Highlights of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy
New Drugs and New Options for Treatment-NaÏVe Patients, Simplified Dosing Regimens and Superior Successor Regimens for Treatment-Experienced Patients
From the perspective of the practicing clinician, the highlight of this year's ICAAC conference was the abundance of clinical data on the many antiretroviral agents now in development. Phase 2 data were presented on a number of particularly promising candidates: a nucleoside analog, dOTC, a non-nucleoside reverse-transcriptase inhibitor, emivirine (formerly MKC-442); the second nucleotide analog, tenofovir (formerly PMPA); a protease inhibitor, ABT-378, that has been the subject of several previous reports in HIV Newsline; and T-20, the first fusion inhibitor.
T-20: T-20 is a peptide that inhibits the ability of HIV to attach to the CD4 cell receptor, thereby thwarting fusion between the virus and the cell membrane. For heavily pretreated patients, this fusion inhibitor represents the most promising treatment advance of the past year, because it offers an effective therapeutic option to individuals who have developed high-level resistance to most of the currently available agents and classes of agents.
In a non-controlled, single-arm study, 71 patients who had been enrolled in prior T-20 studies received open-label T-20 (50 mg IM twice daily) for 16 weeks (1). All of the study subjects had extensive prior treatment: 93% had previously received drugs from all three major classes (nucleoside analogs, NNRTIs, and protease inhibitors). The median number of prior antiretroviral drugs was 11. The median baseline HIV RNA in the cohort was 4.9 logs (approximately 80,000 copies/mL). Baseline genotypic analysis revealed a median of 13 mutations associated with resistance to currently available agents.
Data were presented at ICAAC on the first 64 patients to reach week 16 of follow-up on T-20, which was taken in combination with the most potent antiretroviral regimen available to these heavily pretreated patients, based on genotypic testing. The 16-week intent-to-treat analysis found that 53% of the study subjects had an undetectable HIV RNA level (< 400 copies/mL) or had a greater than one-log decrease in HIV RNA from baseline. Moreover, T-20 appeared to be well tolerated: other than local injection-site reactions, all mild, there were no clear drug-related complications, and the vast majority of patients were able to tolerate twice-daily subcutaneous injections of the drug during the study.
Comment: T-20 is clearly a potent anti-HIV agent, and it should be very effective in treatment-experienced patients. However, because of the uncontrolled nature of this study, it is difficult to determine what role T-20 had in causing the viral suppression seen in these subjects. The patient population was heterogeneous, and a significant number of the participants took a brief "drug holiday" before starting therapy with standard antiretrovirals plus T-20. This washout period may have contributed to an improved 16-week response to therapy. The safety and tolerability data on T-20 are very impressive, however, and we should soon have more information about the efficacy of this novel antiretroviral agent.
Because therapeutic options for patients with three-class virologic failure are severely limited, there will be immense pressure on Trimeris and Hoffmann-La Roche, the developers of T-20, to make the drug available to the increasing number of individuals who fit this category. At present, drug supply remains limited. Moreover, the optimal dose of T-20 has not yet been defined, and there are theoretical concerns that T-20 will generate neutralizing antibodies. Finally, resistance to T-20 may be inevitable, unless effective antiretroviral agents are used concurrently with T-20, and it remains to be seen whether patients can tolerate twice-daily injections indefinitely.
ABT-378: Dr. Harold Kessler, a member of the editorial advisory board of HIV Newsline, first described the potential therapeutic benefits of Abbott Laboratories' new protease inhibitor in these pages two years ago (see "The Next Generation of Antiretroviral Agents -- An Update," Vol. 3, No. 6, pages 143-151). ABT 378, a promising protease inhibitor with an outstanding pharmacokinetic profile, is currently undergoing Phase 3 evaluation. At the moment, ABT-378 is available only through clinical trials or a modest-sized expanded-access program. The drug should become widely available over the next year.
Because ABT-378 has limited oral bioavailability, it must be taken with ritonavir or other inhibitors of the cytochrome P450 system to enhance serum concentrations. In the clinical trials conducted to date, ABT-378 has always been given in combination with low-dose ritonavir (100 to 200 mg b.i.d.). According to investigators at Abbott, when ABT-378 is used in combination with ritonavir, concentrations of the former drug remain more than 30-fold above the protein-corrected IC 95 for ABT-378 alone, even 12 hours after dosing. This investigational drug has a promising resistance profile as well, although the fact that some common mutations do appear -- at codon 84, for example -- suggest that this agent may have reduced efficacy in heavily pretreated patients.
We should soon have the results of two Phase 2 studies of ABT-378, one in treatment-naïve patients, the other in individuals who have experienced early failure on a regimen containing another protease inhibitor. Interim data through week 36 of both studies suggest that the drug is well tolerated: in 170 patients enrolled in these two trials, there have been only two drug discontinuations for adverse events related to ABT-378.
Among treatment-naïve patients, ABT-378 plus low-dose ritonavir, taken in combination with d4T and 3TC, resulted in impressive levels of viral suppression: 89% of the study subjects had HIV RNA levels less than 50 copies/mL at week 36 (2). When an intent-to-treat analysis was used, approximately 75% to 80% of the participants had undetectable HIV RNA at week 36.
Although the data on ABT-378 therapy in treatment-naïve patients are indeed impressive, it is the 36-week data from the salvage arm of the study that generated the most interest at ICAAC (2). This cohort of NNRTI-naïve patients who were failing their first protease-inhibitor-containing regimen received ABT-378 for two weeks, then modified their nucleoside analogs and added nevirapine. The mean viral load at study entry was low (about 10,000 copies/mL). The intent-to-treat analysis revealed that 67% of the study subjects had undetectable HIV RNA levels (< 400 copies/mL) at week 36.
Comment: The emerging data on ABT-378 are certainly impressive, and most of the clinical investigators working with the drug believe it to be well tolerated. The efficacy of this new agent probably reflects the fact that suppression of viral replication is partially dependent on how consistently the virus is exposed to anti-HIV drugs -- and exposure, in turn, is determined by drug metabolism and by adherence. In this regard the serum concentrations of ABT-378 that are achieved when this drug is given in combination with a low dose of ritonavir provide consistent exposure to high levels of circulating drug, which gives ABT-378 an advantage over protease inhibitors that do not achieve such high levels and/or do not have as long a half-life.
TENOFOVIR DISOPROXIL: Tenofovir disoproxil, also known as PMPA, is an oral nucleotide analog in development at Gilead Pharmaceuticals. Schooley and colleagues randomized 189 patients (median baseline HIV RNA: approximately 3.75 logs) who had been on multidrug antiretroviral therapy for at least eight weeks to receive 75, 150, or 300 mg of tenofovir or a look-alike placebo once daily in addition to their other anti-HIV drugs (3). At week 24, the median declines in HIV RNA were 0.29, 0.33, and 0.83 log for the 75-, 150-, and 300-mg arms, respectively. The placebo group experienced a median increase in HIV RNA of 0.28 log.
All patients on the placebo arm were rolled over to the 300-mg arm after 24 weeks. Of the patients on active treatment, 4.4% discontinued therapy, versus 7.4% of the patients on placebo. Despite significant reductions in viral load, there was no CD4 cell rise. Serious adverse events were infrequent, and no evidence of nephrotoxicity was observed.
Comment: Tenofovir is a well-tolerated drug that has shown activity against resistant viral strains. Given that the participants in this study very likely had already achieved partial viral suppression on their initial multidrug regimens, the additional 0.83- log decline seen when tenofovir was added to these therapies is especially impressive. More importantly, the lack of nephrotoxicity in these closely monitored patients suggests that this drug should prove to be safer than adefovir dipivoxil. (For further information on the safety of adefovir, see "Adefovir effective in patients resistant to ZDV and 3TC: New safety data and monitoring guidelines clarify role of the lone nucleotide analog," on pages 40-41 of the newsline section of the October 1999 issue of HIV Newsline.)
EMIVIRINE: Emivirine (MKC-442, Coactinon®) is a uracil analog with a nucleoside structure that functions as a non-nucleoside reverse-transcriptase inhibitor. It is being developed by Triangle Pharmaceuticals. Johnson and colleagues enrolled 203 South African patients in a study that compared two doses of emivirine: arm A took 500 mg b.i.d. and arm B took 750 mg b.i.d., with both arms receiving d4T and ddI at the standard doses (4). In addition, there were two dose-escalation arms: arm C got 250 mg EMV b.i.d., while arm D got 375 mg EMV b.i.d., both for three days, followed by 750 mg EMV b.i.d. thereafter, again in combination with d4T and ddI. The participants in this study had no previous exposure to protease inhibitors or NNRTIs at entry, and they had less than 28 days of exposure to nucleoside analogs.
The investigators concluded that the combination of emivirine, d4T, and ddI resulted in significant suppression of HIV RNA and was well tolerated. In a separate presentation, scientists from Triangle reported on the resistance profiles of patients who failed an emivirine-containing regimen. The K103N mutation, which is associated with high-level cross-resistance to all of the currently available NNRTIs, was common in these individuals.
Comment: Emivirine appears to be an effective NNRTI for patients who have never been exposed to this class of drugs. Questions remain about the drug's safety, tolerability, and activity against resistant viruses. Based on the drug's in vitro and in vivo resistance profiles, it seems unlikely that emivirine will be effective in patients who have developed significant resistance to one or more of the currently available NNRTIs. The same data make it seem unlikely that patients failing emivirine will respond to efavirenz, nevirapine, or delavirdine.
dOTC (BCH-10652): A nucleoside analog that is structurally similar to lamivudine, dOTC is a racemic mixture of two enantiomers, each with its own activity and resistance patterns. According to virologists at BioChem Pharma, resistance to dOTC emerges slowly in vitro. Although the drug does select for a mutation at position M184V (which is commonly seen in persons exposed to 3TC), this mutation is not associated with high-level phenotypic resistance -- a situation analogous to that with M184V and abacavir. The drug may therefore have activity in treatment-experienced patients.
Wood and colleagues conducted a double-blind, placebo-controlled Phase 1/2 study of dOTC monotherapy in antiretroviral-naïve male patients with HIV RNA levels between 5,000 and 100,000 copies/mL and CD4 counts of at least 200 cells/mm3 (5). Patients were randomized in an 8:2 ratio to receive either dOTC or placebo over seven days. Patients on active dOTC therapy received either 200, 300, or 400 mg b.i.d. or 400, 600, or 800 mg once daily. Safety, efficacy, and pharmacokinetics were analyzed.
At day 8, patients on dOTC experienced an average drop in HIV RNA of between 1 and 1.5 logs. More than 90% of the participants experienced a greater than 1-log drop in HIV RNA or had their viral levels fall below 400 copies/mL. Aside from one grade 4 elevation in creatinine kinase that spontaneously resolved, adverse events -- primarily headache, asthenia, and fever -- were mild or moderate. There was no relationship between adverse events and dose level, and resistance did not emerge over the brief study period. The investigators concluded that dOTC was potent and well tolerated over the course of this dose-ranging study.
Comment: The early safety and efficacy data on dOTC are very promising. It remains unclear at this point whether this new nucleoside analog will be truly effective against highly-resistant viral isolates.
Expanding options for treatment-naïve patients
Care providers are only too aware that most patients on protease-inhibitor-containing regimens have adherence problems (see "Compliance: How You Can Help," Vol. 3, No. 3, pages 67-72, and "Strategies to Establish and Maintain Optimal Adherence," the pull out and save section of that issue). We also know that many patients on multidrug antiretroviral therapy develop lipodystrophy and other metabolic disorders thought to be associated with protease inhibitor use (see "Update: Treatment of HIV-Associated Body-Composition Abnormalities," Vol. 5, No. 4, pages 50-59). As a result, interest in protease-sparing regimens has grown considerably in the past year.
TRIPLE NUCLEOSIDE THERAPY: Staszewski and colleagues conducted a randomized, double-blind, 48-week study comparing a triple-nucleoside regimen of abacavir and Combivir® (combination ZDV/3TC) with a protease-inhibitor-based regimen of indinavir and Combivir (6). The study enrolled 562 therapy-naïve patients with CD4 counts greater than 100 cells/mm3, who were then stratified by HIV RNA levels into two groups: stratum A, with viral loads between 10,000 and 100,000 copies/mL, and stratum B, with more than 100,000 copies m/L. The study was placebo-controlled, and all participants were required to adhere to t.i.d. dosing regimens and food restrictions, regardless of study arm.
Unfortunately, the dropout rate in this study was exceedingly high, eventually reaching almost 40%, and we must therefore exercise particular care in drawing conclusions from the data. The rate and reasons for premature discontinuations were similar in both treatment arms, however, and very few patients discontinued therapy because of clear virologic failure.
In the intent-to-treat analysis, patients in both strata had a comparable virologic response to treatment, with close to half achieving HIV RNA levels below 50 copies/mL by week 48 of the trial. In the stratum that had HIV RNA levels greater than 100,000 copies/mL, 45% of the patients who received indinavir plus Combivir had their viral loads drop below 50 copies/mL by week 48. Only 31% of the patients treated with abacavir plus Combivir reached this level of viral suppression by the end of the trial.
Comment: This study supports the concept that protease-inhibitor- and NNRTI-sparing regimens are a reasonable alternative for treatment-naïve patients with early-stage disease. The trend suggesting that the abacavir-containing arm performed less well than the indinavir-containing arm reinforces the perception that three-nucleoside regimens may not be completely suppressive, even in patients who have never been exposed to antiretroviral agents. Long-term follow-up is needed to determine if the trend observed by these investigators achieves statistical significance over time. We also need studies evaluating the level of viral replication in the lymphoid tissue of patients treated with three-nucleoside regimens -- including those patients who achieve "undetectable" HIV RNA levels on therapy.
One aspect of this study requires particular emphasis: this was a double-blind, placebo-controlled study. Patients in the indinavir arm received only 2 placebo pills. Patients in the abacavir arm received 12 placebo pills (including indinavir placebo every 8 hours fasting). We know that pill burden has a direct impact on adherence, and it is fair to wonder wheher the patients in the abacavir arm would have achieved better virologic results than those in the indinavir arm in an open-label study.
THE ATLANTIC STUDY -- 48-WEEK DATA: The question of whether to select a protease-based or protease-sparing initial regimen has received a great deal of attention in the past year, chiefly because of the understandable desire, on the part of care providers, to minimize the side effects of multidrug therapy, improve adherence, and maintain the widest range of future therapeutic options. Researchers have addressed the crucial clinical question with a greater sense of urgency since evidence began to emerge that seemed to link the use of protease inhibitors with marked lipodystrophy (see "Update: Treatment of HIV-Associated Body-Composition Abnormalities," Vol. 5, No. 4, pages 50-59; this article, and earlier reports on "protease paunch" and "buffalo hump," can also be accessed at hivnewsline.com).
The Atlantic Study, a multisite international study conducted by Murphy and colleagues, compared three initial antiretroviral regimens, each based on the dual-nucleoside combination of d4T and ddI (7). The three regimens added either a protease inhibitor (indinavir), an NNRTI (nevirapine), or a third nucleoside analog (3TC) to d4T plus ddI. The 298 participants enrolled in this study were antiretroviral-naïve, were asymptomatic, had CD4 counts above 200 cells/mm3, and had HIV RNA levels above 500 copies/mL.
In the as-treated analysis that was conducted after 48 weeks of treatment, the percentages of patients with HIV RNA levels below 50 copies/mL in the indinavir, nevirapine, and triple-nucleoside arms were 90%, 82%, and 78%, respectively. In the more conservative intent-to-treat analysis, the percentages were 57%, 51%, and 49%. The response among treatment arms, at least at 48 weeks, was similar, although patients with baseline HIV RNA levels above 4.36 logs were less likely to achieve suppression below the level of 50 copies/mL when randomized to the triple-nucleoside arm.
Comment: This study provides further support for the treatment strategy of beginning treatment-naïve patients with low viral loads on protease-sparing regimens. However, the Atlantic Study is not complete at this juncture, and it may not be adequately powered to demonstrate true equivalence among the three treatment approaches. Given how low these study subjects' viral loads were at baseline, differences in efficacy among the tested regimens may emerge only after long-term follow-up. Indeed, the available data already suggest that virologic failure may be more frequent on the triple-nucleoside regimen of d4T, ddI, and 3TC than on either the indinavir- or the nevirapine-containing regimens. One noteworthy aspect of this study is that it was initiated and coordinated by investigators at a number of centers. As a result, the data are often incomplete, as there is no single clinical research organization collecting and interpreting the findings.
EFAVIRENZ -- FURTHER ANALYSIS OF THE DATA FROM STUDY 006: The DuPont 006 study, which is being conducted by Staszewski et al., has randomized patients to the two-nucleoside combination of ZDV and 3TC plus either efavirenz or indinavir. An interim analysis of data collected on the first 450 patients to enroll in the study, presented at the 6th Conference on Retroviruses and Opportunistic Infections, showed that the efavirenz-containing regimen was better tolerated and somewhat more effective in controlling HIV RNA than the indinavir-based regimen.
Data from the full cohort of patients (n = 1,266) confirm these earlier findings (8). The open-label phase of this study included participants who were naïve to protease inhibitors, NNRTIs, and 3TC. Participants were randomized to receive EFV/ZDV/3TC, EFV/IDV, or IDV/ZDV/3TC. The 72-week data on a subset of patients were presented at ICAAC. The time to treatment failure -- which was defined as failure to achieve viral suppression below 400 copies/mL by 24 weeks, virologic rebound above 400 copies/mL following suppression, an AIDS-defining event, or discontinuation from the study -- was significantly longer in the efavirenz-containing arms than in the IDV/ZDV/3TC arm. The durability of virologic response was greater in the EFV/ZDV/3TC arm than in the IDV/ZDV/3TC arm, with little difference between the EFV/IDV arm and the IDV/ ZDV/ 3TC arm.
Comment: The most recent findings from DuPont 006 strongly support the use of two nucleoside analogs and efavirenz in treatment-naïve patients, independent of baseline viral load. However, there are limited data to date concerning the efficacy of this three-drug combination in patients with low baseline CD4 cell counts, and for this reason many clinicians prefer to initiate therapy with a protease-inhibitor-containing regimen in such patients.
The dramatic results of DuPont 006 need to be confirmed by an independent study, and several such studies are being conducted at this time, most of them comparing the NNRTIs efavirenz and nelfinavir in combination with two nucleosides. Confirmation of the immunologic benefit of protease-inhibitor-sparing regimens is also needed -- although there is no reason to believe that the virologic suppression achieved with a protease-inhibitor-sparing regimen will have clinical and immunologic effects that are quantitatively or qualitatively different from those achieved with a protease-inhibitor-containing regimen.
SIMPLIFIED MAINTENANCE THERAPY WITH ABACAVIR PLUS ZDV AND 3TC: The concept of induction/maintenance therapy for HIV, in which a maximally suppressive antiretroviral regimen is followed by a less potent regimen, is of interest because of the adverse effects, the high pill burden, and the dose-scheduling difficulties associated with protease-inhibitor-based regimens. To date, however, studies of induction/maintenance therapy have shown this approach to be ineffective in sustaining suppression of viral replication.
There is, of course, a distinct difference between induction/maintenance therapy and what Opravil and colleagues were assessing in their study: simplified maintenance therapy. This treatment strategy involves switching patients from a complicated regimen -- any indinavir-based regimen, for example -- to a simpler regimen that has similar potency and efficacy. Several such simplified maintenance regimens are actively being studied; they involve the combination of two nucleoside analogs and either abacavir or an NNRTI.
The study conducted by Opravil and coworkers in Switzerland and Italy used a multidrug regimen based on abacavir as maintenance therapy (9). The study enrolled participants who had six months or more of experience on a protease-inhibitor-based regimen, HIV RNA levels below 50 copies/mL, and no mutations at codon 215 (which is associated with high-level ZDV resistance). Participants were randomized to continue their current protease-inhibitor-based regimen or change to a simplified regimen that contained only four pills per day: 300 mg abacavir twice daily and one Combivir tablet (300 mg ZDV/150 mg 3TC) twice daily. Treatment failure was defined as an HIV RNA value of greater than 400 copies/mL on two consecutive tests.
Virologic response was similar in both the continued-therapy and simplified-therapy arms, with three cases of virologic failure in the former arm and five cases in the latter. CD4 cell counts were also comparable between arms. It is noteworthy that decreases in serum triglyceride and cholesterol levels, and increases in HDL levels, were noted in the simplified-therapy arm. This study suggests that shifting treatment-experienced patients from a protease-based regimen to a simplified, abacavir-based regimen may preserve virologic response and reverse certain lipid abnormalities that are associated with protease-inhibitor use.
Comment: Switching patients from a complicated but potent multidrug antiretroviral regimen to a simpler but still potent regimen is a straightforward matter and should work in most patients. However, clinicians do need to consider what residual virus may be present in patients before a change in therapy is made. For example, patients who have developed resistance to zidovudine may nonetheless do well on a protease-inhibitor-containing regimen -- if its overall potency is great enough to overcome the effects of that resistance. When such patients switch to a simpler regimen, such as ZDV/3TC plus abacavir, any residual resistance becomes a more important clinical concern.
Simplified dosing of protease inhibitors
ONCE-DAILY INDINAVIR PLUS RITONAVIR: At present, indinavir is approved only for administration on an empty stomach at eight-hour intervals. Studies have shown that twice-daily dosing of indinavir provides inadequate viral suppression, but deviations from the recommended dosing schedule are common given the lifestyle and dietary restrictions that faithful adherence imposes. A recently completed study, Merck 078, showed that adding low-dose ritonavir to an indinavir-based regimen inhibits P450 cytochrome production sufficiently that clearance of indinavir is slowed substantially and serum concentrations rise dramatically.
Despite the lack of efficacy and safety data for this combination of protease inhibitors, ritonavir and indinavir are now widely prescribed as elements of a b.i.d. regimen -- on the assumption that the combination results in greater exposure to the indinavir. Because the demand for simplified antiretroviral regimens is so great, a number of investigators, encouraged by the data from Merck 078, have been looking into the possibility that adequate viral suppression could be achieved with once-daily dosing of indinavir plus ritonavir. No protease inhibitors can currently be dosed only once a day.
To assess the pharmacokinetics of this combination, Burger and colleagues enrolled 12 healthy volunteers in a study that examined the results of administering 400, 800, or 1200 mg of indinavir once daily in subjects who also received either 200 or 400 mg of ritonavir (10). What the researchers found is that ritonavir inhibited the clearance of indinavir by 50% to 70%, resulting in increased and prolonged indinavir exposure. Based on the pharmacokinetic data and the adverse-event profiles obtained in this small trial, the investigators concluded that an optimal once-daily dosage regimen would be 1200 mg IDV/200 mg RTV. They noted, however, that an initial dose of 1200 mg IDV/400 mg RTV may be necessary to achieve adequate initial drug levels.
In a similar trial, Saah and colleagues randomized healthy volunteers to receive either 800 mg IDV/100 mg RTV, 800 mg IDV/200 mg RTV, 1200 mg IDV/100 mg RTV, IDV placebo/100 mg RTV, or IDV placebo/200 mg RTV (11). All of the once-daily IDV/RTV regimens resulted in indinavir exposure comparable to that of standard t.i.d. therapy, and all were generally well tolerated.
Comment:It is easy to understand the popularity of the b.i.d. indinavir/ritonavir regimen. For one thing, it is considerably more convenient than the mandated indinavir dosing schedule -- eliminating both the necessity of dosing at strict eight-hour intervals and the need to take indinavir on an empty stomach to maximize drug absorption. Additionally, twice-daily ritonavir/indinavir results in considerably higher serum concentrations of indinavir, compared with regimens in which indinavir is the sole protease inhibitor, and by reducing the depth of the troughs that occur when indinavir is administered alone, this two-protease combination reduces the likelihood that patients will develop indinavir-resistant viral isolates.
Neither of these factors applies to the once-daily regimen. Here trough concentrations are at or near those seen when indinavir is administered as the sole protease inhibitor. In the absence of more data on once-daily indinavir/ritonavir, clinicians will have to decide if the modest difference in convenience between twice-daily and once-daily dosing outweighs the potential for viral mutation that occurs at the trough concentrations that seen with once-daily dosing.
ONCE-DAILY SAQUINAVIR PLUS RITONAVIR: The combination of saquinavir and ritonavir is the oldest and most widely prescribed of dual-protease-inhibitor combinations, but it has not previously been evaluated as a once-daily regimen. Saag and colleagues conducted an open-label study with 41 healthy volunteers randomized to receive the soft-gel formulation of saquinavir (Fortovase®) alone or in combination with ritonavir (12). Participants receiving both drugs took 100 mg RTV with either 1200, 1600, or 1800 mg SAQ. There was also an arm receiving 200 mg RTV with 1200 mg SAQ. Based on the pharmacokinetic results, the investigators selected the regimen of 1600 mg SAQ plus 100 mg RTV to be further studied as a once-daily regimen in HIV-positive patients.
RITONAVIR PLUS TIPRANAVIR: Tipranavir, a novel protease inhibitor in development at Pharmacia & Upjohn, belongs to a unique class of compounds. Data presented at the most recent International Workshop on HIV Drug Resistance and Treatment Strategies indicated that tipranavir, which is currently in Phase 2 clinical trials, appears to be active against the majority of HIV isolates that are highly resistant to one or more of the currently available protease inhibitors (see "Tipranavir, first of a new class of non-peptitic protease inhibitors," Vol. 5, No. 3, pages 18-19).
In this in vitro study 135 clinical isolates were taken from patients known to have developed resistance to at least one protease inhibitor. Phenotypic assays for the four protease inhibitors cited above were run on all of the viral isolates, and 107 of 135 proved to have greater than 10-fold resistance to at least three of the four F.D.A.-approved protease inhibitors. Remarkably, 90% of these 107 highly-resistant isolates remained completely susceptible to tipranavir. Another 8% demonstrated intermediate resistance to Pharmacia & Upjohn's investigational agent, and only 2% of the isolates showed a higher degree of resistance.
To date, the development of tipranavir has been impeded by its limited pharmacokinetic properties -- which have made it necessary for patients in these early trials to take up to 30 pills per day to maintain adequate serum concentrations. Fortunately, tipranavir metabolism, like indinavir metabolism, appears to be inhibited by ritonavir. Baldwin et al. examined the pharmacokinetic interaction between tipranavir and ritonavir in patients in two small studies. In each, participants received both drugs twice daily at varying dosages (13). The results showed that a two-way interaction occurred, with tipranavir levels rising as ritonavir levels fell. Side effects included gastrointestinal distress, diarrhea, headache, and increased triglycerides, although no serious adverse events were reported several phase 2 studies of ritonavir/tipranavir are under way.
TWICE-DAILY FORTOVASE -- THE TIDBID STUDY: Fortovase, the soft-gel formulation of saquinavir, is currently approved for t.i.d. dosing. A twice-daily regimen would obviously be preferable, since dosing ease enhances adherence. The TIDBID Study was a randomized, open-label, 48-week trial conducted by Cohen and colleagues that enrolled 840 participants who were either antiretroviral-naïve or had prior exposure only to nucleoside analogs (14). Participants were randomized to receive either 1200 mg SAQ t.i.d. or 1600 mg SAQ b.i.d. (in combination with two nucleosides) or 1200 mg SAQ plus 1250 mg nelfinavir b.i.d. with one nucleoside analog.
The formal 24-week analysis found that immunologic and virologic responses were comparable for the b.i.d. and t.i.d. regimens. The adverse- events profiles were also comparable for the two arms. While five deaths were reported among study participants, none were deemed related to the drug regimens. Clinicians will want to interpret these findings with caution, but in this instance the enhanced compliance that can reasonably be expected with a simplified regimen may well outweigh the potential that b.i.d. dosing of saquinavir will result in reduced drug exposure.
The clinical value of resistance testing
CROSS-RESISTANCE IN NELFINAVIR-TREATED PATIENTS: It is not yet clear which protease inhibitors are more appropriate to use initially, or what the best strategy is for patients who fail their first protease-inhibitor-containing regimen. In order to determine the susceptibility patterns of various protease inhibitors following the failure of an initial protease-based regimen, Haubrich and colleagues used the ViroLogic PhenoSense assay to study viral isolates from 69 patients who were deemed to be failing their current protease-inhibitor-containing regimen, the majority of whom had been treated with nelfinavir (15). The results revealed the following susceptibility rates:
The investigators determined that nelfinavir tended to be less cross-resistant than the other protease inhibitors, at least when used as initial therapy -- a therapeutic advantage first cited in HIV Newsline in December of 1997 (see "The Next Generation of Antiretroviral Agents -- An Update," Vol. 3, No. 6, pages 143-151).
Comment: The phenotypic data from this group of patients, all of whom were experiencing virologic failure on a protease-inhibitor-based regimen, confirm previous findings. Patients failing nelfinavir generally have better-preserved second-line protease-inhibitor options, and of the currently available agents, phenotypic cross-resistance to amprenavir appears to be the most limited.
"ZDV-LIKE" MUTATIONS SELECTED FOR BY d4T: Studies conducted in patients on d4T monotherapy have shown that mutations generally associated with zidovudine may arise with d4T use. These studies also suggest that these mutations should properly be classified as thymidine analog mutations.
Ross and colleagues at Glaxo Wellcome examined resistance mutations from 56 patients who were d4T-experienced but ZDV-naïve (16). Although the patients had not been exposed to ZDV, 43% had mutations associated with ZDV resistance, including those at codons M41L, D67N, K70R, T215Y/F, and K219Q/E, with the 215 mutation being the most common.
Phenotypic assays run on viral isolates from 26 of the patients found that, despite these mutations, the samples were still sensitive to both d4T and ZDV -- an unexpected finding. The investigators conclude that d4T therapy in ZDV-naïve patients may select for "ZDV-like" thymidine-analog resistance mutations, although the possible clinical implications of these findings require further study.
Comment: Several independent groups have reported that d4T selects for genotypic mutations similar to those seen with long-term ZDV use, yet phenotypic resistance to d4T remains very low. The relationship between virologic failure on d4T and the emergence of genotypic and phenotypic resistance has not been determined. These data suggest that prolonged exposure to d4T may well limit the future usefulness of other nucleoside analogs, however, and that ZDV and abacavir may prove to be less effective in patients heavily pretreated with d4T.
Discontinuing therapy in patients with long-term virologic suppression
Nothing is more tantalizing to practitioners and patients alike than the possibility that sustained suppression of viral replication may eventually lead to eradication of HIV -- and permit patients to stop taking the combinations of antiretroviral agents that have produced durable suppression. This prospect has always seemed most likely for patients who began maximally suppressive multidrug therapy shortly after they seroconverted, who are highly compliant with therapy, and whose HIV RNA levels have consistently remained below the level of detection of the most sensitive commercial assays.
Markowitz and colleagues, from the Aaron Diamond Institute in New York City, followed a cohort of patients who started multidrug antiretroviral therapy -- usually ZDV/3TC plus either indinavir or ritonavir -- during the early stages of infection (17). Of the 14 patients who completed roughly three years on one of these potent regimens, four self-selected to discontinue therapy. All four patients had started therapy within 60 days of their primary infection. At the time of discontinuation, all had HIV RNA levels below 50 copies/mL and CD4 counts between 422 and 1306 cells/mm3.
Following discontinuation, HIV RNA rose to detectable levels in all four patients within 14 to 26 days. One patient restarted therapy after 25 days. Viral load peaked at between 14,000 and 22,000 copies/mL for the remaining three patients, although viremia leveled off to between 2,000 and 5,000 copies/mL after five to seven months. A drop in CD4 percentage was also observed.
Despite close to three years of fully suppressive therapy, as measured by commercial HIV RNA assays, all of the patients who opted to discontinue therapy experienced a rapid rise in HIV RNA, although viral rebound occurred later than it has in published studies of other patients who stopped maximally suppressive therapy. In addition, some control of HIV RNA seems to be maintained in these patients, at least in the short term. The investigators hypothesize that this is an immune-mediated effect attributable to immune reconstitution that occurred during the period of near-total suppression.
Ortiz et al. of the Aaron Diamond group recently published data on six other patients who elected to discontinue therapy (18). In this cohort, two patients did not experience viremic rebound -- through 12 months for one patient and 24 months for the other. Strong HIV-1-specific immunity was present at the time multidrug therapy was discontinued in these two patients. How long these patients will remain free of detectable HIV RNA remains to be seen, but the fact that they have achieved at least transient " remission" suggests that it may eventually be possible to wean responsive patients off therapy for extended periods of time. Along similar lines, a group from the NIH presented early data from an ongoing prospective study entitled "NoHRT" (19). In this single-arm study, patients who have been on maximally suppressive therapy for more than a year, have had HIV RNA levels below 500 copies/mL for at least a year, and have had successive CD4 counts above 350 cells/mm3 discontinue therapy and are followed closely.
Data from 18 patients were presented at ICAAC. (Of the 18 subjects, 12 had been on prior IL-2 therapy.) At baseline, patients had a median CD4 count of 921 cells/mm3 and had had no detectable HIV RNA for an average of 108 weeks. Three of these patients had no detectable HIV RNA even when tested with a highly-sensitive nested gag PCR technique, one patient had no detectable HIV DNA, and seven patients had no detectable latently-infected CD4 cells. Despite the high levels of viral suppression achieved in this cohort, and despite the prior use of IL-2 -- which is thought to help "flush out" viral reservoirs -- virologic rebound occurred rapidly, usually within two weeks of the cessation of therapy. The median time to a viral rebound above 500 copies/mL was 18 days.
Comment: With the exception of the two patients described by Ortiz and his colleagues -- individuals who have, at least temporarily, contained viral replication following the discontinuation of maximally suppressive antiretroviral therapy -- virologic rebound has occurred rapidly after drug discontinuation, even in patients who have had undetectable HIV RNA for three years or more. Fortunately, studies have suggested that these patients do well once therapy is restarted. Why some patients have limited or delayed rebounds remains to be determined, but at present the evidence points toward the development and maintenance of strong and broad HIV-1-specific immunity as the key factor.
Steven G. Deeks, M.D., is Assistant Clinical Professor of Medicine, UCSF Medical School.
Greg Szekeres is HIV InSite Medical Producer, UCSF Positive Health Program, San Francisco, CA.
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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.