Post-exposure prophylaxis – does it matter which medicines we use?

Editor’s notes: Two studies this month looked at alternative post-exposure prophylaxis (PEP) regimens.  PEP is often not well tolerated and this leads to non-completion of the one month course.  In London a randomized trial by Milinkovic A and colleagues compared the tolerability and completion rates between 213 individuals given twice daily maraviroc or ritonavir-boosted lopinavir in addition to daily tenofovir disproxil fumarate with emitricitabine (TDF-FTC) daily.  Completion rates were very similar (71% vs. 65%) but maraviroc was associated with fewer mild-moderate side effects (70% vs. 91%) and less use of anti-diarrhoeal medication (25% vs. 67%).  There were no serious side effects in either arm and similar numbers of individuals stopped taking their medication (18%). In Australia, in an open label, non-randomized study, 100 individuals were offered once daily dolutegravir as the third drug (also with TDF-FTC). 90 people completed the one month course, 9 were lost to follow up and one stopped because of headaches.  Side effects were also common in this study (similar to the London study); around a quarter of people complained of fatigue, nausea or diarrhoea [Mcallister J et al.]. Although no seroconversions were seen in either study, despite well documented risks at entry to treatment, the studies are not large enough to shed much light on the effectiveness of the regimens.  They demonstrate the ongoing challenges in finding PEP regimens that have fewer side effects.  Whether completion rates would be as high in less controlled settings than a clinical trial is not clear.  Nonetheless it seems that dolutegravir daily or maraviroc twice daily may be a suitable replacement for ritonavir-boosted lopinavir as the third drug for use as PEP.

 

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).

Milinkovic A, Benn P, Arenas-Pinto A, Brima N, Copas A, ClarkeA, Fisher M, Schembri G, Hawkins D, Williams A, Gilson R; MiPEP Trial Team.J Antimicrob Chemother. 2017 Mar 20. doi: 10.1093/jac/dkx062. [Epub ahead ofprint]

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir.

Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3or 4 clinical or laboratory adverse events (AEs) related to the PEP medication.

Results: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P  =   0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period.

Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.

Abstract access [1] 

Dolutegravir with tenofovir disoproxil fumarate - emtricitabine as HIV post-exposure prophylaxis in gay and bisexual men.

Mcallister J, Towns JM, Mcnulty A, Pierce AB, Foster R, Richardson R, Carr A. AIDS. 2017 Mar 15. doi: 10.1097/QAD.0000000000001447. [Epub ahead of print]

Objectives: Completion rates for HIV post-exposure prophylaxis (PEP) are often low. We investigated the adherence and safety of dolutegravir (DTG 50 mg daily) with tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF-FTC) as3-drug PEP in gay and bisexual men (GBM).

Design: Open-label, single-arm study at 3 sexual health clinics and 2 emergency departments in Australia.

Methods: One hundred HIV-uninfected GBM requiring PEP received DTG plus TDF-FTC for 28 days. The primary endpoint was PEP failure (premature PEP cessation or primary HIV infection through Week 12). Additional endpoints were: adherence by self-report (n = 98) and pill count (n = 55); safety; and plasma drug levels at Day 28.

Results: PEP completion was 90% (95%CI 84% to 96%). Failures (occurring at a median 9 days, IQR 3-16) comprised loss to follow-up (9%) and adverse event resulting in study drug discontinuation (headache, 1%). No participant was found to acquire HIV through Week 12. Adherence to PEP was 98% by self-report and in the 55 participants with corresponding pill count data. The most common clinical adverse events (AEs) were fatigue (26%), nausea (25%), diarrhoea (21%), and headache (10%). There were only four Grade 3-4 subjective AEs. The most common laboratory AE was raised alanine aminotransferase (22%), but there was no case of clinical hepatitis. At Day 28, the mean estimated glomerular filtration rate (eGFR) decrease was 14 ml/min/1.73m (SD 17, p = 0.001); an eGFR of<60 ml/min/1.73m occurred in 3%.

Conclusions: DTG with TDF-FTC is a safe and well-tolerated option for once-daily PEP.

Abstract access [2] 

Europe [6], Oceania [7]
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