Joseph J. Eron, Jr., MD
Several interesting studies were presented at the 13th Conference on Retroviruses and Opportunistic Infections on novel agents in clinical development for the treatment of HIV infection, with the most noteworthy data coming from 2 presentations of clinical trials of HIV integrase inhibitors. In a phase IIb, double-blind study, Grinsztejn and colleagues[1] randomized 167 patients with multiclass-resistant HIV to receive either placebo or 1 of 3 doses of the integrase inhibitor MK-0518 (200 mg twice daily, 400 mg twice daily, or 600 mg twice daily) along with an optimized background regimen (Capsule Summary). Patients had HIV-1 RNA levels greater than 5000 copies/mL and CD4+ cell counts greater than 50 cells/mm3, and harbored HIV resistant to at least 1 PI, NRTI, and NNRTI. Preliminary 16‑week results were presented at this conference, and notably, not all patients had reached 16 weeks at the time the data were analyzed.
More than one half of the patients receiving MK-0518 achieved viral suppression to less than 50 copies/mL after 16 weeks of treatment. Specifically, at Week 16, the proportion of patients with HIV-1 RNA levels below 50 copies/mL varied from 56% to 72% with MK-0518 vs less than 20% with placebo. This was a very high rate of suppression for such a highly experienced patient population. The majority of patients had few sensitive drugs available, with approximately 50% of patients having a baseline phenotypic susceptibility score of 0. Approximately one third of the patients also received the fusion inhibitor enfuvirtide on study, but the investigators did not differentiate results based on use of this drug.
MK-0518 appeared very well tolerated with no apparent differences from placebo in adverse events or laboratory toxicities after 16 weeks of treatment. Only 2 patients discontinued treatment during the course of the study; 1 discontinued due to nonresponse and the other patient died. Overall, I think these were very promising results for this agent and for the field of HIV medicine in general.
Daniel R. Kuritzkes, MD
There were also data presented at this meeting on another integrase inhibitor in early clinical development, GS-9137. Although GS-9137 works by a similar mechanism of action as MK-0518, it is metabolized in a different way: GS-9137 is metabolized by the cytochrome P450 system, whereas MK-0518 is metabolized by glucuronidation. GS-9137 is a moderate inducer of CYP3A4, and its half‑life is markedly extended by coadministration with ritonavir.
DeJesus and colleagues[2] conducted a small, double-blind, placebo-controlled, 10-day monotherapy study to evaluate the safety and efficacy of GS-9137 (Capsule Summary). In this phase IIa trial, the investigators randomized 40 patients to 1 of 4 doses of GS-9137 without ritonavir (200 mg twice daily, 400 mg twice daily, 800 mg twice daily, or 800 mg once daily) or GS-9137 with ritonavir (50/100 mg once daily). Each arm was then further randomized to actually receive the assigned dose of GS-9137 (n = 6) or to receive placebo (n = 2). Patients enrolled in this trial had HIV-1 RNA levels between 10,000 and 300,000 copies/mL and CD4+ cell counts above 200 cells/mm3 and were not currently on antiretroviral therapy.
Overall, the investigators observed a significantly greater reduction in HIV-1 RNA levels with GS-9137, with responses ranging from 1-2 log10 reductions in a dose-dependent manner. Of note, the magnitude of response achieved when GS-9137 (50 mg/day) was administered with low-dose ritonavir once daily was similar to that seen with GS-9137 400 mg twice daily dosed without ritonavir. All GS-9137 doses were similarly well tolerated with no particularly frequent or serious adverse events such as cardiac toxicity, although further study with more patients and longer treatment is needed. Expanded clinical trials of GS-9137 are planned, so we will likely hear more data on this agent in the near future.
Brian Gazzard, MD
This new class of antiretrovirals represents quite a major advance for HIV medicine, particularly for our patients in the salvage setting with few, if any, treatment options. The patients in the MK-0518 study were highly drug resistant: 92% were resistant at baseline to all currently approved PIs, and 50% were resistant to all currently approved NRTIs, NNRTIs, and PIs (although susceptibility to enfuvirtide was not assessed). The efficacy results, showing that more than one half (and up to 72%) of MK-0518-treated patients achieved virologic suppression to undetectable levels (< 50 copies/mL), are even more striking when the extent of resistance in the study population is considered.
Joseph J. Eron, Jr., MD
Given the extent of baseline resistance in this population, I was surprised to see that patients who received optimized background therapy alone achieved a viral load reduction of 0.8 log10 copies/mL at 16 weeks, which is much greater than I would have predicted.
Brian Gazzard, MD
Yes, this is better than I would have expected the background regimen to perform and is a little better than the performance of the background regimen in the RESIST and TORO studies in which about 20% of patients were suppressed on background regimen alone. This may be in part due to the impact of enfuvirtide use in this study; however, such data are not yet available.
Although cross-study comparisons must always be viewed with caution, the rates of virologic suppression seen with MK-0518 were similar to—if not better than—the rates seen with the investigational PI darunavir (TMC114) in the POWER studies and were substantially better than those reported with enfuvirtide in the TORO trials and with tipranavir/ritonavir in the RESIST trials. Questions remain regarding the durability of virologic response and whether integrase inhibitors in general will remain potent for 48 weeks and beyond. We do not yet have a clear perspective on the resistance pattern of this class of drugs and when and if resistance will develop. Clearly, both MK-0518 and GS-9137 appear to be very potent and safe drugs, although both are at relatively early stages in their development.
Joseph J. Eron, Jr., MD
I think Professor Gazzard raises an important point. There are no data yet available on the emergence of resistance to this class of drugs in clinical trials, although both groups noted that they are examining the impact of baseline resistance mutations on response as well as evolution of resistance mutations on treatment.
Also, as Dr. Kuritzkes pointed out, MK-0518 is metabolized by glucuronidation, as is atazanavir. There have been no data presented, but one might expect a possible interaction with atazanavir, given their overlapping metabolism pathways. Further data are needed, but this is likely to have little importance in the salvage setting given that atazanavir is not commonly used in highly experienced patients. GS-9137 is metabolized by the cytochrome P450 system as evidenced by the substantial increase in exposure when given with ritonavir. Although no data are yet available, one might anticipate that there will be some interaction with other PIs, and there may also be interactions with NNRTIs and P450 inducers such as rifampin.
Brian Gazzard, MD
The investigators did mention that MK-0518 levels increased by about 30% to 40% in the presence of atazanavir and while they did not show the data, they did report that stratification of the results according to atazanavir use had no impact on the outcome. Another important interaction to note, particularly for the salvage setting, is that tipranavir is a strong inducer of glucuronidation and when coadministered with MK-0518 it reduces levels of the integrase inhibitor by about 30%. Because of this, use of tipranavir was not allowed in the study by Grinsztejn and colleagues.
Joseph J. Eron, Jr., MD
Overall, I am very encouraged by the findings from these trials; though they are still preliminary and the report from the MK-0518 trial did not yet include data from all the enrolled patients through 16 weeks. I am also pleased to see there are 2 good candidates in this new class with potential for further development.
High Failure Rate With Vicriviroc in HIV-Infected Treatment-Naive Patients
Daniel R. Kuritzkes, MD
The class of novel antiretrovirals that is furthest advanced in clinical development is the CCR5 antagonists, with some agents now in phase III study. Last fall, it was announced that the development of the CCR5 inhibitor aplaviroc was halted because of concern over several cases of severe hepatotoxicity in clinical trials of treatment-naive and treatment-experienced patients. Clinical development of 2 other CCR5 inhibitors, maraviroc and vicriviroc, continues; however, the phase IIb vicriviroc trial in treatment-naive patients was recently halted because of a higher rate of virologic failures seen with vicriviroc vs efavirenz-based treatment. Specific data from this study were presented by Greaves and colleagues[3] at the Conference on Retroviruses and Opportunistic Infections (Capsule Summary).
The phase IIb, randomized study compared the use of various doses of vicriviroc with efavirenz in a cohort of 92 treatment-naive patients. Vicriviroc was administered as 25 mg, 50 mg, or 75 mg once daily for 14 days, after which fixed-dose zidovudine/lamivudine was added to the treatment regimen. In a previous phase IIa trial, the investigators had evaluated twice‑daily doses of vicriviroc but projected that once‑daily doses would be sufficient.[4] Results from the 14-day monotherapy phase were compared with a placebo group and results from the combination therapy phase were compared with a group randomized to receive zidovudine/lamivudine plus efavirenz (600 mg/day).
Greaves and colleagues reported the best response in the 75 mg/day vicriviroc arm, with a 1.3 log10 reduction in HIV-1 RNA after 14 days of vicriviroc monotherapy. Notably, this response was roughly 0.4 log10 copies/mL lower than that reported in the previous phase IIa study.[4] Virologic failures were first observed in the lowest‑dose arm and were later observed in each of the other vicriviroc arms, resulting in termination of the entire study. Rates of virologic failure (HIV-1 RNA > 50 copies/mL) during combination therapy were quite high in the vicriviroc arms: 56% in the 25-mg vicriviroc arm, 41% in the 50-mg vicriviroc arm, and 17% in the 75-mg vicriviroc arm. In comparison, only 4% of patients given efavirenz-based combination therapy experienced virologic failure.
Further analysis determined that virologic response at Day 14 was predictive of risk of virologic failure. Patients experiencing less than a 1.5 log10 reduction in viral load after 14 days of treatment had a 5-fold greater risk of virologic failure than those with a 1.5 log10 or greater response, and if patients also had a baseline viral load above 100,000 copies/mL, the risk increased to 6.5 fold.
Interestingly, genotyping of isolates from patients who failed vicriviroc showed that the lamivudine resistance mutation M184V emerged in all the failures. This suggests that the patients were all taking their medications, but that the activity of the regimen was not sufficient to prevent rapid emergence of resistance. There was no correlation between baseline susceptibility to vicriviroc and treatment response. There were no noticeable shifts in the IC50 of vicriviroc, nor were there any consistent changes in viral envelope sequence among the few envelopes that were sequenced from the failures. Tropism shifts occurred in all the vicriviroc treatment arms, although more occurred with the lowest dose.
Brian Gazzard, MD
I think it is important to highlight that the tropism shifts occurred primarily in the first 2 weeks of monotherapy. Given the short course of treatment, it is possible that these shifts were the result of selection of minority populations of dual-tropic virus, although this cannot be known for certain.
Daniel R. Kuritzkes, MD
Overall, this is a disappointing study result, which unfortunately has left more questions than answers. It is unclear whether the doses chosen for vicriviroc were insufficient, whether the 2-week lead‑in period of vicriviroc monotherapy predisposed patients to fail, or whether this drug is simply not as potent as efavirenz, which seems likely given these results. There are also no clear implications for the ongoing salvage therapy studies, in which the endpoints are somewhat different and vicriviroc is being boosted with ritonavir. Further analysis of the resistance mutations that emerged during suboptimal vicriviroc treatment is needed, and additional doses need to be explored.
Brian Gazzard, MD
That being said, one must also consider that the major dose‑limiting side effect of this drug identified in animal studies was seizures. The doses used in this study were well below the peak level; however, we must be cautious with much higher drug exposure. I think doses of 100 mg or 125 mg once daily would still be safe but not a significantly higher dose.
Joseph J. Eron, Jr., MD
Alternatively, dosing more frequently than once daily to maintain an adequate trough level (Cmin) may be a better strategy; however, given the availability of approved once-daily antiretroviral regimens with low pill burden and good tolerability in patients who are treatment-naive or have limited experience, the competition in this setting is very steep.
One positive result from this study was the lack of hepatotoxicity, which was the cause of discontinuation of aplaviroc development.[5] This result confirms the suspicion that the hepatotoxicity of aplaviroc was related to the specific drug and was not necessarily related to the mechanism of the CCR5 inhibitor class as a whole. The ongoing vicriviroc studies in treatment‑experienced patients have not been stopped, although new vicriviroc studies have been placed on hold until further data are collected.
Other Novel Classes of Antiretroviral Agents in Development: Maturation Inhibitors and Cyclophilin A Inhibitors
Daniel R. Kuritzkes, MD
The maturation inhibitors represent another new class of antiretroviral drugs with a novel mechanism of action. Maturation inhibitors target the later steps of the HIV life cycle. Specifically, the maturation inhibitor PA-457 blocks proteolytic cleavage of the mature capsid protein (CA) from the precursor spacer protein (SP1) by binding the CA-SP1 cleavage site.[6]
Smith and colleagues[7] presented results from a phase II study evaluating the pharmacokinetics and pharmacodynamics of the maturation inhibitor PA-457 in HIV-infected adults (Capsule Summary). This was a follow-up to the study Beatty and colleagues[8] presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, DC, in December 2005 evaluating the short-term efficacy and safety of PA-457 monotherapy in patients who were not on antiretroviral therapy (Capsule Summary). Overall, the investigators observed a dose-dependent response to PA-457. At Day 11, the median HIV-1 RNA level decreased by 0.17 log10 copies/mL with 50 mg PA-457, 0.48 log10 copies/mL with 100 mg PA-457, and 1.1 log10 copies/mL with 200 mg PA-457 (P ≤ .05 vs placebo). Increased plasma drug exposure—higher area under the curve and higher Cmin—was associated with a more potent response. Of note, the maximally potent dose was not achieved in this study, so it might be possible to give higher doses than 200 mg and achieve even better results. Notably, a couple patients in the clinical trial had little to no response despite adequate exposure to PA-457, which was unusual. Whether these patients were actually sensitive to PA-457 at baseline was not determined, as further information regarding resistance is still needed.
In a separate presentation by Adamson and colleagues,[9] in vitro data were presented on the emergence of resistance mutations in the presence of PA-457 (Capsule Summary). Adamson and colleagues described several different mutations around the CA-SP1 cleavage site that led to in vitro resistance to PA-457. Of greater clinical relevance was the fact that the same group also examined patients from the phase IIa study and did not find any mutations in CA-SP1 region.
Because this is a new antiretroviral class with a novel mechanism of action, we do not know to what extent mutations in other parts of the polyprotein precursor could affect cleavage at the CA-SP1 site and therefore susceptibility to PA-457. This region of the viral genome is not included in commercially available phenotype assays, so a novel approach is needed for susceptibility testing.
Joseph J. Eron, Jr., MD
Data were also presented on another novel antiretroviral agent, the cyclophilin A inhibitor Debio-025. For some viruses, cyclophilin A is required for the virus to enter the cell and shed its capsid so that reverse transcription can take place. Cyclophilin A has also been shown to bind the immunosuppressant drug cyclosporine and its derivatives, and cyclosporine itself has very modest antiretroviral activity. Debio-025 was developed to allow cyclophilin A binding without cyclosporine binding and therefore does not have the immunosuppressive effects of cyclosporine. Initial in vitro studies indicated that Debio-025 would have antiviral activity.[10]
Steyn and colleagues[11] conducted a double-blind, placebo-controlled study of Debio-025 (50, 400, or 1200 mg once daily) in treatment-naive HIV-infected patients. Although the agent seemed promising in vitro, the investigators found no significant difference in viral load reductions vs placebo in this trial. While this may represent a novel mechanism for targeting HIV, it was essentially a negative study for this particular agent, although higher doses or drug modifications may give different results.
Brian Gazzard, MD
I think all these drugs are at too early a stage of development to have any certainty about whether they will become clinically available drugs. The maturation inhibitor is the most advanced of these. It is clear from studies presented at CROI that this drug is not being dosed at its maximal level yet, but at the highest dose used, 2 patients for some reason did not respond. This does not appear to be because of low plasma levels of drug nor is it because of mutations in the cleavage site; but it must be presumed that these individuals have reduced sensitivity to the drug possibly because of mutations in another part of the viral genome.
Second-Generation NRTIs in Clinical Development
Daniel R. Kuritzkes, MD
Along with data on novel antiretroviral classes, results were also presented on the continued development of second-generation NRTIs, NNRTIs, and PIs. Margolis and colleagues[12] presented a study evaluating use of the second-generation NRTI amdoxovir with and without mycophenolate mofetil in heavily pretreated HIV-infected patients (Capsule Summary). This is the second of 2 AIDS Clinical Trial Group (ACTG) studies of amdoxovir. The first was a pilot trial presented at the 2005 Conference on Retroviruses and Opportunistic Infections that showed no significant virologic or immunologic benefit of combining amdoxovir with enfuvirtide and other antiretrovirals in HIV-infected patients; however, this study was small and underpowered.[13] In the current study by Margolis and colleagues, 40 patients on a failing HAART regimen with ≥ 1 NRTI resistance mutation were randomized to receive amdoxovir 500 mg twice daily with or without mycophenolate mofetil for 2 weeks. The strategy of combining amdoxovir and mycophenolate mofetil was based on data demonstrating that mycophenolate mofetil alters intracellular triphosphate concentrations and may therefore increase the activity of amdoxovir.
After 2 weeks of treatment, there was a small overall response to amdoxovir, a 0.26 log10 reduction in HIV-1 RNA (P < .0001 vs baseline). This response was extremely modest compared with that seen with other investigational agents at this stage; for example, it was a lower viral load reduction than that observed with tenofovir, the most recently approved reverse transcriptase inhibitor. Furthermore, the investigators did not observe a benefit of mycophenolate mofetil; a median 0.23 log10 reduction in HIV-1 RNA was observed in the amdoxovir plus mycophenolate mofetil arm and a 0.37 log10 reduction in the amdoxovir only arm.
The one positive outcome of this study was the alleviation of concern regarding potential ocular toxicity and nephrotoxicity that had been seen at much higher doses in monkeys. No such toxicity was observed in this study or the other earlier ACTG study.
I think it is fair to say that the clinical development of amdoxovir is now uncertain.
Brian Gazzard, MD
Yes, I would have to agree. It is difficult to believe that it will continue development at this point.
There were also some interesting preclinical data on a new NRTI GS-9148 (Capsule Summary).[14] The development of second-generation NRTIs has focused on agents that retain activity against virus with the M184V mutation. This in vitro study of GS-9148 demonstrated that this agent has broad spectrum activity against a variety of HIV variants with NRTI resistance mutations, including the K65R mutation. The oral bioavailability of a prodrug of this agent also looked good in animals.[15]
Joseph J. Eron, Jr., MD
Yes, high concentrations of GS-9148 were achieved within peripheral blood mononuclear cells, and previous animal experiments showed very good concentrations within lymph nodes. These in vitro data are promising for this agent.
In addition, Lennerstrand and colleagues[16] presented in vitro data on another NRTI known as 1-(β-D-dioxolane)thymine or DOT (Capsule Summary). In reverse transcription assays, DOT had similar or greater activity than zidovudine, stavudine, tenofovir, and abacavir against viruses with thymidine analogue mutations (TAMs), M184V, and K65R, although it did have reduced activity in virus with both TAMs and the T69SSG insertion.
Brian Gazzard, MD
Agents with broader activity against virus with NRTI resistance mutations, particularly K65R and TAMs, would certainly be useful in strategies for the sequential use of NRTIs. I look forward to the further development of the second generation of this important antiretroviral class.
In Vitro Studies of Candidate Entry Inhibitors
Joseph J. Eron, Jr., MD
There were several presentations of in vitro data supporting the further development of candidate fusion inhibitors and CXCR4 coreceptor inhibitors at this meeting.
Delmedico and colleagues[17] presented in vitro data on 2 candidate fusion inhibitors: TRI-999 and TRI-1144 (Capsule Summary). These peptides were derived from a peptide called T-651, which was designed for optimal binding to the HR2 region of the viral envelope protein gp41; TRI-999 and TRI-1144 were selected for their improved pharmacokinetics and potency. Delmedico and colleagues tested the activity of these candidates against a panel of 13 HIV variants resistant to fusion inhibitors such as enfuvirtide and T-1249. Compared with enfuvirtide, the peptides demonstrated similar activity against wild‑type viruses and were 150-fold (TRI-1144) and 250-fold (TRI-999) more potent than enfuvirtide against fusion inhibitor–resistant strains. Furthermore, the agents demonstrated a markedly prolonged half‑life of about 50 hours in cynomolgus monkeys.
Brian Gazzard, MD
The investigators argued that this half-life would allow once-weekly dosing; however, one could also interpret the data as indicating that twice-weekly dosing is likely to be necessary. Even if that is the case, development of sustained release formulations of these drugs may allow once-weekly dosing. Another consideration for the development of these agents is that the injection volume should ideally be kept below 1 mL, as higher subcutaneous injections can be unpleasant for the patient.
The potential convenience of a new agent with a once-weekly injection requirement is somewhat undermined if all other agents in the regimen are administered orally on a daily basis. However, a single injection given once or twice a week that included the entire antiretroviral regimen is an intriguing idea that would greatly aid patients with poor adherence. Tenofovir and the investigational NNRTI TMC278 are 2 agents with half-lives conducive to this approach.
Joseph J. Eron, Jr., MD
Even if the regimen comprises a mix of injectable and oral agents that could be given once weekly, methadone clinics and other observed settings might be an efficient way to administer such antiretroviral therapy.
Thus far, the use of enfuvirtide as the only injectable antiretroviral agent, administered twice daily, has only been accepted in the salvage setting. It would be interesting to see whether an injectable agent that was administered only once or twice weekly proved more acceptable in the larger HIV-infected population, especially if there is still the high incidence of injection‑site reactions as seen with enfuvirtide.
Brian Gazzard, MD
A single weekly injection is a very different scenario from the twice-daily injection, with 45 minutes of preparation, currently required with enfuvirtide. A one-shot-per-week formulation could change the paradigm, particularly if it was one shot for the entire regimen.
Although these second-generation fusion inhibitors are still in the very early stages of development, I applaud the approach and the fact that the researchers are evaluating agents that would retain activity in patients who have developed resistance to enfuvirtide.
Daniel R. Kuritzkes, MD
In a separate study, Tanaka and colleagues[18] presented positive preclinical data on 2 potential oral CXCR4 antagonists: KRH-3955 and KRH-3140.
AMD-070 is the only CXCR4 inhibitor currently in clinical development and is now entering phase IIa study; other candidate CXCR4 inhibitors are in earlier stages of development. The importance of CXCR4 inhibitors is supported by data suggesting that CXCR4-tropic HIV-1 is associated with more rapid progression to AIDS and death. Furthermore, there is some concern that use of CCR5 inhibitors could potentially select for CXCR4-tropic virus as a form of resistance. The combination of both CCR5 and CXCR4 inhibitors in treatment regimens is potentially attractive.
Tanaka and colleagues evaluated in vitro binding specificity and in vivo anti-HIV activity, toxicity, and pharmacokinetics of the CXCR4 inhibitor candidates KRH-3955 and KRH-3140 (Capsule Summary).[18] The data demonstrated that both candidates were active in vitro and in vivo against an X4 HIV variant; the animal data also showed good oral bioavailability and minimal toxicity.
Joseph J. Eron, Jr., MD
In the severe combined immunodeficiency (SCID) mouse model, the mice were challenged with an X4 HIV variant. Most mice that were administered a placebo were infected with the virus, whereas a much smaller percentage of mice given the CXCR4 candidate drugs were infected.
Daniel R. Kuritzkes, MD
KRH-3955 and KRH-3140 clearly inhibit X4 viruses, at least in vitro and in animals. One clinical consideration for this class in general is that most patients with X4 virus either have a mixed population of R5 and X4 virus or have virus that is dual tropic (ie, can bind both the CCR5 and CXCR4 coreceptor). The question is whether inhibiting only CXCR4 binding will be sufficient to prevent HIV entry.
The group intends to move these CXCR4 candidates into phase I human studies; however, whether this class of drugs can be successfully developed remains to be determined.
Current Status of the Drug Pipeline for Salvage Therapy
Brian Gazzard, MD
Overall, coming out of this meeting, I am very encouraged about the health of the drug pipeline for salvage therapy. There are presently more drugs in the pipeline for the treatment of HIV than there are in the pipeline for any other microbial infection, including the whole range of bacterial infections. To have 2 drugs from an entirely new class, namely MK-0518 and GS-9137, that are clearly very potent in the salvage setting and highly active against multiclass‑resistant viruses is a major advance.
I think what will be most interesting with regard to drug development this coming year is how agents in the pipeline will be evaluated in an ethical way that does not significantly extend the time to approval. We need to learn to use investigational HIV drugs judiciously and properly, learn from previous mistakes, and think differently about how to design clinical trials. Some of the trial designs we are currently using are becoming increasingly difficult to justify. Monotherapy is strongly contraindicated in salvage therapy. Studies involving single new drugs can therefore be performed either in patients who do not actually need them, which can contribute to the development of resistance that precludes the use of the drug in later settings, or in a very restricted group of patients who have no other treatment options, making use of a placebo control arm potentially unethical. Therefore, the options are to design a study in the deep salvage setting that includes 2 investigational agents together or to move the study into an earlier treatment setting in which patients are likely to have multiple active drug options for their background regimen. The complication is that in earlier settings in which current regimens already achieve high rates of virologic suppression, it is difficult to discern the effects of an individual investigational drug from that of the other potent agents included in the combination regimen.
Daniel R. Kuritzkes, MD
I think the US Food and Drug Administration would be open to evaluating drugs for approval from trials with multiple investigational agents, even in the phase II setting. The greater challenge is in determining which toxicities are associated with which individual drugs. Initial evidence, perhaps from a 10‑day monotherapy study, could minimize some of the difficulty in determining which drug was most likely responsible for a particular toxicity.
Joseph J. Eron, Jr., MD
I too share Professor Gazzard’s enthusiasm about the health of the salvage drug pipeline. In 2005, we saw the approval of tipranavir, which has demonstrated clear activity in patients with extensive PI experience when boosted with ritonavir, and other new second-generation agents are emerging. A new drug application for the investigational PI darunavir (TMC114) was submitted December 2005, and phase III studies of the investigational NNRTI etravirine (TMC125) are currently enrolling. With regard to novel classes on the horizon, the CCR5 inhibitor, maraviroc, is in phase III development with studies either fully enrolled or enrolling. The integrase inhibitor MK-0518 is on the cusp of phase III study as well. The reported activity of both MK-0518 and darunavir has been very promising in treatment-experienced patients, and I think that the horizon is relatively bright in terms of drugs in the pipeline.
References
1. Grinsztejn B, Nguyen BY, Katlama C, et al. Potent antiretroviral effect of MD-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 159LB. (Capsule Summary)
2. DeJesus E, Berger D, Markowitz M, et al. The HIV integrase inhibitor GS-9137 (JTK-303) exhibits potent antiviral activity in treatment naive and experienced patients. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 160LB. (Capsule Summary)
3. Greaves W, Landovitz R, Fatkenheuer G, et al. Late virologic breakthrough in treatment naive patients on a regimen of Combivir + vicriviroc. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 161LB. (Capsule Summary)
4. Schuermann D, Pechardscheck C, Rouzier R, et al. SCH 417690: antiviral activity of a potent new CCR5 receptor antagonist. Program and abstracts of the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract TuOa0205.
5. Nichols W, Steel H, Bonny T, et al. Hepatotoxicity observed in clinical trials of aplaviroc (APL, 873140). Program and abstracts of the 1st International Workshop on Targeting HIV Entry; December 2-3, 2005; Bethesda, Maryland. Abstract 26.
6. Li F, Goila-Gaur R, Salzwedel K, et al. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci U S A. 2003;100:13555-13560.
7. Smith P, Forrest A, Beatty G, et al. Pharmacokinetics/pharmacodynamics of PA-457 in a 10-day multiple dose monotherapy trial in HIV-infected patients. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 52. (Capsule Summary)
8. Beatty G, Lalezari J, Eron J, et al. Safety and antiviral activity of PA-457, the first-in-class maturation inhibitor, in a 10-day monotherapy study in HIV-1 infected patients. Program and abstracts of the 45th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, DC. Abstract H-416d. (Capsule Summary)
9. Adamson C, Salzwedel K, Castillo A, et al. Viral resistance to PA-457, a novel inhibitor of HIV-1 maturation. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 156. (Capsule Summary)
10. Rosenwirth B, De Bethune MP, Ptak RG, et al. Debio-025, a novel non-immunosuppressive cyclosporine analog with potent anti-human immunodeficiency virus type I activity: pharmacological activities and mode of action. Antiviral Res. 2005;65:A42-A43.
11. Steyn D, Richman D, Aeschlimann C, et al. A double-blind, placebo-controlled study in HIV-1-infected subjects on the safety, pharmacokinetics, and antiviral effect of cyclophilin A targeting DEBIO-025. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 516.
12. Margolis D, Mukherjee L, Hogg E, et al. A phase I/II randomized, double-blind, placebo-controlled pilot study of beta-D-2,6-diaminopurine dioxolane vs DAPD + mycophenolate mofetil in treatment-experienced subjects (ACTG 5165). Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 517. (Capsule Summary)
13. Gripshover B, Santana J, Ribaudo H, et al. A randomized, placebo-controlled trial of amdoxovir vs placebo with enfuvirtide plus optimized background therapy for HIV-infected subjects failing current therapy (AACTG 5118). Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 553.
14. Cihlar T, Ray A, Boojamra D, et al. GS9148: a novel nucleotide active against HIV-1 variants with drug-resistance mutations in reverse transcriptase. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 45. (Capsule Summary)
15. Ray A, Vela J, Mackman R, et al. Amidate prodrug of a nucleotide analog GS9148 enhances the in vitro intracellular delivery of the active diphosphate metabolite: potential for clinical efficacy. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 498.
16. Lennerstrand J, Bluemling G, Ruckstuhl M, et al. 1-(ß-D-dioxolane) thymine is effective against HIV-1-containing TAM and M184V. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 46. (Capsule Summary)
17. Delmedico M, Bray B, Cammack N, et al. Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 48. (Capsule Summary)
18. Tanaka Y, Okuma K, Tanaka R, et al. Development of novel orally bioavailable CXCR4 antagonists, KRH-3955 and KRH-3140: binding specificity, pharmacokinetics and anti-HIV-1 activity in vivo and in vitro. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 49LB. (Capsule Summary)
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