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ICAAC 2011: Medically Important Highlights
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David H Shepp, MD,
Hofstra NSLIJ Medical School
Division of Infectious Diseases
North Shore University Hospital - Manhasset
Novel Treatments for HIV
Adoptive Transfer of CCR5-Modified T-cells. Combination antiretroviral therapy (ART) can suppress the growth of HIV and restore immunity to opportunistic illnesses. However, latent virus is not eliminated, requiring lifelong treatment to maintain benefit. An important thrust of current HIV research is directed to finding therapies that will allow ART to be discontinued. The apparent cure of HIV infection in a patient with leukemia who received allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5 delta 32 homozygous donor has triggered renewed interest in gene therapy for treatment of HIV. Since such donors are rare and HSCT carries high risk, investigators at Sangamo Bioscience and clinical collaborators are exploring adoptive transfer of CCR5 modified autologous T-cells as therapy for HIV. CD4+ T-cell harvested by leukopheresis from HIV-infected patients well controlled on ART were infected ex-vivo with an replication defective adenovirus vector that delivers a zinc-finger nuclease capable of interrupting the CCR5 gene. The cells are then expanded and re-infused. The first report of this form of therapy created considerable excitement at CROI last February. Abstracts presented at ICAAC 2011 provided an update1,2. When reinfused, modified cells were shown to comprise about 5% of peripheral CD4+ T-cells and a variable proportion in rectal biopsy tissue (2-10% in most patients). Cells persisted at similar levels after as much as a year of follow-up. Reinfusion of the treated cells also resulted in a large increase in peripheral CD4+ counts, far greater than could be explained by the fairly modest proportion of treated cells present. The effect of a 12 week ART interruption was described in 7 patients. All experienced rebound in HIV RNA, followed by modest declines. A single patient, a CCR5 delta 32 heterozygote at baseline, declined to undetectable at a single time point prior to resuming ART. This patient also had the highest observed level of bi-allelic CCR5 modified cells. Transient infusion-related adverse effects such as fever, chills, headache, sweats, fatigue, and back pain were common and mostly mild or moderate in severity.
Many questions remain about this technology. It is unclear if the viral load pattern observed during treatment interruption is substantially different than what may be seen during treatment interruption without adoptive cell transfer. To become a clinically useful therapy, it would need to achieve much greater control of HIV replication, comparable in potency and durability to ART. If a clear antiretroviral effect is demonstrated, is it mediated by modified T-cells and by what immune mechanism? The mechanism driving expansion of untreated T-cells in peripheral blood and their functional characteristics need to be determined. Also, the long-term safety of genetically modified T-cell infusions needs to be established.
New Antiretroviral Agents
Several new antiretroviral agents (ARVs) were featured at ICAAC 2011. It is gratifying that development of novel drugs to treat HIV continues, as recent improvements to ART already have made first line regimens, simpler, safer, more tolerable and highly effective for most patients. At the same time, the number of patients with treatment-resistant HIV has been greatly reduced.
BI 224436. Boehringer Ingleheim presented pre-clinical and phase 1a data on BI 224436, a novel HIV integrase inhibitor3-6. This drug is not a strand transfer inhibitor like raltegravir and elvitegravir and dolutegravir. Instead, it interferes with 3'-processing of the HIV LTR DNA by binding in a pocket used by LEDGF, a cellular protein that is essential to formation of the active pre-integration complex. Therefore, BI 224436 can be considered an entirely new class of antiretroviral known as non-catalytic site integrase inhibitors (NCINI). In vitro, BI 224436 is fully active against HIV strains that exhibit resistance to raltegravir. Preclinical testing suggested the drug should have favorable pharmacokinetics and a low potential for drug-drug interactions. Single doses ranging from 25-200 mg were administered to healthy volunteers, using an oral solution formulation. Plasma half-life was 7.1 hours and the 100 mg dose produced 24 hour plasma levels well in excess of the IC95 for wild type HIV, suggesting this drug will be suitable for once daily administration. No significant safety signals were identified. These presentations suggest BI 22436 is a promising novel antiretroviral with unique mechanism of action that warrants further trials in HIV-infected individuals. A tablet formulation will need to be developed.
Ibalizumab. Ibalizumab is an entry inhibitor that binds CD4, the primary cellular receptor for HIV. It does not prevent binding of the HIV envelope to CD4, but prevents subsequent entry events. No currently available ARV exploits this mechanism and as such, ibalizumab represents another new class of ARV. It is a fully humanized monoclonal antibody that requires parenteral administration. Lewis et al reported 24 week results from a phase 2b trial that randomized treatment-experienced patients failing ART to ibalizumab 800 mg IV every 2 weeks or 2g every 4 weeks given with an optimized background regimen (OBR) containing at least one fully active ARV7,8. Median HIV RNA declines were 1.8 and 1.4 logs and 44% and 28% achieved viral load <50 copies for the q2 and q4 week regimens, respectively. Moderate CD4 increases that seemed appropriate for patients with advanced HIV (mean baseline CD4 109) were observed. Serious adverse events and deaths occurred but appeared to be related to underlying illness. Because the study design lacked a control group, it was not possible to determine the relative contribution of ibalizumab vs. the OBR to the observed benefits. However, previous studies have demonstrated HIV RNA declines of a little more than 1 log following comparable doses of ibalizumab monotherapy. Although ibalizumab has potentially useful antiretroviral activity and a novel mechanism of action, it is unclear what niche an ARV administered by intermittent infusion would occupy. Critically ill patients who cannot receive oral medication and patients who are very adherent to medical follow-up but are nevertheless poor pill takers, might be candidates, but complimentary injectable companion drugs to complete the regimen would need to be developed. Studies of ibalizumab as a self-administered subcutaneous injection are planned. Large volumes and/or multiple injections per dose would likely be required. If administered in this fashion, it could be useful as a drug of last resort in highly drug-resistant but treatment adherent patients, currently a very small niche occupied by enfuvirtide.
Cobicistat. Although not an ARV, cobicistat (COBI) is an investigational phamacokinetic enhancer being developed by Gilead Sciences as an alternative to ritonavir to improve the pharmacokinetics of HIV protease inhibitors and the investigational integrase inhibitor elvitegravir. It's main advantage over ritonavir appears to be lack of antiretroviral activity, making it suitable for use with elvitegravir in regimens that don't contain a PI, and its availability for coformulation. A published phase II trial using COBI to boost atazanavir did not suggest a clear safety or tolerability advantage over ritonavir, but the results of larger studies are needed. Clinical trials have found that creatinine increases and declines in estimated GFR occur in COBI treated patients. Investigators from Gilead presented studies conducted in HIV-negative volunteers with normal or mildly decreased renal function, demonstrating that 7 days of COBI resulted in reversible declines in estimated GFR of 10-14 mg/dL using either the Cockcraft-Gault or MDRD equations, but that actual GFR as measured directly by iohexol clearance was unaffected9. In vitro, COBI was shown to inhibit the renal tubular efflux transporter MATE-1, which was proposed as the mechanism of inhibition of creatinine secretion and the resulting elevation of serum levels10. This type of creatinine elevation has been recognized with other drugs such as trimethoprim, cimetidine and more recently the newly approved NNRTI rilpivirine and the investigational integrase inhibitor dolutegravir (see below). Since actual GFR is unaltered, these creatinine elevations are thought to be benign, although clinical management can be affected since commonly used GFR estimating equations will underestimate true GFR. This may become important if COBI is widely used with tenofovir, another drug that elevates creatinine by a mechanism that has never been adequately explained.
Dolutegravir. Dolutegravir (DTG) is a promising, late clinical development stage integrase inhibitor dosed once daily without pharmacokinetic boosting. It has "second generation" properties, meaning it retains virologic activity against many isolates that have common single raltegravir resistance mutations. However, common mutation combinations increase resistance to DTG and could emerge to cause treatment failure, even if present as low-frequency minority variants. However, some drug resistant mutants do not emerge to due impaired replication capacity. To examine this possibility, Clavel et al studied HIV clones bearing a variety of single or combination raltegravir resistance mutations, determining their "selective advantage profile"11. This assay incorporates both resistance and replication capacity to determine whether wild-type virus or the resistant mutant is favored at a variety of drug concentrations. None of the common single raltegravir resistance mutations had a selective advantage over wild-type at any drug concentration. Certain dual mutations exhibited a modest selective advantage at 10-100 nM DTG. All were disfavored again at higher concentrations, except for N155H plus E92Q, which maintained a slight advantage. Only a clone with a combination of Q148H plus 3 other mutations had both sufficiently high resistance and replication capacity to have a large competitive advantage at most concentrations of DTG tested. By comparison, single, double and quadruple mutants were clearly favored at most concentrations when raltegravir was the test drug. DTG has been investigated clinically at 50 mg once or twice daily to treat raltegravir-resistant HIV. Activity has been demonstrated at both doses. It's not clear exactly how the plasma levels achieved in patients relate to the concentrations used in the selective advantage assay. However, the study bodes well for the activity of DTG, suggesting most raltegravir resistant mutants are unlikely to emerge to cause treatment failure, especially if high plasma concentrations can be maintained with twice daily dosing.
DTG is another drug that has been found to elevate serum creatinine. Investigators at ViiV Healthcare and GSK measured actual GFR by iohexol and renal plasma flow by para-aminohippurate clearance in healthy volunteers receiving DTG for 14 days12. Neither parameter was affected, although creatinine clearance measured by 24 hour urine collection declined 10-14%. The proposed mechanism for inhibition of creatinine secretion for DTG involves inhibition of the OAT-2 renal tubular transporter.
Rilpivirine. Efavirenz (EFV) is the NNRTI most often used to anchor initial ART regimens. Although most patients are successful on EFV, usually given as a fixed-dose combination (FDC) with tenofovir DF and emtricitabine, EFV causes frequent but transient dizziness and other CNS symptoms, leading to discontinuation in a small number of patients. However, low level sleep disturbance, neurocognitive impairment and mood disturbance may persist in some patients. EFV also causes lipid elevations, although its use has not been linked to an increased risk of cardiovascular disease, and should be avoided in pregnancy due to risk of fetal malformations (pregnancy category D). Rilpivirine (RPV) is a recently approved once daily NNRTI that has some safety and tolerability advantages over EFV. It is also available as an FDC with tenofovir and emtricitabine. RPV's use is associated with a low risk of CNS effects, does not significantly disturb lipids, and is pregnancy category B, although experience with its use in pregnancy is extremely limited. For initiation of therapy, it appears to be less potent than EFV with higher failure rates when the baseline viral load exceeds 100,000. For patients already virologically controlled on EFV but with ongoing safety or tolerability concerns, switching to RPV is an attractive option. However, RPV is metabolized by CYP3A . EFV is potent inducer of this enzyme while RPV is not. An earlier PK study demonstrated RPV exposure was 16-46% lower during the first 3 weeks when given immediately after a 14 day course of EFV. This raised a concern that switching directly from EFV might further impair the potency of RPV. To address this concern, Mills et al conducted an open-label, single arm study switching patients who were virologically suppressed on the EFV FDC to the RPV FDC13. RPV levels were below the therapeutic range during the first week, but then rose and remained in range at weeks 2-12. EFV levels remained high for several weeks after discontinuation, more than adequately covering the early period of low RPV levels. All 49 patients studied maintained undetectable HIV RNA at week 12. These patients will be followed to week 48, but the short term results are reassuring that despite the PK interaction, directly switching from EFV to RPV will be effective in patients already fully suppressed. However, this may not be true for patients with early, acute EFV toxicities that require a switch prior to adequate control of viral load, especially if baseline viral load is high.
Hepatitis C Treatment
Chronic hepatitis C (HCV) is a common co-infection in HIV and accounts for substantial morbidity and mortality in patients who are otherwise living longer due to the success of ART. HIV accelerates the natural history of HCV, increasing the risk of progression to cirrhosis and hepatocellular cancer. Treatment of HCV with pegylated interferon and ribavirin (P/R) is suboptimal, especially for genotype 1, the most prevalent genotype in co-infected patients, and response rates and cure rates are lower in co-infection. HCV treatment has experienced a significant advance in recent months with the approval of telaprevir and boceprevir, two first-in-class HCV protease inhibitors. When added to standard therapy, both of these drugs improve cure rates and allow for shorter courses of treatment for many monoinfected genotype 1 patients. However, the added pill burden, adverse effects and drug-drug interactions from these agents will make extending treatment benefit to co-infected patients a challenge. Studies of these agents in co-infected patients are ongoing but were not reported at ICAAC. For those who cannot benefit from triple therapy with HCV protease inhibitors, a second wave of HCV antivirals that promise to be easier to use and more tolerable are in clinical development.
TMC 435. One of drugs in that second wave of new HCV antivirals is TMC 435, an investigational HCV protease inhibitor with once daily dosing. Interim, 24 week analyses from two phase 2b studies of TMC 435 in combination with P/R for treatment of HCV genotype 1 monoinfection were reported14. The PILLAR study enrolled treatment-naive patients while ASPIRE enrolled patients with prior relapse, partial or null responses to standard therapy. Both studies had complicated designs involving randomization to 5 (PILLAR) and 7 (ASPIRE) arms using different doses and durations of TMC 435 or placebo. ASPIRE results also were broken down according to outcome of prior treatment. In PILLAR, the proportion of participants achieving undetectable HCV RNA at 4 and 12 weeks was higher with TMC 435 than placebo. By week 24, the TMC arms had very high undetectable rates (94-97%), as did the placebo arm, which inexplicably achieved 82% undetectability. Very similar results were seen for prior relapsers in ASPIRE. Much bigger differences in undetectability rates were found between TMC 435 and placebo recipients at all 3 time points in partial and null responders, who achieved 83-89% and 70-87% undetectability, respectively, at week 24, compared to 20% and 45% in the placebo arms. The response rates did not seem to differ according to dose or duration of TMC 435 (75mg v. 150 mg and 12 v. 24 weeks in PILLAR; 100 mg v. 150 mg and 12 v. 24 weeks in ASPIRE) with the possible exception of a somewhat higher response to 150 mg given for 24 weeks in null responders. Adverse effects were common but generally similar to those in patients receiving P/R alone, except for hyperbilirubinemia (direct and indirect) not associated with other evidence of hepatic injury. PILLAR contains a response-guided therapy component and ASPIRE will also evaluate 48 weeks of TMC 435 treatment. Complete follow-up data, including SVR rates, are needed to better evaluate the potential of this drug, but it appears to offer an improved safety profile and ease of administration compared to the first wave of HV protease inhibitors. Response rates at 24 weeks were high, but responses to placebo were also surprisingly high in these studies. This unusual result and differences in the effect of dose and duration of treatment should be clarified by further follow-up, and by phase 3 studies.
BMS 790052. The NS5a protein is an essential component of the HCV replication complex. BMS 790052 is a novel antiviral agent that inhibits the action of NS5a. Pol et al reported final results of a phase 2a study comparing with 3, 10 or 60 mg once daily of BMS 790052 or placebo, each combined with P/R for 48 weeks15. Eligible patients were treatment-naive, non-cirrhotic, HCV genotype 1 mono-infected. The 3 mg dose was less active, but rates of rapid virologic response (RVR) and sustained virologic response (SVR) with both the 10 and 60 mg dose were very high (92% and 83%, respectively for RVR; 83% SVR for both doses) compared to only 8% and 25% for the placebo group. No dose related safety concerns were identified, and the profile of adverse events was similar in the BMS 790052 and placebo groups. Emergent resistance mutations were identified in all patients with virologic failure, which was most frequent in the 3 mg arm. BMS 790052 appears to be a very promising, highly active, novel antiviral that is easy to use and well tolerated. Limitations of this early phase data include the small number of patients in each arm, the exclusion of cirrhotics and the lack of a response-guided therapy component. These concerns should be addressed in subsequent studies.
Treatment of co-infected patients. A pilot trial of telaprevir plus P/R is underway in co-infected patients with very early results reported at CROI 2011. Because of extensive drug-drug interactions between many ARVs and telaprevir, this study enrolled only patients receiving tenofovir DF plus emtricitabine or lamivudine with either ritonavir-boosted atazanavir or efavirenz, and patients not receiving ART. Many co-infected patients are receiving other ART regimens and cannot or will not change to one of these regimens. A new pharmacokinetic study of the interaction between telaprevir and raltegravir found telaprevir exposure is not significantly altered, while raltegravir AUC is increased by 31%16. This increase should not require dose adjustment, as raltegravir has been well tolerated over a range of doses. This study adds raltegravir to a short list of agents that can be used to configure ART regimens in co-infected patients who are candidates for triple HCV therapy containing telaprevir. It should allow more patients to benefit from the improved cure rates achievable with this new agent.
Since many co-infected patients will not take, cannot tolerate or do not respond to standard therapy with P/R, other treatments to reduce progression of liver disease are needed. Maraviroc (MVC) is an HIV entry inhibitor that binds CCR5, altering the ability of HIV envelope to bind to its co-receptor. It is generally safe and well tolerated. MVC also alters the action the natural substrates for CCR5, the c-c chemokines, and so has immunomodulatory effects. CCR5 is expressed on hepatic stellate cells, which are important mediators of the fibrotic response to inflammation. Investigators from Italy reported preliminary results of a study of MVC for HCV liver disease17. Co-infected patients with untreated HCV, on ART with tenofovir DF, emtricitabine and ritonavir-boosted atazanavir were randomly assigned to add MVC or no additional treatment. Changes in liver stiffness, a surrogate marker for fibrosis and/or inflammation, were assessed using transient elastometry, a non-invasive tool widely used in Europe as an alternate to liver biopsy. The abstract reported on 44 patients who had baseline and 24 week assessments. MVC treated and control patients had similar baseline characteristics. Liver stiffness declined in the MVC group and increased slightly in the control group, giving a difference between arms that was statistically significant. More patients in the MVC arm had a decline in stiffness stage while more control patients had an increase, a result that was somewhat surprising given the short duration of follow-up. Enrollment of more patients and 96 weeks of follow are planned. If confirmed by subsequent analyses, use of MVC in patients who cannot benefit from specific anti-HCV therapy might be a simple, easily tolerated intervention to delay progression of fibrosis in co-infected patients.
The goal of HCV treatment is a virologic cure, usually defined by an SVR, or an undetectable HCV RNA in plasma 24 weeks after completion of therapy. Patients achieving an SVR have improved liver function, reduced fibrosis and a greatly reduced risk of liver-related disease and death. Only a minority of co-infected patients achieve an SVR with standard P/R therapy, and it's unclear if patients who fail treatment derive any benefit. To explore this issue, investigator from Spain utilized transient elastometry to monitor changes in liver stiffness in a cohort of co-infected patients treated with standard P/R18,19. Assessments were made before, at the end, and at an average 3 years after treatment. A control group, consisting of patients that were candidates for but declined treatment, was assessed at the time treatment was offered and again approximately 3 years later. In all treated patients, liver stiffness was improved at the end of therapy, nearly as much in non-responders as in SVR patients. However, SVR achievers sustained improvement to the 3 year mark, while non-responders worsened, remaining slightly below the pre-treatment baseline. The control group had worsening liver stiffness. When the non-responders were subdivided according to pattern of response, relapsers remained well below the baseline level of liver stiffness at last follow-up. Patients who never achieved a virologic response (who mostly had treatment terminated early) had progression beyond baseline, but still had less progression than was observed in untreated controls. In multivariate analysis, both achieving an SVR and receiving P/R (regardless of outcome) were associated with improved liver stiffness. While this non-randomized, observational cohort analysis cannot be regarded as definitive, it does provide some reassurance for both clinicians and patients that HCV treatment may still be of some benefit even for many patients who are not cured.
References
1. Mitsuyasu R, et al. Abstract H1-375
2. Ando D, et al. Abstract H2-794a
3. Yoakim C, et al. Abstract F1-1369
4. Fenwick C, et al. Abstract F1-1370
5. Aslanyan S, et al. Abstract A1-1725
6. Brown A, et al. Abstract A1-1726
7. Lewis S, et al., Abstract H2-794a
8. Khanlou, H et al., Abstract H2-794b
9. German, et al. Abstract H2-804
10. Lepist E-I, et al. Abstract A1-1724
11. Clavel F, et al. Abstract H1-374
12. Koteff J, et al. Abstract A1-728
13. Mills A, et al. Abstract H2-794c
14. Pol S, et al. Abstract H1-367
15. Fried MW, et al. Abstract H3-815a
16. van Heeswijk R, et al. Abstract A1-1738a
17. Nasta P, et al. Abstract H3-810
18. Carton JA, et al. Abstract H3-812
19. Carton JA, et al. Abstract H3-813
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