The Next Generation of Antiretroviral Agents
Potent and Promising New Drugs Will Soon Be Available to Combat HIV Infection
In the last two years significant advances have been made in the treatment of HIV disease. Largely as a result of these advances, the Centers for Disease Control recently reported the first decline in AIDS-related mortality since the C.D.C. began tracking the epidemic in the early 1980s. Overall, AIDS deaths dropped 13% in 1996 -- from the previous year's all-time high of 50,000 (1). Declines in AIDS-related mortality have been even more dramatic in some parts of the country. In New York City, for example, the death rate fell fully 30% in 1996 (see "C.D.C. reports substantial drop in AIDS deaths," Vol. 3, No. 2).
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 patients 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 so-called highly-active antiretroviral therapies, which combine one or more protease inhibitors with nucleoside and non-nucleoside reverse transcriptase inhibitors. HAART regimens are now the standard of care for patients with advanced HIV infection. They do not work with equal efficacy 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 (see the two related articles in this issue, "The Problem of Protease Resistance" and "Compliance: How You Can Help").
In the last two years we have seen significant advances made in the treatment of HIV disease. In the next two years we will see further advances, as drugs and drug combinations now being evaluated are added to the clinician's armamentarium. Among these new regimens is the triple-drug combination of ZDV, 3TC, and indinavir. This combination was studied in AIDS Clinical Trials Group protocol 320, began to generate intense interest when the preliminary data were presented more than a year ago (see "Potent, sustained antiviral activity of ZDV and 3TC combined with indinavir," Vol. 2, No. 1, pages 15-16).
The results of ACTG 320, released in February of this year, reconfirm last year's preliminary findings and underscore the benefits of multidrug regimens in patients with late-stage HIV infection. This randomized, double-blind clinical trial compared the efficacy of two drug combinations: ZDV + 3TC with and without indinavir. The primary endpoints were progression to AIDS-defining events or death. All of the study subjects had CD4 counts below 200 cells/mm3, and all of them had been on ZDV monotherapy for at least three months prior to entry. To be eligible for enrollment, patients had to be protease inhibitor-naïve with less than a week's prior exposure to 3TC. In those patients with a demonstrated intolerance to ZDV, d4T could be substituted.
In all, 1,156 patients were enrolled in ACTG 320. Participants were stratified into two cohorts: those with CD4 counts above 50 cells/mm3 and those with counts below that number. The mean baseline CD4 count was 86 cells/mm3; 439 participants (38%) had baseline counts below 50 cells/mm3. Subjects were followed for a median length of 38 weeks, and only 5% were lost to follow-up. Over the 12 months of the study, 579 patients were randomized to ZDV (or d4T) + 3TC and 577 to ZDV (or d4T) + 3TC + indinavir. A mere 10 patients discontinued treatment due to a protocol-defined toxicity.
By the end of January of this year, 96 patients had reached one of the study's established endpoints. The most common first events were PCP (21 cases), death (17), CMV (16), and MAC (11). Two thirds of these endpoints (63) were seen in subjects on the two-drug regimen, versus one third (33) in those on the triple-drug combination, yielding an estimated hazard ratio of 0.50 (p = 0.001; 95% confidence interval: 0.33 to 0.76).
As investigators had anticipated, progression rates were higher in the cohort with CD4 counts below 50 cells/mm3. What was more noteworthy, therefore, was that progression rates were higher in patients who did not get indinavir irrespective of CD4 stratum. A total of 26 patients died during the course of the trial, 18 in the two-drug arm and 8 in the three-drug arm (p = 0.042). These data are similar to those reported in Abbott 247 and other studies in which ritonavir was added to regimens of one or more nucleoside analogs (see "Two studies establish the safety and efficacy of ritonavir," Vol. 2, No. 1, pages 10-11, and "Update: The Protease Inhibitors," Vol. 2, No. 3, pages 52-61). The final data from ACTG 320 show the clear superiority, in patients with advanced HIV disease, of antiretroviral regimens that include a protease inhibitor.
New nucleoside and nucleotide analogs
GW1592U89 (ABACAVIR): This promising nucleoside analog, now in Phase II/III clinical trials, is a lipophilic, water-soluble guanosine analog that is activated in cells by a unique mechanism. GW1592 -- which Glaxo Wellcome has named abacavir -- has demonstrated in vitro synergy with other reverse transcriptase inhibitors, and it is the only drug in its class that can match ZDV's penetration of the central nervous system. Metabolism is not cytochrome P450-dependent, which reduces the likelihood of adverse drug-drug interactions with phenobarbital, triazolam, dapsone, rifabutin, and azolides.
In general, abacavir has been well tolerated in early clinical trials, and there appears to be no cross-resistance with ZDV or d4T. High-level resistance to 3TC is likely to develop if mutations do occur with chronic use of abacavir, however, because the first RT mutation provoked by this agent occurs at M184V, the codon associated with 3TC resistance. The preliminary evidence suggests that this mutation leads to no more than a two- or three-fold decrease in the susceptibility of HIV to abacavir. Even when additional mutations occur the drug remains moderately active in vitro, with a maximum 10-fold reduction in susceptibility seen with multiple mutations.
The correct clinical dose of abacavir has yet to be established, but Phase I dose-ranging studies have led investigators to conclude that 300 mg b.i.d. will probably be effective. Twelve-week trials of abacavir, both as monotherapy and in combination with ZDV, resulted in 1.7 to 2.1-log reductions in viral load, and 60% of the patients treated with the two-drug combination had their HIV RNA levels drop below 400 particles/mL within two or three months.
Reverse transcriptase mutations could be detected in 60% of the viral isolates taken from patients treated for 12 weeks with abacavir alone, compared with only 13% of isolates from patients who got both abacavir and ZDV. This finding suggests that using these two nucleosides in combination may achieve results similar to those seen when ZDV 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. Nucleotides differ from other RT inhibitors in that they do not require intracellular monophosphorylation; the diphosphorylated metabolite is the active form of these compounds.
This new drug has broad-spectrum in vitro antiviral activity against HIV-1 and -2, hepadnaviruses, and a wide range of herpesviruses including HSV, HHV-6, and CMV. As importantly, in vitro 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 prodrug, adefovir dipivoxil, which is 40% bioavailable and is completely converted to adefovir following absorption. Adefovir diphosphate has an intracellular half-life on roughly 18 hours, which means that patients are required to take it only once a day. A Phase I clinical trial in HIV-infected adults demonstrated that the drug was both safe and well tolerated when given for 14 days.
Based on these favorable results, a double-blind, multicenter Phase I/II trial was conducted in 72 adult patients with advanced HIV disease. These subjects, all of whom had CD4 counts below 200 cells/mm3 and HIV RNA levels above 10,000 particles/mL, were randomized (in a ratio of 2:1) 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 immunologic and 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. The most common dose-related adverse event was nausea (9 of 48 patients), with diarrhea occurring in 4 of 24 patients taking the 250-mg dose.
After the first six weeks of the study, CD4 counts had risen by a mean of 46 cells/mm3 in the 125-mg cohort and 15 cells/mm3 in the 250-mg cohort compared to the placebo arm. These changes persisted at 12 weeks, with mean absolute increases of 57 and 27 cells/mm3, respectively, in the low- and high-dose cohorts. As expected, HIV RNA levels did not change in the placebo group. In the treatment arms, by contrast, viral levels dropped by a median of 0.5 log in the low-dose group and 0.4 log in those getting the higher dose. These benefits endured throughout the 12-week 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 in vitro activity against the common strains of HIV is also comparable to adefovir's. However, PMPA has significantly less in vitro cellular cytotoxicity than adefovir, which at least theoretically might translate into less in vivo toxicity.
When PMPA was given for 28 days to macaques infected with simian immunodeficiency virus, the monkeys' SIV RNA levels fell by as much as 3.0 logs, as did viremia in peripheral blood mononuclear cells. No significant toxicities were seen when PMPA was given at a once-daily dose of 30 mg/kg; at a dose of 75 mg/kg/day, reversible anemia and hypophosphatemia were noted.
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 otheranimal 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.
New protease inhibitors
NELFINAVIR MESYLATE: Nelfinavir is the most recent addition to the growing line-up of approved protease inhibitors and it is the first of these powerful antiretroviral agents to be approved for use in children (see "At last, a protease inhibitor for children as well as adults," Vol. 3, No. 1, pages 18-19). The drug has a molecular weight of 586, which makes it the smallest of the approved protease inhibitors, and it is approximately 80% bioavailable, with absorption not inhibited by food.
Although nelfinavir, unlike abacavir, is metabolized through the cytochrome P450 system, selective inhibitors of this system (such as the azole antifungals and macrolides) and moderate inhibitors of the system (such as rifabutin) are unlikely to alter serum concentrations of nelfinavir to a significant degree. On the other hand, nelfinavir does reduce concentrations of ethinylestradiol by 50% -- which means that increased doses of estrogen will be needed for effective contraception. This is an important clinical consideration, given the number of HIV-positive women who become pregnant despite reported use of barrier contraceptives. Adequate ethinylestradiol levels will prevent contraception, but of course they will not prevent sexual transmission of HIV -- a fact that should be emphasized in discussions with HIV-positive patients and their sexual partners.
Administration of nelfinavir with either saquinavir or ritonavir is likely to result in increased serum concentrations of the older drugs, since these protease inhibitors are also metabolized by P450. Indeed, the early in vitro data indicate that coadministration of ritonavir and nelfinavir leads to dramatic increases in plasma levels of the latter drug. (This is not an altogether surprising finding, given that coadministration of the two older protease inhibitors boosts saquinavir concentrations 40-fold.) Although no data are yet available on the pharmacokinetics of combining nelfinavir and the non-nucleoside RT inhibitor nevirapine, the likelihood is that serum levels of nelfinavir will drop roughly 30%, as they do when this NNRTI is given in combination with other protease inhibitors.
Resistance is a matter of critical concern in the clinical management of HIV infection, and the available data suggest that nelfinavir works better in combination with other antiretrovirals than alone, and it is more effective as initial than as salvage therapy. For example, it has been shown that taking nelfinavir with ZDV and 3TC reduces the risk of nelfinavir resistance nine-fold when this triple-drug combination is compared with nelfinavir monotherapy. HIV strains that have become resistant to indinavir and ritonavir will be cross-resistant to nelfinavir, but nelfinavir-resistant viral strains remain susceptible to all of the other protease inhibitors -- making nelfinavir a particularly appealing candidate for first-line therapy.
Three pivotal Phase II/III clinical trials have evaluated the safety and efficacy of nelfinavir either as monotherapy or in combination with d4T or ZDV + 3TC. The F.D.A.'s approval of nelfinavir was based on the preliminary, 24-week data from these randomized, double-blind, controlled studies; the 40-week data were released a few weeks ago.
In all, 696 patients were ultimately enrolled in these trials, which evaluated nelfinavir at two doses: 500 mg and 750 mg b.i.d. The primary efficacy measurements in all three studies were changes from baseline in CD4 count and plasma HIV RNA level. Study subjects had no prior experience with protease inhibitors and viral burdens in excess of 15,000 particles/mL. Participants in the ZDV/3TC/nelfinavir trial had to be either antiretroviral naïve or treated for less than one month. For the trials of nelfinavir monotherapy and nelfinavir in combination with d4T, participants had to have baseline CD4 counts of 50 cells/mm3 or less.
Slightly more than 300 patients were enrolled in each of these clinical studies. Both of the trials of combination therapy demonstrated that the addition of nelfinavir to d4T or to ZDV + 3TC produced significantly greater reductions in viral load and significantly greater increases in CD4 count than were seen when these nucleoside analogs were given without the protease inhibitor. Mean decreases in HIV RNA ranged from 2.0 to 2.5 logs below baseline, and up to 85% of the study subjects had their viral load drop to undetectably low levels (defined, in these studies, as less than 500 particles/mL). Mean CD4 count increases ranged from 100 to 160 cells/mm3.
There are indications that the 750-mg dose was more effective in reducing viral burden, particularly in patients whose HIV RNA levels were greater than 100,000 particles/mL at the time they enrolled. Only 4% of study subjects (28 of 696) discontinued therapy due to adverse events, and there were no differences in dropout rates between the cohorts who received nelfinavir and those who received nucleosides alone.
The major side effect of nelfinavir therapy is mild to moderate diarrhea, which can be readily controlled with over-the-counter antimotility drugs. No significant laboratory abnormalities were attributable to nelfinavir, and this finding, in combination with the other safety and efficacy data from these studies, indicate that nelfinavir is a very useful addition to the current roster of antiretroviral agents.
GW141W94: GW141 is a non-peptide protease inhibitor with a molecular weight of 505.6, making it the smallest of the protease inhibitors now being studied. The molecule has a sulfonamide backbone -- which may be of particular importance, given what we know about the increased reactogenicity of these drugs in patients with HIV disease. There is no reported cross-resistance with other protease inhibitors, and studies have shown that GW141 has good in vitro synergy with two other antiretroviral agents developed by Glaxo Wellcome, ZDV and abacavir. CNS penetration is limited, but no more than it is with all protease inhibitors.
Preliminary Phase I pharmacokinetic data on GW141 indicate that efficacy is dose-related. When administered to nine patients for four weeks at a dose of 1200 mg b.i.d., GW141 produced a median maximum decrease in viral load of 1.69 log, but only one of the nine subjects had his HIV RNA level drop below 400 particles/mL.
This investigational protease inhibitor has also been administered in combination with abacavir. In a small pilot study, seven patients were given 900 mg of GW141 and 600 mg of abacavir twice daily for four weeks. This two-drug regimen resulted in a median maximal decrease in viral load of 2.08 logs, and five of the subjects had their HIV RNA levels drop below the lower limit of detection in this study. The median maximum increase in CD4 count in this pilot study was 114 cells/mm3 for patients treated with GW141 alone at a dose of 2400 mg/day, compared with 79 cells/mm3 for participants in the GW141/abacavir combination arm.
The most common adverse events reported by patients taking GW141, alone or in combination with abacavir, were diarrhea, nausea, headache, rash, and paresthesias. There were no significant hematologic or biochemical abnormalities noted in any of the study subjects, and there was no clear correlation between the dose given and the incidence of side effects.
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, clinicians should anticipate using both GW141 and abacavir in combination -- either with one another or with other antiretroviral agents.
ABBOTT 378: ABT-378 is a new and novel protease inhibitor currently in Phase I development. Tested to date only in vitro and in rats, this compound is roughly ten times more active in human serum than ritonavir. ABT-378 maintains potent in vitro activity against viral strains resistant to ritonavir. Indeed, this investigational drug is active in the face of multiple mutations, including the mutation at codon 82, which 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. Moreover, this new protease inhibitor is more active than ritonavir in the presence of the cluster of mutations that confer high-level resistance to Abbott's older 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 pharmacologic effect 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 than were 50-fold higher than the level of drug needed to inhibit the drug in vitro.
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 addition to the clinician's antiretroviral armamentarium. The results of the Phase I trials now underway 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, Department of Medicine and Immunology/Microbiology, Rush Medical College, Chicago, IL.
Back to the June 1997 HIV Newsline contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.