Raltegravir-emtricitabine-tenofovir as HIV nonoccupational postexposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med

Objectives Three-drug nonoccupational post-exposure prophylaxis (NPEP) typically includes co-formulated emtricitabine-tenofovir (FTC-TDF) and a protease inhibitor. However, protease inhibitors can cause significant toxicities, can interact with prescribed and illicit drugs, and work late in the viral cycle. Agents that act before viral integration into host DNA may have efficacy advantages. Raltegravir (RAL) is a good candidate for NPEP as it has few side effects or drug interactions and acts prior to HIV integration. The objective of this study was to investigate the use of RAL in 3-drug NPEP in terms of safety, adherence and tolerability. Methods We evaluated 28 days of RAL-FTC-TDF treatment in 86 men and FTC-TDF treatment in 34 men eligible for three-and two-drug NPEP, respectively. We assessed adherence (compared between groups and with nonstudy controls) and clinical and adverse events at weeks 1, 2 and 4, and efficacy at week 12. Analyses were by intention to treat, excluding from the adherence analysis subjects who ceased NPEP because their source was HIV-uninfected. Results No participant became infected with HIV. For RAL-FTC-TDF and FTC-TDF, regimen completion rates were 92% and 91% and medication adherence rates were 89% and 90%, respectively. Eight (9%) RAL recipients developed mild myalgias, with four developing transient grade 4 elevations in creatine kinase (two developed both), all of which improved to grade 2 or less by week 4 without RAL discontinuation. Eight prescribed and 37 potential illicit drug interactions with a protease inhibitor were avoided by use of RAL. Conclusions RAL-FTC-TDF is well tolerated as NPEP, results in high levels of adherence and avoids potential drug−drug interactions. Patients and clinicians should be aware of the potential for acute muscle toxicity when RAL is used as NPEP. ORIGINAL RESEARCH 13 randomized study of ART as pre-exposure prophylaxis in men who have sex with men (MSM); and a randomized trial of ART as prevention in HIV-serodiscordant, heterosexual couples The use of three antiretroviral agents in PEP is common [1-4] but based solely on standard-of-care treatment of HIV infection. The most commonly used third drug is a protease inhibitor Raltegravir (RAL) is an HIV integrase strand transfer inhibitor. The potency of RAL and its safety record, ease of use (infrequent side effects, low pill burden, small tablets, and dosing independently of food), short time from administration to maximum plasma concentration (T max), high tolerability, mode of action prior to HIV integration and low potential for drug interactions make it an attractive candidate for PEP The key objectives of the present study were to investigate RAL in terms of safety, adherence and tolerability when used in combination with co-formulated emtricitabine-tenofovir (FTC-TDF) as a three-drug NPEP regimen, and compare outcomes with those with two-drug NPEP (FTC-TDF) for lower risk exposure and with our standard three-drug NPEP (FTC-TDF-stavudine). Methods Participants Participants were HIV-negative MSM aged 18 years or over who presented following a potential sexual exposure to HIV, defined as unprotected insertive or receptive anal intercourse with an HIV-positive source or a source of unknown HIV status or receptive oral intercourse with ejaculation from a known HIV-positive source. After providing written, informed consent, potential participants were screened for eligibility in two stages. At stage 1, potential participants were ineligible if they were using any medicine contraindicated with the study medications, were known to have chronic active or treated hepatitis B virus (HBV) infection or had received NPEP containing RAL in the past. At stage 2 (3-5 days after NPEP commencement), participants with serology consistent with established or possible primary HIV infection, serum hepatic transaminases > 5 times the upper limit of normal, an estimated glomerular filtration rate (eGFR) of < 60 mL/minBSAc, or serology consistent with chronic active HBV infection were deemed to have failed the second stage screening phase, and so ceased study medication. These individuals were subsequently managed according to Australian standardof-care guidelines for NPEP or newly diagnosed HIV infection MSM presenting for NPEP during the study period who received standard-of-care NPEP provided written, informed consent to demographic and risk event data collection to our HIV database. Study settings The study was conducted in two centres between 1 July 2010 and 31 May 2012. At St Vincent's Hospital, participants were recruited in the Emergency Department on Saturdays and Sundays. At Sydney Sexual Health Centre, participants were recruited during business hours. All patients had all follow-up study visits at the HIV ambulatory care unit in St Vincent's Hospital. The study protocol was approved by the institutional review boards of St Vincent's and Prince of Wales Hospitals. The study protocol was registered at ClinicalTrials.gov (NCT01087840). Interventions This was a nonrandomized, open-label, prospective cohort study. Study three-drug NPEP was RAL 400 mg twice-daily plus FTC 200 mg-TDF 300 mg once-daily for 28 days, and study two-drug NPEP was FTC-TDF once-daily for 28 days. MSM eligible for NPEP but who declined study participation (or were ineligible) received standard-of-care three-drug NPEP (FTC-TDF-stavudine) or two-drug NPEP (FTC-TDF). Participants were reviewed at weeks 1, 2, 4, 5 and 12. Data regarding subjective AEs were collected at each visit and graded according to the Division of AIDS Assessments Blood was sampled and tested at baseline (pre-NPEP), week 2, week 4 (end of NPEP) and week 12. Study-specific testing included: fourth-generation HIV-1, HIV-2 and p24 antigen screening (HIV antigen/antibody combo screen; Abbott Diagnostics, Chicago, IL) at baseline, week 4 and week 12; hepatitis B serology at baseline; and measurement of electrolytes, urea, creatinine, inorganic phosphate, calcium, alanine and aspartate aminotransferases, glucose, amylase, lipase, creatine kinase and lactate, and a full blood count, at baseline, week 2 and week 4. Lactate was measured in a rested state with the tourniquet removed and the lactate sample was collected last in the blood draw. The estimated glomerular filtration rate was derived using the Modification of Diet in Renal Disease (MDRD) equation. Freshly voided urine was collected at baseline, week 2 and week 4 for dip-stick analysis using Multistix®10 (SG Siemens Healthcare Diagnostics Inc., Malvern, Pennsylvania, USA). The 2006 Australian NPEP guidelines recommend testing for HIV at 4 to 6 weeks, 12 weeks and 24 weeks post-exposure Sample size and data analysis Based on an envisaged recruitment period of 2 years, we aimed to recruit 125 subjects, of whom at least 90 would receive RAL-FTC-TDF and 30 would receive FTC-TDF, with the unequal group sizes explained by the predominance of three-drug NPEP prescribed in our local area. Our NPEP completion rate for our current three-drug NPEP regimen is 74%. For an anticipated higher completion rate of 90%, a sample of 90 subjects would provide a 95% confidence interval (CI) of 82 to 95%; a much larger sample of 200 subjects with 90% completion would yield only a slightly smaller 95% CI (85 to 93%). All participants who were eligible for NPEP (who met the eligibility criteria and whose source partner was not subsequently known to be HIV-uninfected) were included in the adherence analyses. All participants were included in the analysis of AEs as all received at least one dose of drug. Descriptive statistics were obtained and tests of significance (Pearson's χ 2 and Fisher's exact tests for independent proportions and two-sample t-test for independent means) were performed using the SPSS statistics package, version 19 (IBM, New York, NY). Significance was set at 0.05 and CIs at 95%. Results Demographics Between July 2010 and May 2012 there were 524 MSM presenting for NPEP to St Vincent's Hospital. Of those, 51% (267 of 524) were assessed for the study and 102 (19%) consented to participate and were enrolled. A further 21 MSM were recruited through Sydney Sexual Health Centre Treatment outcomes Ninety-one MSM were prescribed RAL-FTC-TDF, of whom five stopped NPEP for the following reasons: HIVpositive at baseline (n = 2); eGFR < 60 mL/minBSAc (n = 1); previous enrolment in the study (n = 1); and the 'source' sexual partner was found to be HIV-uninfected (n = 1). Seventy-nine of the remaining 86 participants (92%) completed 28 days of RAL-FTC-TDF treatment Thirty-four MSM were prescribed FTC-TDF alone, of whom 31 (91%) completed 28 days of treatment. The difference in completion rates was not significant between the two arms (P = 0.90). Including the seven subjects in the RAL-FTC-TDF group and the three subjects in the FTC-TDF group who ceased NPEP prematurely, mean regimen adherence in the RAL-FTC-TDF group was 89% [standard deviation (SD) 28%] vs. 90% (SD 29%) in the FTC-TDF group (P = 0.79). The FTC-TDF group was significantly more likely to be 100% adherent than the RAL-FTC-TDF group [74% vs. 52%, respectively; odds ratio (OR) 1.9; 95% CI 1.0-3.8; P = 0.03]. The 48% of RAL-FTC-TDF recipients with < 100% adherence missed a median of 2 doses [range 1-32; interquartile range (IQR) 1-5] and the 26% of FTC-TDF recipients with < 100% adherence missed a median of 1 dose (range 1-21; IQR 1-4). During the study period, 82 MSM received standard-of-care three-drug NPEP (FTC-TDF-stavudine) and 173 MSM received standard-of-care two-drug NPEP (FTC-TDF). The study three-drug NPEP recipients were significantly more likely to complete the 28-day regimen than the standard-of-care three-drug NPEP recipients (OR 2.5; 95% CI 1.2-5.2; P = 0.001). Similarly, the study two-drug NPEP recipients were significantly more likely to complete 28 days of FTC-TDF than the standard-of-care FTC-TDF recipients (OR 8.7; 95% CI 1.2-62.1; P = 0.005). No participant seroconverted to HIV over the duration of the study. Muscle-related adverse events Eight patients (9%) in the RAL-FTC-TDF group and no patient in the FTC-TDF group reported myalgias after baseline (P = 0.10). No patient reported muscle weakness, although more patients receiving RAL reported fatigue (37% vs. 26% in the FTC-TDF group; P = 0.25). For the 115 study participants who had at least one creatine kinase measurement on NPEP, 6% (seven of 115) developed a grade 1 or 2 creatine kinase elevation (three on FTC-TDF alone and four on RAL-FTC-TDF). There was no significant difference in the development of a creatine kinase elevation (any grade) between the FTC-TDF and RAL-FTC-TDF recipients (P = 1.00). Grade 4 creatine kinase elevations occurred in five subjects on RAL-FTC-TDF and no subjects on FTC-TDF alone (P = 0.16). These events were most commonly seen at week 2 (SD 7 days; range 8-26 days) No participant ceased treatment or had their regimen changed. All patients with grade 4 creatine kinase elevations were exercising at the gym and all were advised to desist from exercise and to increase their oral fluid intake Following a second HIV risk event at week 5, one of the five participants with a grade 4 creatine kinase elevation recommenced RAL-FTC-TDF NPEP with residual study medication. Four days later, without exercise, his serum creatine kinase was 2770 U/L. He was asymptomatic with normal renal function and no myoglobinuria. His only concomitant medication was citalopram. RAL was ceased and FTC-TDF continued. His creatine kinase returned to normal without any further intervention. Other clinical adverse events All 125 study participants reported at least one AE, with 333 AEs overall ( Other laboratory adverse events The frequency and severity of other laboratory AEs are detailed in Grade 1−2 elevations in alanine and aspartate aminotransferases occurred in 28 (22%) study participants but grade 3 or 4 was rare (2%) and included two patients with possible rhabdomyolysis. The grade 3 or 4 transaminitis events resolved as both the participants' creatine kinase levels returned to normal. Two (2%) of the RAL-FTC-TDF recipients and five (15%) of the FTC-TDF recipients experienced grade 1 or 2 hyperlactataemia (mean 3.6 mmol/L; reference range 2.4-5.6 mmol/L) at a mean 23 days (range 12-28 days). All were asymptomatic and all completed 28 days of NPEP. These elevations in serum lactate resolved after treatment with the study drug ceased. Concomitant licit and illicit drug use Almost half (46%) of the study participants were taking at least one other prescribed medication regularly. These medicines included antipsychotics, antidepressants, hypnotics, benzodiazepines, opiates, corticosteroids, anticonvulsants, proton pump inhibitors, anti-histamines, beta blockers, calcium channel blockers, angiotensinconverting-enzyme inhibitors, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and phosphodiesterase type 5 (PDE5) inhibitors. We identified eight potential drug interactions in eight study participants in the three-drug arm where, had a protease inhibitor been the third component of the regimen, concomitant protease inhibitor use would have been an absolute contraindication in two cases (simvastatin and St John's Wort) or a relative contraindication in six [phenytoin, sildenafil (two participants), vardenafil, carbamazepine and budesonide]. Of the 125 study participants, 121 (97%) provided a substance use history, of whom 89 (74%) indicated regular drug use. Seventy-three of these (82%) used alcohol and 37 (42%) used at least one illicit, 'recreational' drug Discussion In this population of young men receiving RAL-FTC-TDF as NPEP, 92% completed 28 days of treatment, very similar to the percentage who completed 28 days of FTC-TDF treatment (91%). The use of RAL rather than a protease inhibitor avoided eight known prescribed drug interactions, and 37 potential interactions with illicit drugs. However, 9% of patients receiving RAL-FTC-TDF developed a grade 4 creatine kinase elevation, of whom three had a clinical presentation consistent with a degree of rhabdomyolysis, although none developed renal impairment or ceased RAL as a result. When we compared completion rates for study regimen recipients with those for our clinic standard-of-care threedrug and two-drug NPEP recipients, we found that study three-drug recipients and study two-drug recipients were both significantly more likely to complete 28 days of their allocated regimen than were nonstudy three-and two-drug NPEP recipients. Our completion rate of 92% with RAL-TDF-3TC is also greater than the 57% reported by Mayer et al. in a study of 100 adults (98% male, 92% MSM and 76% White; mean age 33 years) There may be several reasons for the differences seen among these three groups (i.e. our study drug recipients, our nonstudy NPEP recipients, and Mayer et al.'s study drug recipients). First, our study participants received a high level of support, including management by a single nurse consultant with extensive experience in NPEP, frequent clinical review, 24-hour contact with the nurse consultant by mobile phone, appointment reminders by SMS messaging and proactive recall following a missed appointment. Secondly, we provided specific and frequent adherence education. Thirdly, 36% of the RAL-FTC-TDF group and 35% of the FTC-TDF group had previously received NPEP containing FTC-TDF at least once with previous adherence education, so may have been selected for better FTC-TDF tolerability. Fourthly, we possibly introduced a social desirability bias by the explicit expectation of 100% adherence as measured by participant-anticipated pill counting. Overall, the different adherence rates in our study, in the study by Mayer et al. and in our clinic controls suggest that implementation of more intensive education and support may yield improvements in adherence above and beyond any gains achieved with simpler NPEP. Whether other NPEP regimens that can be taken once-daily can result in improved medication adherence needs exploration, although the potential margin for improvement seems small. Five study participants (all on RAL-FTC-TDF) developed a grade 4 creatine kinase elevation (median 72 times the upper normal limit). Of these five participants, two reported myalgias and one had microscopic haematuria. All five cases were confounded by concurrent exercise (although none of the participants was receiving a statin) and no participant ceased NPEP as a result. In a recent overview, grade 3 or 4 creatine kinase elevations were reported in 5 to 13% of HIV-infected adults commencing treatment with an integrase inhibitor, although cases of myopathy or rhabdomyolysis were rare We can also report additional experience with RAL used as NPEP outside of the study protocol. During the study period, a healthy, 32-year-old medical officer received 28 days of RAL-FTC-TDF as OPEP. His creatine kinase was normal at baseline testing, had increased to 18 300 U/L by day 19 and peaked at 46 400 U/L on day 21. He was symptomatic with significant myalgia and his urine was positive for myoglobin. He was exercising at the gym (which he ceased) and was taking no other medicines. He completed his 28 days of RAL-FTC-TDF and his creatine kinase returned to normal within 7 days of completing NPEP. The New York State Department of Health AIDS Institute recently listed RAL-FTC-TDF as its preferred OPEP regimen Subjective AEs in our study were common (mean 2.7 per subject, predictable and mild or moderate in severity. MSM receiving NPEP with RAL-FTC-TDF or FTC-TDF alone should be warned about the nature and frequency of probable AEs but be reassured that these are, in the main, tolerable. We found high rates of 'recreational drug use' but, given that our participants were young (mean age 34 years), the high rate of prescribed co-medication was unexpected. Raltegravir is not a cytochrome P450 substrate, inducer or inhibitor and so P450-related drug interactions between RAL and licit or illicit drugs are not a concern. Eight (6%) of our study participants used prescribed drugs that could adversely interact with a protease inhibitor or cobicistat and 37 (41%) were using illicit, 'recreational' substances including the stimulants ecstasy, amphetamine and cocaine, and the depressant GHB. There is virtually no research in this area, although there have been case reports of death and near-fatal reactions between ecstasy and ritonavir and GHB and saquinavir/ritonavir In summary, RAL-FTC-TDF was well tolerated with high rates of on-drug adherence and treatment completion. Its use (as opposed to a protease inhibitor) avoided potentially dangerous drug interactions in a substantial number of our patients. The muscle-related AEs, while of unclear clinical significance, raise a cautionary note concerning its unmonitored use in PEP. Larger, multicentre randomized trials adequately powered to assess both adherence to and safety of various three-drug NPEP regimens in more diverse patient populations are required