New drugs.

AuthorPozniak, Anton
PositionLEADING ARTICLE - Drug overview


The limitations of the currently available drugs include short- and long-term toxicities, tolerability and resistance. New drugs with greater activity are needed to work against drug-resistant strains of HIV in patients who have experienced virological failure. Convenience and ease of adherence are still important even in second and further lines of therapy and low pill burden with once- or twice-daily dosing are goals for any new drugs. Theoretically, new drugs should also show good penetration into reservoirs such as the CNS and genital tract.


The currently licensed NNRTIs are highly effective as part of HAART regimens and they have a low pill burden and can be co-formulated with other antiviral drugs. In spite of this, there are problems related to this class and the next generation of NNRTIs has a number of obstacles to overcome, particularly those related to their genetic frailty. A single mutation can cause high-level cross-class resistance. and there is also the issue of primary drug resistance. The ease with which resistance to these drugs can develop is a property that new NNRTIs hope to improve upon. The new drugs must have the potential to be active against HIV with mutations associated with first-generation NNRTIs and they must have a high barrier to resistance development.

Toxicity is an important problem for the current NNRTIs and side-effects include rash and hepatotoxicity for nevirapine, and for efavirenz, neuropsychiatric and lipid effects. Teratogenicity of efavirenz is also a fear although data from the Antiviral Pregnancy Registry showed a birth defect rate of 2.4% following first trimester exposure and no difference in rates of overall birth defects when comparing PI- or NNRTI-based therapy.

Two new NNRTIs are now in the later phases of development; etravirine (TMC-125) is already available and Phase III clinical trials of rilpivirine (TMC-278) are planned. Several other new NNRTIs are also in clinical development.


Rilpivirine (Tibotec) is an NNRTI and a di-aryl-pyrimidine (DAPY). It ishighly active againstwildtypeHIV-1andas its terminal half-life is approximately 45 hours, once-daily administration is possible. Its absorption increases when taken with food.


Rilpivirine is highly protein-bound and is predominantly metabolised by the cytochrome P450 3A enzyme system. Exposure to rilpivirine is increased during co-administration with CYP3A4 inhibitors, such as ketoconazole, lopinavir/ritonavir and darunavir/ritonavir and decreased with exposure to 3A4 inducers, such as ethambutol and rifabutin. Omeprazole reduced exposure to rilpivirine by 40% and it is currently not recommended to combine rilpivirine with proton pump inhibitors or with the contraceptive pill as norethindrone levels are reduced by 40% [1].


In the Phase I studies involving 311 subjects (296 were healthy volunteers), there were no apparent differences in incidence of adverse effects between the different doses tested from 12.5 mg to 300 mg single and 25 mg to 150 mg multiple doses for 14 days.


Rilpivirine retains activity against many NNRTI-resistant HIV strains in vitro and appears to have a higher genetic barrier to the emergence of resistance compared with the currently available NNRTIs. In in vitro experiments, resistant mutants to increasing concentrations of rilpivirine emerged within 11 days. Mutations seen in vitro are Y181C alone or in combination with other mutations such as E40K, K101E, V108I, V179F M230I, H221Y, F227C and T386A. Rilpivirine appears to retain antiviral activity against many of the single, double or triple NNRTI mutations. Various double and triple mutations are associated with decreased susceptibility to treatment, such as those seen in combination with K101P, Y181I and Y181V [2,3]


The major clinical study for rilpivirine is the TMC 278C204 study. A planned analysis at 48 weeks was recently reported of this ongoing Phase IIb randomised trial in treatment-naive HIV-1 infected patients that evaluated the dose-response relationship in efficacy and safety of three blinded once-daily doses of rilpivirine, plus an open-label, active-control, efavirenz arm. The 48-week primary analysis included 368 antiretroviral-naive patients, with genotypic sensitivity to selected NRTIs/NNRTIs, and a plasma viral load >5000 HIV-1-RNA copies/ml at baseline. Patients received 25mg, 75mg or 150mg rilpivirine or efavirenz 600mg, in a 1:1:1:1 ratio. All were given once daily, plus two investigator-selected NRTIs. (zidovudine/lamivudine [AZT/3TC] or tenofovir disoproxil fumarate/emtricitabine [TDF/FTC]) to be used as the backbone

Other NNRTIs, PIs, or fusion inhibitors were not allowed during the treatment period. Within-class substitutions and dose adjustments for tolerance reasons were allowed for the NRTIs. Disallowed medications included cytochrome P4503A4 substrates/inducers/ inhibitors and immunomodulators [4].

In general, demographic parameters and baseline disease characteristics were well balanced across the treatment groups. The median age of the patients was 35 years, 45% were white and 33% were female. Backbone use was very dependent on where in the world the patients were recruited and 76% used Combivir and 24% used Truvada. A higher proportion of patients with high baseline viral load (>300,000 copies/ml) was randomised to the rilpivirine groups than the efavirenz group (23.2-26.4% vs. 11.2%, respectively). Baseline median [log.sub.10] viral load was 4.85 copies/ml and median CD4 cell count was 203 cells/[mm.sup.3].

No significant differences in efficacy were observed between any treatment arms. The proportion of patients with confirmed and sustained viral load

Phase III double-blind randomised controlled trials with rilpivirine in treatment-naive HIV patients are being planned.


Several are currently at early stages of development, and include BILR 355 BS...

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