HIV This Week

Baerta L, van ‘t Kloostera G, Dries W, François M, Wouters A, Basstanie E, Iterbeke K, Stappers F, Stevens P, Schueller L, Van Remoortere P, Kraus G, Wigerinck P, Rosier J. Development of a long-acting injectable with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm. 2009;72:502-508.

Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal® technology) in an aqueous carrier. Laser diffraction showed average particle sizes close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5 mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which declining slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20 mg/kg dose (200 nm) did not show relevant differences according to the surfactant used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as a long-acting injectable.

Editors’ note: Injectable formulations of antiretroviral drugs for treatment would enhance adherence by reducing pill burden, would avoid the impact of food on drug bioavailability, and would limit the development of resistance by achieving sustained plasma concentrations, just as do injectable contraceptives and anti-psychotic drugs. This study in dogs and mice shows that nanosuspensions may be suitable as long-acting formulations. Interest in their development for pre-exposure prophylaxis (PrEP) purposes will grow if the current PrEP trials show promise.

Telenti A. Safety concerns about CCR5 as an antiviral target. Curr Opin HIV AIDS. 2009;4:131-5.

Clinical trials of CCR5 antagonists attest to their efficacy and tolerance in HIV treatment. However, there has been debate on their long-term safety because of the role of CCR5 in innate immunity. This review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals. In the mouse model, CCR5 has a role in the response against pathogens as diverse as Toxoplama gondii, West Nile virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, Listeria, and plasmodia. In human cohorts, individuals carrying the defective CCR5Delta32 allele present an increased susceptibility to flavivirus ( West Nile virus and tickborne encephalitis virus). The selective pressures that led to the spread of loss-of-function CCR5 mutations in humans (CCR5Delta32), and in mangabeys (CCR5Delta24) are not understood. The recent availability of CCR5 antagonists has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The consequences of long-term pharmaceutical intervention on CCR5 should be carefully assessed through rigorous postmarketing surveillance.

Editors’ note: Although CCR5 delta 32 deletion appears to make people less likely to acquire HIV infection (if homozygous) and more likely to have slower HIV disease progression (if heterozygous), we do not know if interfering with this receptor’s function pharmacologically with entry inhibitors that are CCR5 antagonists, such as maraviroc and vicriviroc, will have the same effects as congenital absence of the receptor. Because CCR5 appears to play a role in innate immunity against diverse diseases including trypanosomiasis, West Nile virus infection, malaria, and tick-borne encephalitis, it makes sense for people on CCR5 antagonists to limit their exposure to mosquitoes, ticks, and other biting insects until further information becomes available – we should all be trying to do this anyway.

Podzamczer D, Olmo M, Sanz J, Boix V, Negredo E, Knobel H, Domingo P, Pineda JA, Vilades C, Quero JH, Force L, Lahoz JG, Muñoz P, Llibre JM, Mariño A, Ortega E, Dalmau D, Gatell JM, Antón E, Sola J, Galindo MJ, Pedrol E, Sanz J, de Lima JT, Flores J; the NODy Study Group. Safety of Switching Nevirapine Twice Daily to Nevirapine Once Daily in Virologically Suppressed Patients. J Acquir Immune Defic Syndr. 2009;50:390-396.

The strategy of switching nevirapine (NVP) twice daily to once daily was evaluated by means of a forty-eight-week randomized, open, multicentre trial. Stable HIV-infected patients on NVP twice daily for >12-18 weeks with alanine aminotransferase (ALT) <2.5, the upper normal limit were randomized to continue their regimen or switch to NVP 400 mg once daily. Primary end point was the proportion of ALT/aspartate transaminase (AST) >/=grade 3. Two hundred eighty-nine patients were included, mean CD4 620 cells per microliter. Noninferiority was demonstrated in the per protocol analysis, with 97.9% (once daily) and 99.3% (twice daily) of patients event free (difference, 1.4%; 95% confidence interval, -1.95% to 5.4%), whereas 81.8% vs. 93.8% were event free by intent-to-treat switch = toxicity analysis (difference, 12%; 95% confidence interval, 4.6% to 19.4%). Only 4 patients ( 3 once daily, 1 twice daily) had NVP-related grade ¾ ALT/AST increases, but in 2 of them (once daily), transaminases decreased despite continuation with NVP. Two other once daily patients presented grade ¾ ALT/AST increase due to well-documented acute hepatitis A virus or hepatitis C virus infection. Grade 2 ALT/AST increases occurred in 11.2% (once daily) vs. 10.3% (twice daily) of patients (P = 0.80). A larger number of once daily patients were lost to follow-up/violated protocol (15% vs. 5%). In patients on standard twice daily NVP-containing regimens for at least 12-18 weeks, per protocol analysis showed that switching to once daily NVP was not inferior to continued twice daily NVP in terms of the predefined noninferiority margin of 10% for hepatotoxicity.

Editors’ note: Because once daily nevirapine (400 mg) may permit the design of simple once daily regimens that interfere less with daily activities, it is important to know whether it causes more toxicity than twice-daily 200 mg doses. Hypersensitivity to nevirapine in the form of liver toxicity usually presents in the first 12 to 18 weeks of treatment. If treatment guidelines are modified in the light of the findings of this and other studies, the switch to once daily nevirapine would likely not occur until after this initial period of twice-daily dosing. Independent risk factors for nevirapine-associated adverse events, such as gender, genetics, CD4 count, and hepatitis co-infection, remain considerations in prescribing antiretroviral regimens.