelve of the patients showed a greater than 0.5 log10 fall in viral load; seven patients achieved greater than a 1 log10 fall. Patients remained on the nucleoside reverse transcriptase regimens. After the trials, patients could be placed on any antiretroviral regimen available at the discretion of his doctor. ‘‘TMC125 demonstrates significant antiretroviral activity, ’’ Dr. Gazzard said, ‘‘and it is well-tolerated.’’ Diarrhea and headache were the most common of the grade 1 adverse events reported. Overall 11 of the patients reported some adverse event.
NNRTI without the rash
Fewer adverse side effects without sacrifice of efficacy was observed with another NNRTI, Bristol-Myers Squibb's DPC 083 (N. Ruiz et al. Study DPC-083-201: a phase II double-blind comparison of 3 once-daily doses of the NNRTI DPC 083 vs. 600 mg efavirenz in combination with 2 NRTIs in HIV antiretroviral treatment-naive patients. Ninth CROI. Seattle, Washington, February 2002 [abstract 7]).
Nancy Ruiz, MD, a group director for research at the company's Pharmaceutical Research Institute office in Princeton, New Jersey, reported that DPC 083 appears to carry less risk of central nervous system symptoms – headache, insomnia and other problems – than one of the standard NNRTIs, efavirenz. In addition DPC 083 appears to cause less rash than another NNRTI, nevirapine.
Ruiz said the drugs appear to be successful in treating patients whose original therapies are no longer working because of HIV mutations that allow the virus to escape the inhibiting action of the drugs. ‘‘The newer drugs are getting better. They are easier to tolerate. They can be delivered on a once a day regimen,’’ said Richard Colonno, PhD, vice president of infectious drug discovery at Bristol-Myers Squibb. ‘‘These new drugs will help people stay on medication longer because they are more convenient and that may also help reduce development of resistance.’'
However, Dr. Schooley noted, ‘‘Some of these drugs are just entering human trials so that it is unlikely that any of them will be approved for use in the United States this year.’'
So what infected the chimpanzee?
Even as research continues to discover how HIV jumped from primates to humans, Beatrice Hahn, MD, professor of medicine at the University of Alabama at Birmingham, has been investigating how and when SIV may have been introduced into the source of human infection, the chimpanzee itself. ‘‘We now think that chimpanzees may have acqui r ed their lentivirus by cross-species transmission from another primate species most likely in West Central Africa. The timing of this event cannot be determined, but there is reason to believe that this occurred thousands rather than hundreds of thousands of years ago,’’ Dr. Hahn said. (B Hahn, Natural SIV reservoirs and human zoonotic risk. Presented at the Ninth CROI. Seattle, Washington, February 2002). One hypothesis, she said, is that the infection appeared in chimpanzees after West African chimps had become geographically separated from their Central and East African cousins. ‘‘More than 3000 chimpanzees in US and European primate centers originally captured and exported from West Africa have thus far been screened and none has ever been found to be SIV infected,’’ Dr. Hahn said. But SIV has been found in wild troops of chimpanzees native to central and east Africa. This finding led her and her colleagues to conclude that the geographic separation of the West African chimps must have predated the introduction of SIV into chimpanzees.
Recombinant virus at work
The question then becomes, of course, from which species did the chimpanzees in central and east Africa acquires the virus that developed into SIV. Dr. Hahn is fairly certain she knows the answer: ‘‘The chimpanzee SIV appears to be a recombinant virus, comprised of portions related to viruses infecting red-capped mangabeys and greater spot-nosed monkeys.’'
And how did those viruses infect the chimpanzees? ‘‘The chimpanzees hunt and eat these smaller other primates,’’ Dr. Hahn said. ‘‘and red-capped mangabeys, greater spot-nosed monkeys and chimpanzees share the same habitat.’’ However, she stressed, ‘‘this happened a long time ago, long enough for the chimpanzee to adapt to this infection and not to develop disease as a result of it.’'
Interestingly, the subsequent jump of chimpanzee SIV to humans where it turned into HIV-1 – which she predicts probably occurred in the 1930s, give or take 20 years – is thought to have occurred similarly because humans hunt and eat chimpanzees. Dr. Hahn said: ‘‘HIV clades M, N and O could also be the result of independent chimpanzee-to-human cross-species transmission events.’'
And there may be still other SIV lurking to be transmitted to humans. Recent studies of pets and primate bushmeat in Africa revealed several new SIV infections in monkeys other than chimpanzees that were previously not known to harbor these infections. These could provide new sources of human infection. But current scientific tools are not sufficiently sensitive to detect such infections even if they had occurred, Dr. Hahn said, ‘‘We will need to develop strain-specific assays to address this public health concern.’'
Web sites of interest
Conference on Retroviruses and Opportunistic Infections: http://www.retroconference.org
Chelsea and Westminster Healthcare: http://www.chelsea westminster.co.uk
Bristol-Myers Squibb: http://www.bmsvirology.com
Academic Medical Centre of the University of Amsterdam: http://www.amc.uva.nl