Patrick A. Robinson

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study

BACKGROUND The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

A Multicenter Randomized Controlled Trial of Nevirapine Versus a Combination of Zidovudine and Lamivudine to Reduce Intrapartum and Early Postpartum Mother-to-Child Transmission of Human Immunodeficiency Virus Type 1

To determine the efficacy and safety of 2 inexpensive and easily deliverable antiretroviral (ARV) regimens for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) type 1 during labor and delivery, HIV-infected pregnant women were screened at 11 maternity health institutions in South Africa and were enrolled in an open-label short course ARV regimen of either nevirapine (Nvp) or multiple-dose zidovudine and lamivudine (Zdv/3TC). The overall estimated HIV-1 infection rates in 1307 infants by 8 weeks were 12.3% (95% confidence interval [CI], 9.7-15.0) for Nvp and 9.3% (95% CI, 7.0-11.6) for Zdv/3TC (P=.11). Excluding infections detected within 72 h (intrauterine), new HIV-1 infections were detected in 5.7% (95% CI, 3.7-7.8) and 3.6% (95% CI, 2.0-5.3) of infants in the Nvp and Zdv/3TC groups, respectively, in the 8 weeks after birth. There were no drug-related maternal or pediatric serious adverse events. Common complications were obstetrical for mothers (Nvp group, 24.3%; Zdv/3TC group, 26.3%) and respiratory for infants (Nvp group, 16.1%; Zdv/3TC group, 17.0%). This study further confirms the efficacy and safety of short-course ARV regimens in reducing MTCT rates in developing countries.

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy

Background:Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml Methods:Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 × 106 cells/I who were naive to antiretroviral therapy and AIDS-free at enrolment. Results:One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir ≤ (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02–0.12] and 0.37 (95% CI, 0.23–0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir ≤ 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). Conclusions:Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.

A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients.

All classes of antiretroviral (ARV) therapy have been associated with asymptomatic elevations of alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels, and much less frequently with serious, and at times life threatening, clinical liver hepatotoxicity. The relationship between the risk of developing serious clinical liver injury and the rate and severity of elevated asymptomatic ALT/AST levels is poorly understood. Boehringer Ingelheim has recently completed the Viramune® Hepatic Safety Project; its primary objective was to identify risk factors for antiretroviral-associated hepatotoxicity. Data from 1731 nevirapine-treated patients and 1912 control patients who took part in Boehringer Ingelheim-controlled clinical trials as well as 814 nevirapine-treated patients in uncontrolled trials were analyzed. Risk factors for asymptomatic ALT/AST elevations during nevirapine therapy included baseline elevations of ALT/AST levels >2.5× upper limit of normal (RR = 4.3, p < .01) and co-infection with hepatitis B (RR = 2.3, p < .01) or hepatitis C (RR = 5.2, p < .01). An analysis of ALT/AST elevations >5× ULN for patients stratified by baseline CD4 cell count demonstrated that men with ≥400 CD4 cells/mm3 were at increased risk of asymptomatic transaminase elevations while taking nevirapine (RR = 1.6, p < .01). No consistent CD4 cell count cutoff could be identified in women that was associated with an increased risk of ALT/AST elevations. Analyses from five large observational cohorts (N = 8711) demonstrated no significant differences in the rate of serious hepatic events among antiretroviral regimens, including between the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Use of nevirapine was not associated with a significantly increased risk of clinical hepatotoxic events, including liver failure or liver related death, compared to therapy with other antiretroviral drugs.

Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection

Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor widely used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus disease. To establish its safety profile, we conducted a review of data from prospective US and international clinical trials involving a total of 906 adult patients and 468 pediatric patients treated with NVP. Drug-related adverse events were similar in adults and children, with rash and nausea most frequently reported in adults and rash and granulocytopenia most frequently reported in children. A separate analysis of rash based on data from adult patients in controlled trials demonstrated a 16% rate of NVP-attributable rash in these patients. Of patients with NVP-associated rash, 65% developed rash within the first 6 weeks of therapy, and it has been shown that a lower lead-in dose (200 mg/d vs the standard 400 mg/d) for the first 2 weeks of NVP treatment reduces the frequency of drug-associated rash. Serious rash (Stevens-Johnson syndrome [SJS] or SJS/toxic epidermal necrolysis transition syndrome) occurred with an incidence of 0.3% and clinical hepatitis with an incidence of 1.0% among NVP-treated patients in clinical trials. Adverse event data from long-term clinical trials demonstrated a lower incidence of NVP-related adverse events than in short-term trials of NVP therapy. An analysis of abnormal laboratory findings using thresholds similar to those found in the prescribing information for other commonly used antiretroviral agents and data from controlled trials in adults showed that the most frequently observed laboratory abnormalities were elevations in liver function test results. Approximately 50,000 patients in the United States had been treated with marketed NVP at the time of writing, and postmarketing surveillance has supported the overall safety profile observed in clinical trials. NVP has been shown to be well tolerated in both adult and pediatric patients.

Drug-Induced Liver Injury Associated with the Use of Nonnucleoside Reverse-Transcriptase Inhibitors

Human immunodeficiency virus (HIV)-infected patients frequently present with elevated levels of serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). This has often been attributed to the hepatic effects of antiretroviral (ARV) drugs, including nonnucleoside reverse-transcriptase inhibitors (NNRTIs). A review of cohort studies investigating the incidence of hepatotoxicity among patients receiving ARV therapy suggests that the overall rate of ALT and/or AST elevations is similar among all ARVs. The rate of severe hepatotoxicity, ALT and/or ASTlevels >5 times the upper limit of normal (ULN), during therapy with NNRTIs is relatively low but may be significantly higher in patients with concurrent chronic viral hepatitis (hepatitis B or C). A comprehensive analysis of 17 randomized clinical trials of nevirapine demonstrated that 10% of all nevirapine-treated patients developed elevated levels of ALT and/or AST >5 times the ULN; however, almost two-thirds (6.3% of nevirapine-treated patients) of these elevations were asymptomatic. Symptomatic hepatic events were seen in 4.9% (3.2%-8.9%) of nevirapine-treated patients.

Prospective randomized trial of carotid endarterectomy with primary closure and patch angioplasty with saphenous vein, jugular vein, and polytetrafluoroethylene: Long-term follow-up

PURPOSE This study examines the long-term clinical outcome and the incidence of recurrent stenosis (> or = 50%) after carotid endarterectomy (CEA) with primary closure (PC) versus vein patch closure (VPC), saphenous (SVP), and jugular vein (JVP) and polytetrafluoroethylene patch closure (PTFE-P). METHODS A total of 399 CEAs were randomized into the following groups: 135 PC, 134 PTFE-P, and 130 VPC (SVP alternating with JVP). Postoperative duplex ultrasound scans were performed at 1, 6, and 12 months and every year thereafter. The mean follow-up was 30 months with a range of 1 to 62 months, and demographic characteristics were similar in all groups. Kaplan-Meier analysis was used to estimate the risk of restenosis and the stroke-free survival. RESULTS The incidence of ipsilateral stroke was 5% (seven of 135) for PC, 1% (one of 134) for PTFE-P, and 0% for VPC (PC vs VPC, p = 0.008; PC vs PTFE-P, p = 0.034). Seven strokes occurred in the perioperative period. All three groups had similar mortality rates. The cumulative stroke-free survival rate at 48 months was 82% for PC, 84% for PTFE-P, and 88% for VPC (p < 0.01 for PC vs PTFE-P or VPC). PC had a higher incidence of recurrent stenosis and occlusion (34%) than PTFE-P (2%) and VPC (9%) (SVP 9%, JVP 8%) (p < 0.001). PTFE-P had a lower recurrent stenosis rate than VPC (p < 0.045). Restenoses necessitating a redo CEA were also higher for PC (11%) than for PTFE-P (1%) and VPC (2%) (p < 0.001). Women with PC had a higher recurrent stenosis rate than men (46% vs 23%, p = 0.008). Kaplan-Meier analysis showed that freedom from recurrent stenosis at 48 months was 47% for PC, 84% for VPC, and 96% for PTFE-P (p < 0.001). The SVP and JVP results were comparable. The mean operative diameter of the internal carotid artery was similar in patients with or without restenosis. Significantly more late internal carotid artery dilatations occurred in the VPC group compared with the PC group. CONCLUSIONS Patch closure (VPC or PTFE-P) is less likely than PC to cause perioperative stroke. Patching was also superior in lowering the incidence of late recurrent stenoses, especially in women.

Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial.

Neil Martinson and colleagues report a randomized trial of adding short-course zidovudine+lamivudine to reduce drug resistance from single-dose nevirapine used to prevent mother-to-child transmission of HIV.

Prospective randomized trial of carotid endarterectomy with primary closure and patch angioplasty with saphenous vein, jugular vein, and polytetrafluoroethylene: Perioperative (30-day) results

PURPOSE The early outcomes of carotid endarterectomy (CEA) with primary closure (PC) versus vein patch closure (saphenous vein [SVP] and jugular vein [JVP]) and polytetrafluoroethylene patch closure (PTFE-PC) were compared. METHODS Three hundred ninety-nine CEAs were randomized into the following groups: 135 PC, 134 PTFE-PC, and 130 vein patch closure (SVP alternating with JVP). Surviving patients underwent a carotid color duplex ultrasonographic scan 1 month after surgery. Demographic characteristics were similar in all groups. RESULTS The incidence of perioperative cerebrovascular accidents (CVAs) was 4.4% for PC, 0.8% for PTFE-PC, and 0% for vein patch closure (PC vs vein patch, p = 0.0165; PC vs all patching [vein and PTFE], p = 0.007). The perioperative CVA and reversible ischemic neurologic deficit (RIND) combined rates for all patching were superior to PC (1.5% vs 5.2%; p = 0.04). These combined rates were also superior for vein patch closure when compared with PC (0.8% vs 5.2%; p = 0.037). The mean diameter of the internal carotid artery was similar in patients who had perioperative neurologic deficits and those who did not. After 1 month of follow-up, 11.9% of the PC arteries were narrowed 50% or more in contrast to 2.3% for PTFE-PC, 3.1% for SVP, and 10.3% for JVP.

Effect of contralateral severe stenosis or carotid occlusion on duplex criteria of ipsilateral stenoses: Comparative study of various duplex parameters

PURPOSE This study compares the accuracy of various duplex parameters in grading ipsilateral carotid stenoses in patients with contralateral severe stenoses or occlusion. METHODS Four duplex criteria were correlated to arteriography in 356 carotid arteries in blind fashion: (1) standard criteria: a peak systolic frequency (PSF) of the internal carotid artery (ICA) of > or = 4 kHz was used to diagnose > or = 50% stenosis; (2) new criteria: a PSF of the ICA of > or = 4.5 kHz was used; (3) Fujitani criteria: a PSF of the ICA of > 4.5 kHz and an end-diastolic frequency of < 5.0 kHz was used; (4) internal carotid/common carotid artery (ICA/CCA) PSF ratio of > or = 1.5 was used. RESULTS The standard method overestimated 56 (16%) of 356 stenoses in contrast to 3% for the new method (p < 0.001), and this effect was most evident in the 50% to < 80% stenosis category (30%). The Fujitani method underestimated 97 (27%) of 356 stenoses, and the ICA/CCA ratio overestimated stenoses in 77 (22%) of 356. The overall exact correlation was 94%, 82%, 70%, and 75% for the new, standard, Fujitani, and ICA/CCA ratio, respectively. The kappa statistic and corresponding confidence intervals for the new method (kappa = 0.923, +/- 0.016) are significantly higher (p < 0.001) than those for the standard method (kappa = 0.760, +/- 0.027), the Fujitani method (kappa = 0.608, +/- 0.031), and the ICA/CCA ratio method (kappa = 0.642, +/- 0.051). The overall accuracy in diagnosing > or = 50% ipsilateral stenosis in the whole series was 85% for the standard method, 97% for the new method, 95% for the Fujitani method, and 81% for the ICA/CCA ratio. The new method was superior to the standard and ICA/CCA ratio methods (p < 0.001) and the Fujitani method (p = 0.024). CONCLUSIONS The presence of significant contralateral stenosis (> or = 50%) can lead to overestimation of ipsilateral stenosis if the standard criteria are used; however, this problem can be avoided by using a PSF of the ICA of > or = 4.5 kHz for the diagnosis of > or = 50% stenosis.