The Next Generation of Antiretroviral Agents
Potent and Promising New Drugs Will Soon Be Available to Combat HIV Infection
In the past two years, significant advances have been made in the treatment of HIV disease, and these advances have led to the first decline in AIDS-related mortality since the Centers for Disease Control began tracking the epidemic in the early 1980s. Overall, AIDS deaths dropped more than 30% last year -- from the all-time high of 50,000 -- and reductions in AIDS-related mortality have been even more dramatic in some parts of the country.
Although much of this reduced mortality can be attributed to the introduction of the protease inhibitors, which became widely available in early 1996, AIDS deaths actually began to decline in some locations as early as 1993. This suggests that the improved survival we are now seeing in people with advanced HIV disease is probably the result of a number of factors, among them improved access to care, better education of infected populations, more successful prophylaxis against the opportunistic infections seen in these patients, and more effective clinical management of OIs.
All of these factors have contributed to improved survival, but their significance is minor compared to the contribution made by highly-active antiretroviral therapies, which combine one or more protease inhibitors with nucleoside and/or non-nucleoside reverse transcriptase inhibitors. So-called HAART regimens are now the standard of care for patients with advanced HIV infection. They do not work equally well in all patients, and they require that patients remain strictly compliant with highly demanding dosing schedules, but when they do work they frequently achieve almost complete suppression of viral replication.
New drugs, new formulations, new combinationsThe treatment of HIV infection has changed dramatically in the past two years. In the next two years we will see further advances, as new drugs -- and new formulations of old drugs -- are added to the clinician's armamentarium.
These new formulations include Combivir -- which, as its name suggests, combines two widely prescribed antiretroviral agents, AZT and 3TC, in a single tablet. These two drugs are routinely prescribed together because the addition of 3TC to an AZT-containing regimen results in the reversal of high-level resistance to AZT and leads to more durable suppression of viral load.
The particular advantage of Combivir, which is now on pharmacy shelves, is that it allows patients to take fewer pills -- two tablets a day, instead of the four to eight pills per day that patients assigned AZT and 3TC must take. This simplified dosing is likely to enhance adherence to combination antiretroviral regimens that include these two nucleoside analogs. A recent study conducted by Dr. Joseph Eron of the University of North Carolina Medical School supports this supposition.
This category also includes Fortovase, a soft-gel capsule version of saquinavir that has up to ten times the bioavailability of the old formulation when given at the doses used in clinical trials. Low bioavailability has been the chief limitation of saquinavir, which has an acceptable side-effects profile even at doses substantially higher than the standard therapeutic dose.
A recent study showed that this new formulation of Roche Laboratories' protease inhibitor, when used in combination with AZT and 3TC, reduced viral load to undetectable levels in 81% of patients and increased CD4 counts by 170 cells after 16 weeks of therapy. Another study -- the first-ever head-to-head trial of two protease inhibitors -- compared the soft-gel formulation of saquinavir plus AZT and 3TC to indinavir plus those two nucleoside analogs. What researchers found is that the two triple-drug combinations had similar antiretroviral activity, and the regimen that contained saquinavir produced greater increases in CD4 cell counts.
Ongoing clinical trials are testing this new formulation of saquinavir in combination with nucleoside analogs, NNRTIs, and other protease inhibitors.
A number of studies have already established that the addition of ritonavir to a saquinavir-containing regimen increases serum levels of the latter drug -- a synergistic effect that translates into increased efficacy.
It is reasonable to assume that regimens that combine ritonavir and the soft-gel capsule formulation of saquinavir will provide even higher serum concentrations of active drug, leading to even greater antiretroviral activity.
In addition, our ability to treat HIV infection will be enhanced by potent new drug combinations, and the patient's ability to adhere to therapy will be enhanced by new dosing schedules for older drugs. These new dosages -- all of which are currently being tested in clinical trials -- are designed to increase efficacy or, more often, to improve compliance by reducing the number of daily doses of a particular agent that a patient needs to take to achieve adequate serum levels of that drug.
In general, abacavir has been well tolerated in early clinical trials, and there appears to be no cross-resistance with AZT or d4T. High-level resistance to 3TC is likely to develop if mutations do occur with chronic use of abacavir. Headache and GI disturbances are the most common adverse reactions to abacavir therapy. An allergic reaction to the drug was reported in 3% of patients, however. This reaction, which was characterized by fever, malaise, nausea, vomiting, and rash, usually occurred in the first week of therapy. (For further information on this therapy-limiting allergic reaction, see "Hypersensitivity to Abacavir" in the newsline section of this issue.)
Preliminary findings suggest that using abacavir and AZT or d4T in combination may achieve results similar to those seen when AZT and 3TC are combined. Expanded trials of abacavir -- in combination with other nucleosides and with protease inhibitors -- should soon give us additional information on this new and potentially valuable RT inhibitor.
ADEFOVIR DIPIVOXIL: Adefovir is a novel nucleoside analog that is related to a class of compounds called nucleotides, the best-known of which is cidofovir (see "Better Treatments for CMV Retinitis" in this issue). This new drug has broad-spectrum antiviral activity against HIV and a wide range of herpesviruses. As importantly, resistance to this drug has proven difficult to demonstrate, and HIV strains that are resistant to nucleoside RT inhibitors are sensitive to adefovir. Because the parent formulation of adefovir has poor bioavailability, Gilead Sciences has developed a so-called prodrug, adefovir dipivoxil, which is 40% bioavailable and is completely converted to adefovir following absorption. Adefovir diphosphate has a very long half-life, which means that patients are required to take it only once a day -- an important consideration given the complexity of the dosing schedules of most multidrug antiretroviral regimens.
Based on these favorable results, a double-blind multicenter trial was conducted in 72 adult patients with advanced HIV disease. These subjects, all of whom had CD4 counts below 200 and viral levels above 10,000 copies, were randomized to receive drug or placebo for six weeks, followed by six weeks of open-label treatment. Two dosage levels -- 125 mg/day and 250 mg/day -- were evaluated, and assessments were made of the drug's virologic activity as well as its safety and tolerability.
At the lower of the two doses, adefovir was extremely well tolerated, with no patients withdrawing from the study due to therapy-related toxicities. At the 250-mg dose, however, 4 of 36 patients withdrew because of nausea and vomiting, dysuria and genital ulcers, or fever and chills.
After the first six weeks of the study, CD4 counts had risen by an average of 46 cells in the 125-mg group and 15 cells in the 250-mg group, and viral levels fell in both groups -- benefits that endured throughout the three months of the study. The durability of these changes must now be investigated in larger, longer clinical trials, but the evidence at hand suggests that further studies of the 125-mg/day dose of adefovir -- in combination with other antiretroviral agents -- are warranted.
PMPA: This investigational nucleotide analog has a mechanism of action and intracellular metabolism similar to those of adefovir, and the drug's activity against the common strains of HIV is also comparable to adefovir's. When PMPA was given for 28 days to macaque monkeys infected with simian immunodeficiency virus, the monkeys' viral levels fell to undetectable levels.
PMPA has also been used as post-exposure prophylaxis against SIV in macaques, and here it has yielded results that are truly dramatic: in the handful of animal studies done to date, the drug has been 100% effective in preventing infection, even when given as much as 24 hours after exposure. This phenomenon has never before been demonstrated, in this or any other animal model, for any other antiretroviral agent. These preliminary but intriguing findings suggest that PMPA has unusually high antiretroviral activity in simian models and merits study in humans. Phase I trials in HIV-infected adults are now in the early planning stages.
DMP-266 (EFAVIRENZ): This new non-nucleoside reverse-transcriptase inhibitor has potent activity against HIV. DMP-266 -- which is being developed jointly by Merck and DuPont under the chemical name efavirenz and the brand name Sustiva® -- has particularly good activity against strains of HIV that are resistant to nucleoside analogs and/or to indinavir. Strains of HIV that are resistant to nevirapine and delavirdine, the two currently approved NNRTIs, are also susceptible to DMP-266. However, resistance develops rapidly when this drug is used as monotherapy -- which means that DMP-266, like the other NNRTIs, should always be used in combination with nucleoside analogs and/or protease inhibitors. The major side effects of DMP-266 therapy are skin rash and CNS symptoms. Rash has been reported in 5% to 40% of treated patients and is similar in character to the rash seen with other NNRTIs. The most common CNS symptoms are lightheadedness and a feeling of being "drugged" or disengaged. Some patients have reported that the drug has a stimulant-like effect and makes them feel "high." These symptoms are more common at doses above 200 mg/day and tend to wane over a few days to weeks. (To find out how to obtain this experimental NNRTI, see "Ever-Expanding Access" in the newsline section of this issue.)
At this point we have little clinical data on DMP-266. In one small study the new Merck-DuPont drug was given in combination with indinavir. After 24 weeks of therapy, 94% of patients had undetectable viral levels, and their CD4 counts had increased by a mean of 199 cells. This drug combination was well tolerated, with 82% of patients completing the 24-week study. These very impressive results suggest that this NNRTI is significantly more potent than either nevirapine or delavirdine.
New protease inhibitorsGW141W94: GW141 is a new protease inhibitor being developed by Glaxo Wellcome. There is no reported cross-resistance between GW141 and other protease inhibitors, and studies have shown that GW141 has good test-tube synergy with two other antiretroviral agents developed by Glaxo Wellcome, AZT and abacavir.
In a small pilot study, this investigational protease inhibitor was administered in combination with abacavir -- and the two-drug regimen resulted in dramatic decreases in viral load. The most common adverse events reported by patients taking GW141, alone or in combination with abacavir, were diarrhea, nausea, headache, and rash.
It is now well established that protease inhibitors and nucleoside RT inhibitors work better in combination than alone, so the early data reported above come as no surprise. Indeed, we anticipate using both GW141 and abacavir in combination -- either with one another or with other antiretroviral agents (See Table 2).
ABBOTT 378: ABT-378 is a new and novel protease inhibitor currently in Phase I development. Tested to date only in the test tube, this compound is roughly ten times more active in human serum than ritonavir. Significantly, ABT-378 has potent activity against viral strains resistant to ritonavir. Indeed, this investigational drug is active in the face of multiple mutations, including the mutation that denotes the initial stage of resistance to both ritonavir and indinavir. As a result, patients who have been extensively treated with these older protease inhibitors should remain partially sensitive to ABT-378, and patients treated with saquinavir should remain wholly sensitive to Abbott's new drug.
Investigators predict that ABT-378 will achieve and maintain high plasma concentrations, and it is anticipated that this new protease inhibitor will require dosing only once or twice a day. These investigators note that there appears to be a high degree of synergy between Abbott's protease inhibitors. The positive impact of ritonavir on ABT-378 plasma levels is greater than that of ritonavir on any other protease inhibitor studied to date: coadministration of ABT-378 and ritonavir in rats produced plasma levels of the former drug that were 50-fold higher than the level of drug needed to inhibit the drug.
These findings suggest that doses of ritonavir as low as 50 mg/day will enhance the plasma concentrations of ABT-378 -- which would make this combination a valuable alternative for patients who are not doing well on standard therapies. The results of the Phase I trials now under way should give us a better sense of ABT-378's utility before the end of the year.
Harold A. Kessler, M.D., is Professor of Medicine and Immunology/Microbiology at Rush Medical College, Chicago, IL.
Back to the February 1998 AIDS Care contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication AIDS Care.