Important note: Information in this article was accurate in March 2001. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, March 2001
David Gilden
The annual Conference on Retroviruses and Opportunistic Infections, held this year on February 4-8 in Chicago, is supposed to be the premier event for reporting HIV treatment innovations. Though widely discussed in the halls, the biggest story this year went unmentioned in the official program. On February 5, the U.S. Public Health Service announced in Washington new revisions to its guidelines for treating adults with HIV. Those revisions embodied a striking change in tack.
The guidelines previously stood out for their aggressive approach to treating HIV. They recommended that patients consider starting antiretroviral therapy once their CD4+ T-cell counts fall below 500 cells/mm3 or plasma viral load rose above 20,000 copies/mL (as measured by the PCR assay). Now, the threshold for considering therapy is deemed to be a CD4 count of 350 or a viral load above 55,000 - so long as patients do not have "severe" symptoms.
Although there was no official presentation of the guideline revisions at the Retrovirus Conference, they pervaded the presentations by implication. One of the underlying issues behind the shift in the guidelines is the snowballing concern over long-term side effects. A related, more immediate issue is that the drugs just aren't what they were cracked up to be.
“Perhaps the word ‘highly’ in HAART [highly active antiretroviral therapy] should be changed or deleted", quipped HIV researcher David Ho, director of New York's Aaron Diamond AIDS Research Center, in his lecture on residual HIV replication during therapy (lecture S17). Based on the speed with which viral loads decline upon instituting effective antiretroviral treatment, Ho estimated that current combination regimens had an efficiency of less than 80%. (This is the percentage by which HAART reduces HIV infection of new CD4+ T-cells.) Viral loads may drop below detectable limits, but they usually cannot be reduced below a certain minimal amount. Many people will experience transient detectable "blips" in their viral load even if treatment does not fail outright.
The current drugs work very well in the lab, but physical limits to the amount of drugs patients can tolerate - or even ingest - circumscribe their effectiveness in the human body. The body's many barriers to undesirable substances keeps most anti-HIV medication from ever reaching the virus. These barriers include binding to blood proteins, rapid degradation by enzymes in the liver, and expulsion from cells by P-glycoprotein. A whole conference symposium (session 7) was devoted to P-glycoprotein alone.
A Thai trial of AZT, 3TC and the protease inhibitor indinavir (Crixivan) found that indinavir blood levels were of marginal efficacy in a quarter of the trial participants (D Burger et al., poster 730). Suboptimal drug levels that allow appreciable HIV replication (viral loads over 50) induce the evolution of drug resistance, rendering useless the drugs that do get to the virus. One conference study monitored blood levels of 22 patients on the protease inhibitor amprenavir (Agenerase). Eleven had interdose drug levels below the threshold for triggering appearance of a mutation that confers moderate resistance to amprenavir and to most other protease inhibitors as well (R Elston et al., poster 465).
The weakness of drug levels in the best of situations is the reason drug adherence is so critical to fending off HIV and its evolving drug resistance. One San Francisco General Hospital study found that reliable HIV suppression (to below 400 copies/mL) required taking greater than 90% of prescribed pills (D.R. Bangsberg et al., poster 483).
Sharon Little, of the University of California San Diego, detailed the rapid increase in transmission of drug-resistant HIV in North America (slide presentation 756). Little and her colleagues analyzed the HIV of 394 persons with primary HIV infection, which occurs immediately post-transmission. Between 1998 and 1999, cases of HIV with high-level drug resistance (greater than 10-fold loss in susceptibility) shot up. In 1999-2000, a whopping 14% of primary HIV patients had high-level resistance to at least one anti-HIV drug, and 5.8% had such resistance to drugs in more than one class. High-level resistance showed its influence in slower time to suppressing HIV and greater treatment failure.
David Ho's immediate advice was to add more drugs. His colleague Marty Markowitz presented a pilot study that compared a protease inhibitor regimen with intensified support (lopinavir-ritonavir (Kaletra) plus efavirenz (Sustiva), tenofovir, and 3TC) to two simpler PI combinations: saquinavir-ritonavir or nelfinavir plus AZT and 3TC (poster 383). After one week on therapy the viral load of the intensified group had declined 1.4 logs (96%) compared to 1.25 logs (94%) for the saquinavir-ritonavir group and 1.32 logs (95%) for the nelfinavir group. The viral load decline per day was 25% greater for the Kaletra-efavirenz therapy than for the other two, meaning that the efficiencies of the simpler therapies were only about 80% of the intensified one.
A second tiny pilot study added abacavir or abacavir and efavirenz to a regimen of AZT and 3TC plus either nelfinavir or saquinavir-ritonavir (M. Markowitz et al., oral presentation 502). Treatment intensification reduced the number of measurable viral load blips and seemed to speed reduction in the long-lived pool of cells with latent HIV infection, whose replenishment is probably dependent on the extent of residual HIV replication. An analysis of the latent pool's dynamics in the first study is still in progress.
Coadministering the protease inhibitor ritonavir (Norvir), as was done here, has become a popular way to improve other protease inhibitors' concentration both in the bloodstream and within cells. Ritonavir greatly slows PI degradation in the liver by blocking that organ's CYP3A4 enzyme. It may also block P-glycoprotein action (D. Back, lecture S3). The new treatment guidelines add both Kaletra and indinavir-ritonavir to the list of preferred antiretroviral agents. Saquinavir (Fortovase) plus ritonavir was already on that list.
The first preliminary Aaron Diamond study, in which the comparison was made between cohorts drawn from three separate drug trials, did not reveal any benefit from combining ritonavir with another protease inhibitor rather than taking that PI alone. More rigorous and much longer comparative studies would be needed to sort out that effect.
There are now a few such trials with available data. Abbott Laboratories (Kaletra's developer) tested Kaletra plus d4T and 3TC against nelfinavir, d4T and 3TC among 653 persons without prior treatment. At 48 weeks, 67% of those starting in the Kaletra arm had viral loads under 50 copies/mL whereas 52% in the nelfinavir arm did so (B. Bernstein et al., poster 453).
A new Thai study of indinavir-ritonavir recruited 106 volunteers whose only prior treatment history consisted of AZT, ddI and ddC (D. Burger et al., poster 826). The volunteers received AZT, 3TC, and indinavir with or without ritonavir. Adding ritonavir allowed for a twice daily indinavir dosing schedule and reduced the pill burden. There was no apparent virologic or side effect advantage to the indinavir-ritonavir combination. After 48 weeks, virologic results in the standard indinavir and the indinavir-ritonavir arms were equivalent: about 60% were below 50 copies/mL.
Ritonavir-enhancement has led to higher drug levels and simplified dosing schedules, but it has yet to demonstrate any clear breakthrough in controlling HIV. And it comes with additional toxicities, especially increased risk of cardiovascular disease due to higher blood lipids. Also, ritonavir affects so many drugs besides protease inhibitors that the management of concomitant medications becomes very complicated.
Better drugs may be on the way. Both DuPont Pharmaceuticals (S. Erikson-Viitanen et al. slide presentation 11) and the upstart company Tibotec (J. Erikson et al., slide presentation 12) described their new protease inhibitors. Tibotec also has a new nonnucleoside reverse transcriptase inhibitor (NNRTI) (B. Gurzdev et al., slide presentation 13).
Both companies claim that their drugs are largely unaffected by the classic drug resistance-conferring mutations that occur in HIV. DPC 681 and 684, the DuPont protease inhibitors, require, on average, drug concentrations about ten times less than lopinavir does to suppress 90% of HIV replication. TMC126, the PI from Tibotec, has a structure that closely resembles amprenavir. It was designed to stick tightly to the HIV protease enzyme in such a way that resistance mutations do not affect it. This is achieved through a flexible structure that attaches to the water molecules linked to the protease enzyme.
Both companies' analyses are subject to the usual caveats: Drug potency depends on which HIV strains are chosen for testing and says little about how well that drug can enter the body and reach cells. It was clear from Tibotec's and DuPont's presentations that significant drug resistance can develop when the protease accumulates enough of the right mutations.
Tibotec's NNRTI, TMC120, has undergone a one-week monotherapy trial in 43 treatment-naïve volunteers. Viral loads during that brief period declined by impressive amounts - 1.44 to 1.51 logs (96% to 97%), depending on the dose. In the lab, TMC120's activity is unaffected by most of the known mutations conferring resistance to NNRTIs. Major exceptions include mutations that cause moderate resistance to efavirenz or very high resistance to nevirapine.
These and other compounds restore hope to a field that has been battered over the past two years by withdrawals due to drug toxicities. On the eve of the Retrovirus Conference, trials for capravirine, a new NNRTI from Agouron Pharmaceuticals, were put on hold when it turned out that high doses of the agent caused vasculitis (inflammed blood vessels) in dogs.
There may be hope for improvements in conventional drugs. There would be greater hope if there were new classes of drugs unburdened by current resistance and blood level problems. The latest thing in the field of antiretrovirals is blocking HIV's ability to latch onto and enter uninfected cells.
The most advanced of the compounds in this new field is T-20, which is being developed by Trimeris in partnership with Roche. T-20, a peptide composed of 36 amino acids, interferes with HIV's ability to fuse with cells via gp41, a harpoon-like structure on its envelope protein. The gp41 penetrates cell membranes and draws HIV into contact with the cell. A phase II trial in persons who have failed one PI regimen now has 16-week data available for 53 of the 71 trial enrollees (oral latebreaker LB5). The trial participants, all NNRTI-naïve, were placed on abacavir, efavirenz and amprenavir plus low-dose ritonavir. They also received either placebo or T-20 at twice daily doses of 50 mg, 75 mg or 100 mg. After 16 weeks, 48% of those starting on T-20 had viral loads below 50, versus 37% of those enrolled in the control arm.
The Trimeris-Roche partnership is also developing a more potent version of T-20 known as T-1249 (J. Eron et al., slide presentation 14). T-1249, a slightly longer peptide than T-20, anchors itself in a pocket within gp41. It is active against T-20-resistant HIV, and vice versa. It is more stable in the body, too. A 14-day trial that administered T-20 alone to 63 persons obtained viral load declines ranging from zero with 6.25 mg daily to 1.32 logs (95%) with 25 mg twice a day. Some people on the lower doses experienced viral rebounds in the course of the trial. Perhaps some sort of resistance - either metabolic or viral - had developed.
Another heavily researched means of keeping HIV out of uninfected cells is to block the cell surface molecules that HIV grabs onto before opening up and extending its gp41 harpoon. These molecules include the CD4 receptor and a second receptor from the chemokine receptor family (Ordinarily, these receptors guide immune cells toward one of the beacons of infection - the chemokines - sent out from tissue in trouble.)
The most advanced of the new agents is Schering-C, which blocks the chemokine receptor known as CCR5 and is approximately as potent as AZT (G. Reyes, lecture L11). Unlike T-20 and T-1249, which must be injected, Schering-C is an oral drug that is well absorbed. Initial human testing found that large, effective amounts remain in the body for over 24 hours. The new agent's most worrisome side effect so far is perturbation of cardiac rhythm. Schering also has discovered Schering-D, which is ten times more potent in the lab than the C compound and somewhat better absorbed in animals.
The big question with these compounds is whether blocking the CCR5 receptor will merely force HIV to evolve to use other chemokine receptors, notably CXCR4. A switch to CXCR4 frequently occurs naturally during advanced disease and is associated with the rapid disease progression.
This switch has not occurred in Schering-C- resistant HIV that arose in a mouse model of HIV. Robert Doms, of the University of Pennsylvania, pointed out in his review talk on entry inhibitors (lecture L4) that such agents' effectiveness depends on several other factors. HIV could circumvent entry inhibitors simply by increasing envelope protein's power to bind to chemokine receptors. Such added affinity makes up for the scarcity of available receptors imposed by receptor blockers. It also speeds up viral fusion, giving T-20 and T-1249 less chance to do their job. A virus that joins to cells more quickly is probably a more pathogenic virus, but combining entry inhibitors may create an anti-HIV synergy that avoids this turn of events.
None of these new agents will come on the market any time soon, and they may never live up to their promise. Given the drawbacks of current agents, it seems best to use treatment sparingly. Three studies at the Retrovirus Conference provided reassuring data for those who want to defer therapy even beyond what the federal guidelines now advise.
The largest study was a review of 5,110 patients' records in 11 cities as part of the Adult and Adolescent Spectrum of Diseases Project (J. Kaplan et al., slide presentation 520). The calculated two-year rate of survival ranged from 93% to 98% for those starting therapy with CD4 counts at various levels over 200. The survival rate progressively decreased in those initiating therapy at CD4 counts below 200. For those with CD4 counts below 50, the two-year survival rate was only 65%. Similar trends were found in somewhat smaller studies from the University of Alabama (R.Y. Chen et al., poster 341) and the University of British Columbia (R.S. Hogg et al., poster 342) and Johns Hopkins University (T.R. Sterling et al., slide presentation 519).
The body can tolerate quite a lot of HIV for quite a long time without suffering serious permanent damage. Aside from delaying the start of anti-HIV therapy, a patient could take the drugs only intermittently. Managing HIV through careful "structured intermittent therapy" (SIT) promises to minimize the harm done by the infection while also minimizing the cost of medication and, one would hope, its toxicity as well (A. Fauci, lecture S16). National Institutes of Health investigators under Tony Fauci presented their latest SIT data at the Retrovirus Conference. The Fauci team has two pilot trials ongoing, which were first described last summer at the World AIDS Conference.
One trial has now enrolled ten people with viral loads below 50 (M. Dybul et al., poster 354). They take d4T, 3TC and indinavir plus ritonavir in cycles of seven days on and seven days off. After 16 to 40 weeks of observation, only two have had major rebounds - one who went off drugs for three weeks and one who went off for ten days. One volunteer had a minor viral blip while the rest have kept their viral loads below 50 throughout the on and off cycles. CD4+ T-cell counts have been stable, and in the three persons carefully tested, there has been no sign of HIV drug resistance through six months.
The second trial follows 70 volunteers who entered the study with viral loads below 50 (M. Dybul et al., poster 364). It assigned half the participants to remain on continuous therapy and the other half to take their drugs for two months out of every three. Fifteen of the trial participants have now completed at least three intermittent treatment cycles. Eleven of the 15 have experienced major HIV rebounds (to above 6,000 copies/mL) during the therapy interruptions. CD4+ T-cell counts went down in conjunction with the viral upsurges but recovered after the return to therapy brought viral loads back down. HIV in two of the participants developed new resistance to drugs in their regimens - one to efavirenz and one to 3TC. Overall, the results in the SIT cohort so far have been similar to that of the control group on continuous treatment.
The NIH's Community Project for Clinical Research on AIDS (CPCRA) is now considering a 6,000-person intermittent therapy trial to test stopping therapy when patients' CD4 counts reach 400. Treatment would restart months to years later when counts fall below 250. Both Fauci in his lecture and his associate Mark Dybul in an interview expressed their preference for the short seven days on and off cycle because patients never have detectable viral loads and therefore are less likely to transmit HIV to other people.
The U.S. Centers for Disease Control and Prevention (CDC) is also weighing in on this question through Project SAFE, its ambitious program to halve the rate of HIV transmission by focusing on infected individuals. This prevention program includes a strong treatment counseling component that seeks to lower viral loads.
Project SAFE was debuted at a sparsely attended Retrovirus Conference symposium (R. Janssen, lecture S20). Left unexamined was the potential clash between individuals' interest in deferring treatment and the public's interest in promoting it. That may turn out to be the biggest Retrovirus Conference story of them all.
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Copyright © 2001 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).
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