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CLINICAL SCIENCE

A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk

Jackson, J Brooks; Barnett, Scott; Piwowar-Manning, Estelle; Apuzzo, Linda; Raines, Charles; Hendrix, Craig; Hamzeh, Fayez; Gallant, Joel

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Abstract

Introduction

At present there is no vaccine that has proven to be effective in preventing sexual or blood-borne HIV-1 transmission. The HIVNET 012 randomized controlled trial was able to show that a single dose of nevirapine safely and effectively reduced mother-to-infant HIV-1 transmission by 47% at 14–16 weeks of age when given in labor to the mother and to the infant within 3 days of birth [1]. Therefore, a low-dose regimen of nevirapine may be effective and safe in preventing HIV-1 sexual or blood-borne transmission in adults practicing high-risk behaviors. The use of a low-dose regimen of nevirapine for pre-exposure prophylaxis of an individual is particularly attractive if targeted to seronegative high-risk individuals, such as commercial sex workers, injection drug users, men who have sex with men, and seronegative individuals with HIV-infected sex partners (i.e., discordant couples). The use of such a regimen during periods of high-risk exposure may be effective and feasible, much like the weekly use of mefloquine for malaria prophylaxis. This type of intervention may be cost effective for individuals at very high risk for limited periods of time and could be used as part of a substance abuse rehabilitation program, during the first several months of an HIV-1 vaccine regimen, during periods of commercial sexual activity, or during periods of sexual activity with known HIV-1-positive sexual partners. Such a potentially toxic intervention would also be ethical especially in populations in which behavioral interventions have had limited success and HIV-1 seroincidence is high. The cost of a 6-month course of nevirapine taken once a week would be approximately $10 using the publicly stated 90% price discount for developing countries.

Nevirapine is a licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for use in the treatment of HIV-1 infection (when used in combination with other antiretroviral drugs) and for the prevention of HIV-1 perinatal transmission in some developing countries. Nevirapine has a number of desirable characteristics, such as rapid absorption, a long half-life, excellent tissue penetration, low plasma protein binding (60%), rapid and potent antiretroviral activity, activity against intracellular and extracellular virus, and minimal side effects at low doses [1–4]. The concentration to give 50% inhibition (IC50) for nevirapine is approximately 10 ng/ml, which is approximately 400–500 times lower than the steady-state plasma concentrations achieved with treatment dosing regimens of 400 mg per day [5]. The half-life of nevirapine is approximately 25–30 h with a daily 400 mg oral dose and 60 h after a single 200 mg dose [2,3,5]. The pharmacokinetics of chronic low-dose nevirapine regimens are not known, nor is the plasma nevirapine concentration needed to prevent HIV-1 transmission, which may be different for prevention of perinatal, sexual, and blood-borne transmission.

This phase I/II three-arm dose escalation trial (HIVHOP 101) was carried out to evaluate the safety, tolerability, and nevirapine trough levels when HIV-1-uninfected participants at high risk for HIV-1 infection were given 200 mg nevirapine once weekly, twice weekly, or every other day for 12 weeks. Although the blood concentration level of nevirapine needed to protect against HIV-1 infection is not known, dosing regimens were chosen that could potentially keep the trough level of nevirapine above 100 ng/ml, which is 10× the IC50.

Methods

Study design

The HIVHOP 101 study protocol was approved by the Institutional Review Board at Johns Hopkins School of Medicine, and informed consent was obtained from all study participants prior to study enrollment. The study was originally designed as a three-arm sequential dose escalation trial consisting of 12 participants per arm. The sample size of 12 subjects per arm was based on having a 93% probability of seeing at least one life-threatening adverse event if the true probability of such an event were 0.2.

Subject population

Participants were men and women recruited through advertisements placed on the Johns Hopkins Medical campus, in local community newspapers, and by the HIV clinical trials outreach team. Interested subjects were seen by trained counselors in the Moore Clinic at the Johns Hopkins Hospital. Following pretest counseling and consented screening for HIV-1 infection, subjects were eligible for the study if they were aged 18 years or older, were HIV-1 antibody negative, and were injection drug users, sex partners of injection drug users, a man who has sex with other men, sex partners of known HIV-1-infected individuals, and/or individuals with unprotected sexual exposures with multiple partners within the past 12 months. To be eligible for the study, subjects also had to have the following laboratory values at screening (2 weeks prior to enrollment) and at enrollment: hemoglobin ≥ 11.0 g/dl (≥ 110 g/l), creatinine ≤ 2.0 mg/dl (≤ 20 g/l), alanine aminotransferase (ALT), aspartamine aminotransferase (AST), and glutamyl transpeptidase (GGT) no more than three times (≤ 3×) upper limit of normal (ULN) for that assay. Subjects were also tested for hepatitis B surface antigen (HbsAg) and antibody to hepatitis C virus (HCV), but positivity for either of these markers was not an exclusion criterion provided there was no evidence of clinical hepatitis and ALT, AST and GGT were ≤ 3 ULN. Women of child-bearing age had to use a reliable method of birth control other than hormonal contraceptives. Subjects were excluded from the study for hypersensitivity to benzodiazepines; uncontrolled hypertension; current use of amoxicillin/clavulanate (Augmentin), antiretroviral drugs, or drugs with a half-life that is affected by nevirapine; or if the protocol chair believed that the presence of a serious medical condition put the subject at increased medical risk or at risk for being unable to complete the protocol.

Subjects were specifically counseled about how to minimize their risk for HIV-1 infection and told that they should not engage in high-risk behavior in the belief that nevirapine might be protective. Subjects were also specifically informed that if they became infected with HIV-1 during the study while taking nevirapine their treatment options with nevirapine and other NNRTI might be limited because of the possibility of nevirapine resistance engendered as a result of their participation in the study [6–9].

Dosing regimen

Subjects in cohorts A, B, and C orally self-administered a 200 mg tablet of nevirapine once weekly, twice weekly, or every other day for 12 weeks, respectively. The nevirapine tablets were provided in sufficient quantity in blister packs labeled with the study dose. Subjects stopped taking nevirapine if the ALT, AST, or GGT values increased to > 5× ULN and > 4× their baseline value at entry. If on stopping study drug, liver enzymes returned to baseline levels, dosing of nevirapine was restarted, and the regimen was completed if tolerated. Study visits were scheduled so that subjects were able to take their next dose of nevirapine during the study visit, allowing a nevirapine trough level to be obtained and allowing administration of study drug to be directly observed during those study visits.

Subject evaluations

Subjects had a medical history and a limited physical examination performed 2 weeks prior to entry, at entry to the study, and 1, 2, 4, 6, 9, 12, and 16 weeks after entry. Participants were assessed for signs and symptoms of potential toxicity using the National Institutes of Health Division of AIDS Tables for Grading Severity of Adverse Experiences and the Supplemental Table for Grading of Cutaneous/Skin Rashes/Dermatitis at the same time points and were also called by phone at 20 weeks after study entry to assess signs or symptoms that might be related to drug.

Laboratory testing

After screening, peripheral blood was drawn for liver enzyme levels (ALT, AST, GGT), creatinine concentration, and complete blood count at entry and at 1, 2, 4, 6, 9, 12 and 16 weeks. Plasma nevirapine trough levels were determined using high performance liquid chromatography [10] on blood samples collected at entry and at the study visits at 1, 2, 4, 6, 9, and 12 weeks immediately before the nevirapine dose. The lower limit of detection of this quantitative nevirapine assay is approximately 25 ng/ml. HIV-1 antibody testing was performed at screening and at week 16 using a licensed enzyme immunoassay.

Statistics

A Wilcoxon matched-pairs signed–rank test was used to compare the values for AST, ALT, GGT, creatinine, neutrophil count, hemoglobin level, and platelet count between study entry and week 12 for each cohort, and values for nevirapine levels between week 1 and week 12. Two-sided tests were performed with P < 0.05 defined as statistically significant.

Results

Of 49 subjects screened for the trial, 13 were excluded based on entry criteria (nine with one or more abnormally elevated liver enzyme values, two with hemoglobin < 11.0 g/dl, and two with positive HIV serologies). Three eligible subjects decided not to enroll. Of the 33 eligible subjects who were enrolled, there were 21 men and 12 women (eight white males, 10 African-American males, 12 African-American females, two Hispanic males, and one Asian male). The major HIV risk factors for this group were having an HIV-infected sex partner (eight), men who had sex with men (eight), non-monogomous unprotected sex (10), and injection drug use and/or sex with an injecting drug user (seven). Twelve subjects were enrolled in cohort A (one 200 mg tablet once per week), 12 in cohort B (one 200 mg tablet twice weekly), and nine in cohort C (one 200 mg tablet every other day). Of the 12 subjects in cohort A, 11 completed the 12-week regimen as scheduled except for one subject whose dosing was stopped and then restarted. One subject was HbsAg positive and another was HCV antibody positive. In cohort B, eight subjects completed the 12-week regimen as scheduled except for one subject whose dosing was stopped and then restarted. Four subjects in this cohort were HCV antibody positive at entry. In cohort C, five subjects completed the 12-week treatment regimen. Two subjects in this cohort were HCV antibody positive.

Of the nine subjects (five African-American women, three African-American males, and one Hispanic male) who did not complete their assigned regimen in the study, seven were lost to follow-up and could not be contacted and two subjects in cohort C stopped taking their drug at week 1 and week 9 because they had difficulty remembering to take the every other day regimen and wanted to drop out of the study. Both subjects were contacted for follow-up and reported no adverse events.

In terms of clinical adverse events, 8 of 12 enrolled subjects in cohort A, 5 of 12 in cohort B, and 5 of 9 in cohort C experienced at least one clinical adverse event (Table 1). The adverse events were variable in nature among the three cohorts and did not appear to increase with dose (see Table 1). No subject in any of the cohorts experienced clinical signs or symptoms attributed to the study drug, including rash. Of the 30 clinical adverse events after entry into the study, 25 were graded as mild and five as moderate. None were considered severe or life threatening.

Table 1
Table 1:
Clinical adverse events among subjects enrolled in the study.

Median entry and 12-week liver enzyme values are shown for the cohorts in Table 2. There were no statistically significant changes in AST, ALT, or GGT values in cohort A from entry to week 12 although one subject's ALT and AST increased to > 5× ULN and > 4× the level at entry. This HCV antibody-negative subject had an increase in AST (30 to 168 IU/l) and ALT (41 to 364 IU/l) between weeks 4 and 6, but this was thought to be related to a significant exposure to methylene chloride while stripping furniture and not related to nevirapine. This subject, whose last dose was at week 6, was restarted on nevirapine 6 weeks later, when his AST and ALT had returned to baseline levels (AST, 31 IU/l; ALT, 38 IU/l). Subsequently, his AST and ALT values were less than 41 and 56 IU/l, respectively, for the remaining 4 weeks the subject received nevirapine. One other subject in cohort A, who had had a positive HBsAg for 17 years, became HBsAg negative 2 weeks after initiation of nevirapine and remained HbsAg negative and hepatitis B DNA negative 10 weeks after stopping nevirapine at 12 weeks. He was taking no treatment for hepatitis B infection. His liver enzymes were in the normal range throughout the study duration.

Table 2
Table 2:
Median liver enzyme values for subjects followed through week 12.

In cohort B, there were no statistically significant changes in AST or ALT values from entry to week 12, but there was an average twofold increase in GGT level (P = 0.01) with one HCV antibody-positive subject having an increase > 5× ULN and > 4× the level at entry (101 IU/l at entry to 414 IU/l by week 12). His GGT value returned to baseline (118 IU/l) 4 weeks later (week 16) after his last dose (week 12). Another HCV antibody-positive subject, who reported frequent alcohol and injection heroin use, had a significant increase in AST (38 to 524 IU/l) and ALT (46 to 264 IU/l) between weeks 4 and 6.5, during which time he had stopped using heroin and began drinking one or two bottles of whiskey and 12 beers per day. Nevirapine was stopped after 6.5 weeks, and the subject was counseled to stop drinking, which he did. The subject's liver enzymes returned to near baseline levels (AST, 49 IU/l; ALT, 70 IU/l) within 2 weeks, and nevirapine was resumed for an additional 4 weeks with no subsequent increase in liver enzymes.

In cohort C, there was no statistically significant increase in liver enzyme values from entry to week 12. However, one subject, who was HCV antibody positive, experienced an increase in AST, ALT, and GGT values from 31 to 67 IU/l, 32 to 144 IU/l, and 17 to 123 IU/l, respectively, from entry to week 12.

Of the six HCV antibody-positive subjects followed after entry into the study, liver enzyme values generally increased (Table 3), with two subjects having an increase of at least one liver enzyme value during the study that was > 5× ULN and > 4× the level at entry.

Table 3
Table 3:
Change in liver enzyme values from baseline to week 12 in hepatitis C-positive subjects.

Overall, of 33 subjects enrolled, three subjects experienced a grade 3 elevation in one or more liver function tests (> 5× ULN), and one of these subjects also experienced a grade 4 toxicity (> 10 ULN) at some point during the study. The grade 4 toxicity and one grade 3 toxicity were not thought to be nevirapine related, as described above. However, 9 of 33 subjects did not complete their assigned regimen (seven of whom were lost to follow-up), so the toxicity rates may have been higher.

No significant changes were noted in creatinine, absolute neutrophil count, hemoglobin level, or platelet count over the 12-week period in cohorts A, B, and C.

Nevirapine trough levels for the cohorts at weeks 1 and 12 are shown in Table 4, and the proportion of subjects with nevirapine levels > 100 ng/ml (10× the IC50) or > 25 ng/ml (lower limit of detection) at each time point is shown in Table 5. In cohort A, nevirapine levels > 25 ng/ml were detected in trough level samples of 7 of 11 participants at all six time points through weeks 1 to 12 (range, 85–385), in 2 of 11 participants at five of six time points (range, < 25–315), and in 2 of 11 participants at two of six time points (range, < 25–1065). In cohort B, nevirapine levels > 25 ng/ml were detected in seven of eight participants at all six time points through weeks 1 to 12 (range, 26–2708) and in one subject at five of six time points. In cohort C, nevirapine levels > 25 ng/ml were detected in all five participants at each time point tested through weeks 1 to 12 (range, 31–9261). There was no significant difference in trough level between weeks 1 and 12 in cohorts A, B, and C, but the median level at 12 weeks was approximately half that seen at week 1 in cohort C. Three subjects in cohort B attained nevirapine trough levels between 2000 and 3700 ng/ml at several time points. Three of five subjects in cohort C attained nevirapine trough levels > 2500 ng/ml at several time points, with one subject having a level of 9261 ng/ml. However, three subjects in cohort B and two subjects in cohort C had nevirapine trough levels that varied by more than fivefold, which could not be explained by different dosing intervals and suggested poor adherence and/or variable dosing in some subjects.

Table 4
Table 4:
Nevirapine trough levels for subjects followed through week 12
Table 5
Table 5:
Proportion of subjects with plasma nevirapine trough levels greater than 10× the IC 50 (100 ng/ml) or > 25 ng/ml (limit of detection).

In terms of risk activity, 16 of 33 subjects reported that they had engaged in high-risk activity during the trial. However, none of the 24 participants tested in cohorts A, B, and C developed a positive HIV-1 antibody 4 weeks after stopping study drug at week 12 of the trial.

Discussion

These data suggest that a single 200 mg dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was well tolerated, resulted in minimal or no hematologic or liver toxicity, and achieved nevirapine trough plasma levels > 100 ng/ml in most subjects.

The overall reported incidence of nevirapine-related serious adverse events in adults who received nevirapine monotherapy for treatment is 3.3%, with rash being the most commonly observed serious adverse event, occurring in 1.4% of patients [11]. The Centers for Disease Control and Prevention (CDC) have not included nevirapine on the expanded list of antiretroviral drugs recommended for post-exposure prophylaxis because of reported serious life-threatening liver toxicity and rash with the use of nevirapine for post-exposure prophylaxis in HIV-1-uninfected individuals [12]. However, the doses of nevirapine used in those instances were 2 to 14 times the dosing used in this protocol. Moreover, at least 21 of 22 subjects who experienced serious toxicities with post-exposure prophylaxis in this CDC report were also taking at least two other potentially toxic antiretroviral drugs in addition to nevirapine. In our study, three subjects had an increase in one or more liver enzymes > 5× ULN and > 4× the level at entry, but in at least two of these subjects the increases were thought to be unlikely related to nevirapine. However, subjects with elevated liver enzymes > 3× ULN were excluded from the study, so toxicity may have been greater had they been enrolled. Likewise, 9 of 33 enrolled subjects dropped out of the study before completion of the 12-week regimen, so adverse events among these subjects cannot be excluded. The percentage of subjects who dropped out of the study did increase with increasing dose, suggesting a possible toxicity problem. However, in this dose escalation trial, the increasing dosing frequency may have been a deterrent to staying in the study. The increasing loss to follow-up rates in each cohort with increasing dose could also have reflected the differences in the subject population in each cohort. For example, gay white males constituted 8 of 12 subjects in cohort A, 2 of 12 in cohort B, and none of 9 in cohort C.

Seven of the subjects in this study were infected with HCV, of whom six were followed after entry. Two of these subjects showed a modest increase in liver enzymes, and a third had > 5 ULN and > 4× the level at entry for AST and ALT, which was thought to be a consequence of heavy alcohol ingestion. These data suggest that low-dose nevirapine should be used cautiously in HCV-infected subjects, especially if taken chronically. The one subject with chronic HBV infection became HBsAg negative within 2 weeks of starting a once weekly dose of nevirapine. This observation deserves further study in additional subjects.

In our study, there appeared to be no decrease in nevirapine trough levels from week 1 to week 12 at either once weekly or twice weekly dosing, but the trough levels at week 12 were approximately half those at study entry in cohort C, taking the drug every other day. These results are consistent with the observation that nevirapine is an inducer of hepatic cytochrome P450 metabolic enzymes such that autoinduction by nevirapine results in a corresponding decrease in its terminal phase half-life in plasma from approximately 45 h (single dose) to approximately 25–30 h following multiple dosing with 200–400 mg/day [5]. The autoinduction of nevirapine metabolism appears to be concentration related given the absence of this phenomenon at the lower concentrations associated with the less-frequent dosing intervals. The vast majority of nevirapine-associated rash and hepatitis toxicity occurs during the first 6 weeks of chronic nevirapine administration and may be immune related; consequently, it is unlikely that toxicities will increase with prolonged use [11]. However, long-term safety in this population needs to be assessed.

The fact that several participants in cohorts B and C had nevirapine trough levels frequently > 2000 ng/ml, and in one case > 9000 ng/ml, is worrisome, as the steady-state nevirapine trough levels attained at 400 mg/day is 4500 ± 1900 ng/ml, a level at which rash and/or liver toxicity may occur. Given the variability of trough levels in some subjects in our study, these high levels may be caused by erratic self-administration of nevirapine. It should be noted that a 200 mg dose of nevirapine every other day is one-fourth the recommended treatment dose. The data suggest that even with weekly dosing the trough level is > 10× the IC50 of nevirapine in the majority of participants and should be well above the IC50 nearly all the time if doses are taken as directed. However, because the level of regimen needed to prevent blood-borne or sexual HIV-1 transmission is unknown, a more frequent dosing schedule may be more effective. In addition, isolates from HIV-1-infected subjects taking nevirapine monotherapy develop reduced susceptibility to nevirapine (> 100-fold IC50 or > 1000 ng/ml) by 8 weeks from time of initiation of drug [8]. Therefore, at least every other day dosing might be required to keep trough levels of nevirapine high enough to protect against transmission of resistant virus.

A potential drawback to the use of nevirapine or any NNRTI as a protective measure is that high-level resistance will emerge quickly should a subject have or acquire HIV-1 infection while taking a monotherapy regimen, which will potentially limit treatment options with NNRTI. However, if such a pre-exposure prophylactic regimen is effective in preventing HIV-1 transmission, then the risk of resistance would seem acceptable from a public health perspective. Other recently licensed drugs such as tenofovir, which has less cross-resistance, less potential toxicity, and a long half-life, would also be good candidates for this type of intervention.

Given the sustained plasma nevirapine levels reported in this study, a larger safety trial is warranted, which may be designed to collect preliminary information regarding efficacy using one or more of these low-dose nevirapine regimens.

Acknowledgements

Sponsorship: Nevirapine assay concentrations were performed and supported by the HIV Prevention Trials Network Central Laboratory (NIH/Division of AIDS/NIAID U01-AI-46745).

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Keywords:

nevirapine; pre-exposure prophylaxis; HIV prevention; HIVHOP 101

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