Raltegravir + FTC/TDF as HIV nPEP in MSM
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 standard-of-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.
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).
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 Table for Grading the Severity of Adult and Paediatric Adverse Events (Version 1.0). NPEP adherence was measured by pill count at weeks 2, 4 and 5 and calculated by dividing the number of doses returned by the number of doses dispensed, expressed as the percentage of doses taken. Data were collected at each visit regarding any concomitant drug use.
All participants were managed by and received standardized education (including written information) from a single experienced nurse consultant regarding potential NPEP side effects, signs and symptoms of primary HIV infection, the need for 100% adherence and what to do in the event of a missed medication dose. All participants had 24-hour contact with the same nurse consultant by mobile phone, received appointment reminders by SMS and were subject to proactive recall if an appointment was missed.
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. These were in a process of review at the time the study commenced. In keeping with these draft guidelines, testing for HIV post-NPEP in the study concluded at 12 weeks post-exposure. There are no definite cases of delayed HIV seroconversion (beyond week 12) in occupational and nonoccupational PEP settings. The fourth-generation HIV-1, HIV-2 and p24 antigen screening assay used in our study would be expected to identify cases of HIV seroconversion within 12 weeks of HIV infection.
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 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%.
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 standard-of-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 Table for Grading the Severity of Adult and Paediatric Adverse Events (Version 1.0). NPEP adherence was measured by pill count at weeks 2, 4 and 5 and calculated by dividing the number of doses returned by the number of doses dispensed, expressed as the percentage of doses taken. Data were collected at each visit regarding any concomitant drug use.
All participants were managed by and received standardized education (including written information) from a single experienced nurse consultant regarding potential NPEP side effects, signs and symptoms of primary HIV infection, the need for 100% adherence and what to do in the event of a missed medication dose. All participants had 24-hour contact with the same nurse consultant by mobile phone, received appointment reminders by SMS and were subject to proactive recall if an appointment was missed.
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. These were in a process of review at the time the study commenced. In keeping with these draft guidelines, testing for HIV post-NPEP in the study concluded at 12 weeks post-exposure. There are no definite cases of delayed HIV seroconversion (beyond week 12) in occupational and nonoccupational PEP settings. The fourth-generation HIV-1, HIV-2 and p24 antigen screening assay used in our study would be expected to identify cases of HIV seroconversion within 12 weeks of HIV infection.
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 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%.
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