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1.  Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings 
PLoS Medicine  2012;9(8):e1001290.
Thomas Campbell and colleagues report findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing.
Background
Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.
Methods and Findings
1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.
An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007).
Conclusion
EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.
Trial Registration
www.ClinicalTrials.gov NCT00084136
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Despite the enormous gains in reducing HIV-related illness and death over the past decade, there are still considerable challenges to meeting the global goal of universal access to highly active antiretroviral treatment—a combination of effective drugs that attack the HIV virus in various ways—to everyone living with HIV/AIDS who could benefit from treatment. In recognition of the related financial, technical, and system obstacles to providing universal access to HIV treatment, in 2010 the UN agency responsible for HIV/AIDS—UNAIDS—launched an ambitious plan called Treatment 2.0, which aims to simplify the way HIV treatment is currently provided. One of the main focuses of Treatment 2.0 is to simplify drug regimes for the treatment of HIV and to make treatment regimes less toxic. In line with Treatment 2.0, the World Health Organization currently recommends that antiretroviral regimens for the initial treatment of HIV should include two nucleoside reverse transcriptase inhibitors (zidovudine or tenofovir disoproxil fumarate [DF] with lamivudine or emtricitabine) and a non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine.)
Why Was This Study Done?
Most of the evidence about the safety and effectiveness of clinical trials come from clinical trials in high-income countries and thus is not generally representative of the majority of people with HIV. So in this study, the researchers conducted a randomized controlled trial in diverse populations in many different settings to investigate whether antiretroviral regimens administered once daily were as effective as twice-daily regimens and also whether a regimen containing the drug atazanavir administered once daily was as safe and effective as a regimen containing efavirenz—data from previous studies have suggested that atazanavir has characteristics, such as its side effect profile, which may make it more suitable for low income settings.
What Did the Researchers Do and Find?
The researchers recruited eligible patients from centers in Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand, the United States, and Zimbabwe—almost half (47%) were women. Then the researchers randomly assigned participants to one of three regimens: efavirenz 600 mg daily plus co-formulated lamivudine-zidovudine 150 mg/300 mg twice daily (EFV+3TC-ZDV); or atazanavir 400 mg once daily, plus didanosine-EC 400 mg once daily, plus emtricitabine 200 mg once daily (ATV+DDI+FTC); or efavirenz 600 mg once daily plus coformulated emtricitabine-tenofovir-DF 200 mg/300 mg once daily (EFV+FTC-TDF). During the study period ATV+DDI+FTC was found to be inferior to EFV+3TC-ZDV, so the Multinational Data Safety Monitoring Board ordered this arm of the trial to stop. Then a year later, due to the low number of treatment failures (deaths, severe HIV disease, or serious opportunistic infections) in the remaining two arms, the board advised the trial to stop early. So the researchers analyzed the data obtained up to this point and pooled the results from all of the centers.
The researchers found that during an average of 184 weeks of follow-up, there were 95 treatment failures (18%) among 526 participants taking EFV+FTC-TDF compared to 98 failures among 519 participants taking EFV+3TC-ZDV. During an average 81 weeks follow-up, there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV. As for safety, 243 (46%) participants assigned to EFV+FTC-TDF reached a safety endpoint (grade 3 disease, abnormal lab measurement, or the need to change drug) compared to 313 (60%) in the EFV+3TC-ZDV group. Importantly, the researchers found that there was greater risk of safety events for women assigned to EFV+3TC-ZDV and also that the atazanavir-based regimen had a higher relative efficacy in women compared to men.
What Do These Findings Mean?
These findings suggest that in diverse populations, EFV+FTC-TDF is as effective as EFV+3TC-ZDV but importantly, the once-daily dosing of EFV+FTC-TDF makes this regimen useful for the initial treatment of HIV, especially in low-income countries. Therefore, as per the guidance in Treatment 2.0, EFV+FTC-TDF in a single combination tablet that can be taken once a day is an attractive option. These findings also indicate that as ATV+DDI+FTC was found to be inferior to the other regimens, this combination should not be used in the initial treatment of HIV. These findings also add to the evidence that antiretroviral efficacy and safety can differ between women and men and support further development of sex-specific recommendations for antiretroviral regimen options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001290.
The UNAIDS website has more information about Treatment 2.0; and the WHO website provides technical information
For an introduction to the treatment of HIV/AIDS see http://www.avert.org/treatment.htm; the AVERT site also has personal stories from women living with HIV/AIDS
AIDSmap provides information for individuals and communities affected by HIV/AIDS
The ACTG website provides information about research to improve treatment of HIV and related complications
doi:10.1371/journal.pmed.1001290
PMCID: PMC3419182  PMID: 22936892
2.  The relation between efavirenz versus nevirapine and virologic failure in Johannesburg, South Africa 
Introduction
Previous research has raised concerns that patients given nevirapine (NVP)-based regimens experience more virologic failure than patients given efavirenz (EFV)-based regimens. We investigated this hypothesis in a cohort of HIV-positive patients at a large HIV treatment clinic in South Africa.
Methods
All antiretroviral therapy (ART)-naïve non-pregnant patients, ≥18 years old, without tuberculosis, who initiated treatment with either NVP or EFV from April 2004 to August 2011 at the Themba Lethu Clinic in Johannesburg, South Africa, were included. Log-binomial regression and modified Poisson regression were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for predictors of virologic failure, virologic suppression, and loss to follow-up (LTF), whereas a Cox proportional hazards model was used to estimate the risk of death, all within one year.
Results
Of 12,840 included patients, 62.0% were female and the median baseline CD4 count was 98 cells/mm3 (36–169). Of these patients, 93.2% initiated an EFV-based regimen. After adjusting for baseline characteristics, no difference in death (adjusted Hazards Ratio (aHR): 0.92; 95% CI: 0.68–1.25), LTF (adjusted Risk Ratio (aRR): 1.00; 95% CI: 0.79–1.25), nor suppression (aRR: 0.98; 95% CI: 0.95–1.00) at one year was found between regimens. Among patients with ≥1 viral load ≥4 months after ART initiation, 4% (n=350) experienced virologic failure within 12 months of initiation. Patients initiating NVP-based regimens were 60% more likely to fail than patients initiating EFV-based regimens (aRR: 1.58; 95% CI: 1.13–2.22).
Conclusions
In this cohort, patients initiating NVP-based regimens experienced more virologic failure than patients initiating EFV-based regimens. Future guidelines should consider the implications of different efficacy profiles when making recommendations for which drugs to prioritize.
doi:10.7448/IAS.17.1.19065
PMCID: PMC4215701  PMID: 25361827
nevirapine; efavirenz; virologic failure; viral suppression; mortality; loss to follow-up; resource-limited settings
3.  More virological failure with lamivudine than emtricitabine in efavirenz and nevirapine regimens in the Dutch nationwide HIV Cohort 
Journal of the International AIDS Society  2014;17(4Suppl 3):19491.
Introduction
Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable by HIV-1 guidelines in first-line tenofovir/efavirenz (TDF/EFV) and TDF/nevirapine (NVP) combination antiretroviral therapy (cART). Data from trials on equivalence of 3TC and FTC are inconsistent. We examined the effectiveness of 3TC and FTC in the national HIV cohort in the Netherlands.
Material and Methods
Observational cohort study on cART naïve HIV-1 patients. Therapy was initiated as 3TC or FTC with TDF/EFV or TDF/NVP between 2002 and 2012. Patients with baseline resistance or prior cART experience were excluded. Main outcomes were Week 48 virological failure (VF) by on treatment analysis, time to HIV-RNA <400 copies/mL within 48 weeks and VF within 240 weeks after at least one HIV-RNA <400 copies/mL. Acquired resistance to reverse transcriptase was evaluated. Analyses were done by logistic regression and Cox proportional hazard models. Propensity score adjusted models and intention to treat evaluations were included as sensitivity analysis.
Results
A total of 4836 patients initiated 3TC/TDF/EFV (n=546), FTC/TDF/EFV (n=3391), 3TC/TDF/NVP (n=207) or FTC/TDF/NVP (n=692). Ninety-six patients were excluded for baseline resistance or prior cART experience. By Week 48, VF proportions were higher for 3TC/TDF/EFV (10.8%) compared to FTC/TDF/EFV (3.6%) and for 3TC/TDF/NVP (27.0%) compared to FTC/TDF/NVP (11.0%). The multivariable adjusted odds ratio (OR) on VF was 1.78 (95% CI 1.11–2.84; p=0.016) with 3TC/TDF/EFV compared to FTC/TDF/EFV and 2.09 (95% CI 1.25–3.52; p=0.005) with 3TC/TDF/NVP compared to FTC/TDF/NVP. Propensity score adjusted models and intention to treat analyses showed comparable results. The time to virological suppression within 48 weeks was not influenced by using 3TC or FTC in cART. If HIV-RNA <400 copies/mL was achieved on initial cART first, no differences in VF within 240 weeks were observed between 3TC and FTC with TDF/EFV (p=0.090) or TDF/NVP (P=0.255). Patients failing 3TC-containing cART had higher median HIV-RNA at VF compared to FTC containing cART (p<0.001) and 89.8% had acquired resistance on 3TC compared to 81.2% on FTC.
Conclusions
Including FTC in cART is associated with better virological responses compared to 3TC. As cost constraints may call for the use of generic 3TC, a well-powered randomized trial to confirm the presumed equivalence of 3TC and FTC is needed.
doi:10.7448/IAS.17.4.19491
PMCID: PMC4224847  PMID: 25394000
4.  Effectiveness of Efavirenz-Based Regimens in Young HIV-Infected Children Treated for Tuberculosis: A Treatment Option for Resource-Limited Settings 
PLoS ONE  2013;8(1):e55111.
Background
Antiretroviral treatment (ART) options for young children co-infected with HIV and tuberculosis are limited in resource-poor settings due to limited data on the use of efavirenz (EFV). Using available pharmacokinetic data, an EFV dosing schedule was developed for young co-infected children and implemented as the standard of care at Macha Hospital in Southern Province, Zambia. Treatment outcomes inchildren younger than 3 years of age or weighing less than 10 kg receiving either EFV-based ART plus anti-tuberculous treatment or nevirapine-based (NVP) ART were compared.
Methods
Treatment outcomes were measured in a cohort of HIV-infected children seeking care at Macha Hospital in rural Zambia from 2007 to 2010. Informationon the diagnosis and treatment of tuberculosis was abstracted from medical records.
Results
Forty-five children treated for tuberculosis initiated an EFV-based regimen and 69 children initiated a NVP-based regimen, 7 of whom also were treated for tuberculosis. Children receiving both regimens were comparable in age, but children receiving EFV started ART with a lower CD4+ T-cell percentage and weight-for-age z-score. Children receiving EFV experienced increases in both CD4+ T-cell percentage and weight-for-age z-score during follow-up, such that levels were comparable to children receiving NVP after two years of ART. Cumulative survival after 12 months of ART did not differ between groups (NVP:87%;EFV:80%;p = 0.25). Eleven children experienced virologic failure during follow-up.The adjusted hazard ratio of virologic failure comparing EFV to NVP was 0.25 (95% CI:0.05,1.24) and 0.13 (95% CI:0.03,0.62) using thresholds of 5000 and 400 copies/mL, respectively.Five children receiving EFV were reported to have had convulsions after ART initiation compared to only one child receiving NVP (p = 0.04).
Conclusions
Despite poorer health at ART initiation, children treated for tuberculosis and receiving EFV-based regimens showed significant improvements comparable to children receiving NVP-based regimens. EFV-based regimens should be considered for young HIV-infected children co-infected with tuberculosis in resource-limited settings.
doi:10.1371/journal.pone.0055111
PMCID: PMC3555823  PMID: 23372824
5.  Comparative durability of nevirapine versus efavirenz in first-line regimens during the first year of initiating antiretroviral therapy among Swaziland HIV-infected adults 
Nevirapine (NVP) and Efavirenz (EFV) have generally comparable clinical and virologic efficacy. However, data comparing NVP durability to EFV are imprecise. We analyzed cohort data to compare durability of NVP to EFV among patients initiating ART in Mbabane, Swaziland. The primary outcome was poor regimen durability defined as any modification of NVP or EFV to the ART regimen. Multivariate Cox proportional hazards models were employed to estimate the risk of poor regimen durability (all-cause) for the two regimens and also separately to estimate risk of drug-related toxicity. We analyzed records for 769 patients initiating ART in Mbabane, Swaziland from March 2006 to December 2007. 30 patients (3.9%) changed their NVP or EFV-based regimen during follow up. Cumulative incidence for poor regimen durability was 5.3% and 2.7% for NVP and EFV, respectively. Cumulative incidence for drug-related toxicity was 1.9% and 2.7% for NVP and EFV, respectively. Burden of TB was high and 14 (46.7%) modifications were due to patients substituting NVP due to beginning TB treatment. Though the estimates were imprecise, use of NVP - based regimens seemed to be associated with higher risk of modifications compared to use of EFV - based regimens (HR 2.03 95%CI 0.58 - 7.05) and NVP - based regimens had a small advantage over EFV - based regimens with regard to toxicity - related modifications (HR 0.87 95%CI 0.26 - 2.90). Due to the high burden of TB and a significant proportion of patients changing their ART regimen after starting TB treatment, use of EFV as the preferred NNRTI over NVP in high TB endemic settings may result in improved first-line regimen tolerance. Further studies comparing the cost-effectiveness of delivering these two NNRTIs in light of their different limitations are required.
doi:10.11604/pamj.2013.15.5.1889
PMCID: PMC3708322  PMID: 23847702
Tolerability; Toxicity; Efavirenz; Nevirapine; Antiretroviral therapy; Resource limited setting; Swaziland
6.  Efavirenz- but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant 
Journal of the International AIDS Society  2014;17(4Suppl 3):19484.
Introduction
Sub-dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long-acting contraception, but their use among HIV-positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A-mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub-dermal implant over six months in HIV-positive Ugandan women on nevirapine (NVP)- or efavirenz (EFV)-based ART.
Material and Methods
This non-randomized, parallel group study compared LNG pharmacokinetics between HIV-positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP- (n=20) or EFV- (n=20) based ART. The two-rod (75 mg/rod) LNG sub-dermal implant was inserted at study enrolment. LNG sampling was obtained pre-implant and at weeks 1, 4, 12 and 24 post-insertion. LNG concentrations were analyzed using a validated LC-MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit.
Results
At enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV-RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p<0.01). By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03). LNG concentrations are reported in the table.
Conclusions
Over a 24-week period, LNG concentrations were 40–54% lower in women on EFV-based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP-based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP-based ART.
doi:10.7448/IAS.17.4.19484
PMCID: PMC4224805  PMID: 25393993
7.  Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS databases, Abidjan, Côte d’Ivoire 
Background
An increasing number of HIV-infected women become pregnant while receiving efavirenz (EFV). We compared the pregnancy outcomes of women exposed to EFV and to nevirapine (NVP) during the first trimester.
Methods
A retrospective study in four HIV care centers participating to clinical trials and international cohort collaboration. All HIV-infected pregnant women who conceived on EFV or NVP-based antiretroviral therapy (ART) between 2003 and 2009 were included. Pregnancy outcomes were: abortion (voluntary termination), miscarriage (unwanted termination <20 weeks of amenorrhea [WA]), stillborn (death ≥20 WA), preterm delivery [PTD] (live-birth <37 WA) and low birth weight [LBW] (<2,500 grams).
Results
Overall, 344 HIV-infected pregnant women conceived on ART (213 on EFV and 131 on NVP). Median age was 29 years and median CD4 count 217 cells/μl at ART initiation. The overall proportion was 11.7% for abortion, 5.2% for miscarriage, 6.7% for stillborn, 10.8% for PTD and 20.2% for LBW. There was no difference between EFV and NVP exposure, except for abortion (14.3% vs 7.3%; p=0.05). No external and visible congenital malformation was observed neither in women exposed to EFV nor in women exposed to NVP.
Conclusion
Among women exposed to EFV, no significant increased risk of unfavorable pregnancy outcome was reported except for abortion.
doi:10.1097/QAI.0b013e3181ff04e6
PMCID: PMC3045727  PMID: 21084995
Efavirenz; HIV infection; congenital abnormalities; pregnancy outcomes; Africa
8.  Long-term virological outcome in children on antiretroviral therapy in the UK and Ireland 
AIDS (London, England)  2014;28(16):2395-2405.
Objective:
To assess factors at the start of antiretroviral therapy (ART) associated with long-term virological response in children.
Design:
Multicentre national cohort.
Methods:
Factors associated with viral load below 400 copies/ml by 12 months and virologic failure among children starting 3/4-drug ART in the UK/Irish Collaborative HIV Paediatric Study were assessed using Poisson models.
Results:
Nine hundred and ninety-seven children started ART at a median age of 7.7 years (inter-quartile range 2.9–11.7), 251 (25%) below 3 years: 411 (41%) with efavirenz and two nucleoside reverse transcriptase inhibitors (EFV + 2NRTIs), 264 (26%) with nevirapine and two NRTIs (NVP + 2NRTIs), 119 (12%; 106 NVP, 13 EFV) with non-nucleoside reverse transcriptase inhibitor and three NRTIs (NNRTI + 3NRTIs), and 203 (20%) with boosted protease inhibitor-based regimens. Median follow-up after ART initiation was 5.7 (3.0–8.8) years. Viral load was less than 400 copies/ml by 12 months in 92% [95% confidence interval (CI) 91–94%] of the children. Time to suppression was similar across regimens (P = 0.10), but faster over calendar time, with older age and lower baseline viral load. Three hundred and thirty-nine (34%) children experienced virological failure. Although progression to failure varied by regimen (P < 0.001) and was fastest for NVP + 2NRTIs regimens, risk after 2 years on therapy was similar for EFV + 2NRTIs and NVP + 2NRTIs, and lowest for NNRTI + 3NRTIs regimens (P-interaction = 0.03). Older age, earlier calendar periods and maternal ART exposure were associated with increased failure risk. Early treatment discontinuation for toxicity occurred more frequently for NVP-based regimens, but 5-year cumulative incidence was similar: 6.1% (95% CI 3.9–8.9%) NVP, 8.3% (95% CI 5.6–11.6) EFV, and 9.8% (95% CI 5.7–15.3%) protease inhibitor-based regimens (P = 0.48).
Conclusion:
Viral load suppression by 12 months was high with all regimens. NVP + 3NRTIs regimens were particularly efficacious in the longer term and may be a good alternative to protease inhibitor-based ART in young children.
doi:10.1097/QAD.0000000000000438
PMCID: PMC4210689  PMID: 25389551
antiretroviral therapy; children; HIV; UK/Ireland; virological outcome
9.  Initial Viral Decay to Assess the Relative Antiretroviral Potency of PI-, NNRTI- and NRTI-Sparing Regimens for First Line Therapy of HIV Infection 
AIDS (London, England)  2011;25(18):2269-2278.
Objectives
To evaluate the effects of gender and initial antiretroviral regimen on decay of HIV RNA and virologic outcome.
Methods
We conducted a viral dynamics sub-study of A5142, a trial comparing lopinavir/ritonavir+efavirenz (LPV/EFV) versus LPV+2 NRTI (LPV) versus EFV+2 NRTI (EFV) in ARV-naive subjects. HIV RNA was measured at days 2, 10, and 14 in the sub-study and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the sub-study with bi-exponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV RNA change was assessed as a predictor of virologic failure (HIV RNA above 50/200 copies/mL) at weeks 24–96 using logistic regression.
Results
68 subjects were enrolled in the sub-study (median HIV RNA 4.9 log10 copies/mL). Median rates of phase-1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) day−1. Phase-1 decay was significantly faster for EFV than LPV (P=0.023); other comparisons were not significant (P>0.11). Viral decay did not differ by gender (P=0.10). Week 1 HIV RNA change, calculated in 571 participants of A5142, was greater for the EFV (median - 1.47 log10 copies/ml) than either the LPV/EFV or LPV groups (−1.21 and −1.16 log10 copies/ml, respectively; P<0.001). Week 1 HIV RNA change was associated with virologic failure above 50 copies/mL at weeks 24 and 48 (P≤0.018), but not above 200 copies/mL or at week 96.
Conclusions
Phase-1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV RNA change predicted virologic outcome to week 48, but not at week 96.
doi:10.1097/QAD.0b013e32834d0c20
PMCID: PMC3572727  PMID: 21941167
Antiretroviral therapy; viral dynamics; treatment outcome; protease inhibitor; non nucleoside reverse transcriptase inhibitor
10.  Comparative Effectiveness of Initial Antiretroviral Therapy Regimens: ACTG 5095 and 5142 Clinical Trials Relative to ART-CC Cohort Study 
Background
The generalizability of antiretroviral therapy (ART) clinical trial efficacy findings to routine care settings is not well studied. We compared the relative effectiveness of initial ART regimens estimated in AIDS Clinical Trial Group (ACTG) randomized controlled trials with that among patients receiving ART at Antiretroviral Therapy Cohort Collaboration (ART-CC) study sites.
Methods
Treatment-naive HIV-infected patients initiating identical ART regimens in ACTG trials (A5095 and A5142) and at 15 ART-CC cohort study sites were included. Virological failure (HIV-1 RNA >200 copies/ml) at 24- and 48-weeks, incident AIDS-defining events and mortality were measured according to study design (ART-CC cohort vs. ACTG trial) and stratified by 3rd drug [Abacavir (ABC), Efavirenz (EFV), and Lopinavir/r (LPV/r)]. We used logistic regression to estimate and compare odds ratios for virological failure between different regimens and study designs, and used Cox models to estimate and compare hazard ratios for AIDS and death.
Results
Compared with patients receiving ABC, those receiving EFV had roughly half the odds of 24-week virologic failure (>200 copies/mL) in both ACTG 5095 (OR=0.53, 95% CI 0.36–0.79) and ART-CC (0.46, 0.37–0.57). Virologic superiority of EFV (vs. ABC) appeared comparable in ART-CC and ACTG 5095 (ratio of ORs 0.86, 95% CI 0.54–1.35). Odds ratios for 48-week virologic failure, comparing EFV with LPV/r, were also comparable in ACTG 5142 and ART-CC (ratio of ORs 0.87, 0.45–1.69).
Conclusions
Between ART regimen virologic efficacy of 3rd drugs ABC, EFV, and LPV/r observed in the ACTG 5095 and 5142 trials appear generalizable to the routine care setting of ART-CC clinical cohorts.
doi:10.1097/QAI.0b013e318230372e
PMCID: PMC3196673  PMID: 21857357
HIV; AIDS; Antiretroviral therapy; Comparative effectiveness; Viral load
11.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
12.  Bone Mineral Density Effects of Randomized Regimen and Nucleoside Reverse Transcriptase Inhibitor (NRTI) Selection from ACTG A5142 
HIV clinical trials  2013;14(5):224-234.
Objective
To compare the longitudinal changes in total bone mineral density (TBMD) across antiretroviral (ARV) regimens.
Methods
A5142 was an open-label study comparing 3 ARV regimens for the initial treatment of HIV-1. Subjects were randomized equally to efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir (LPV/r) plus 2 NRTIs, or LPV/r plus EFV without NRTI. The NRTI regimen (lamivudine [3TC] plus zidovudine [ZDV], stavudine [d4T], or tenofovir [TDF]) was selected prior to randomization. TBMD was assessed via whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 48 and 96 weeks. Analysis was modified intent-to-treat (ITT) ignoring regimen changes using all evaluations.
Results
Significant mean declines in TBMD at week 48 were observed among subjects. In repeated-measures analysis of changes (including randomized regimen, NRTI used, and time), there was a significant difference in the NRTI-containing arms in mean percentage change in TBMD at week 48 according to NRTI used (P < .001). Subjects taking ZDV had similar changes to those taking d4T (P = .970), whereas those taking TDF had larger declines (P < .001). There was a nonsignificant trend toward greater mean declines among subjects taking LPV/r versus EFV (P = .080). Overall, TDF-containing regimens demonstrated the greatest losses in TBMD, while EFV regimens without TDF had lesser TBMD reductions even compared to the NRTI-sparing arm. From week 48 to 96, all treatment groups continued to lose TBMD at similar rates.
Conclusions
Among NRTI-containing arms, NRTI selection, especially use of TDF, had a greater effect on TBMD change than randomized regimen. The long-term clinical significance remains to be demonstrated.
doi:10.1310/hct1405-224
PMCID: PMC3956746  PMID: 24144899
antiretroviral therapy; bone density; HIV
13.  Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice? 
AIDS (London, England)  2008;22(18):2481-2492.
Objective
To determine if differences in short-term virologic failure among commonly used ART regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART.
Design
Observational cohort study of patients initiating ART between January 2000 and December 2005.
Setting
The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States.
Subjects, participants
A total of 13,546 antiretroviral-naïve HIV-positive patients initiating ART with efavirenz (EFV), nevirapine (NVP), lopinavir/ritonavir (LPV/r), nelfinavir (NFV), or abacavir (ABC) as third drugs in combination with a zidovudine and lamivudine NRTI backbone.
Main outcome measures
Short-term (24-week) virologic failure (>500 copies/mL) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes).
Results
Compared with EFV as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; NVP (adjusted odds ratio=1.87, 95%CI=1.58,2.22), LPV/r (1.32, 95%CI=1.12–1.57), NFV (3.20, 95%CI=2.74,3.74), and ABC (2.13, 95%CI=1.82,2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with NVP (adjusted hazard ratio for composite outcome measure 1.27, 95%CI=1.04,1.56) and ABC (1.22, 95%CI=1.00,1.48).
Conclusions
Among antiretroviral-naïve patients initiating therapy, between-ART regimen differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.
doi:10.1097/QAD.0b013e328318f130
PMCID: PMC2793403  PMID: 19005271
Adolescent; Adult; Anti-Retroviral Agents; therapeutic use; Disease-Free Survival; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Epidemiologic Methods; Female; HIV Infections; drug therapy; immunology; virology; HIV-1; Humans; Male; Middle Aged; Odds Ratio; RNA, Viral; metabolism; Reverse Transcriptase Inhibitors; therapeutic use; Treatment Outcome; Viral Load; Young Adult; HIV; AIDS; Antiretroviral Therapy; Highly Active; Cohort analysis; Viral load; AIDS-related Opportunistic Infections; Mortality
14.  Comparative impact of antiretroviral drugs on markers of inflammation and immune activation during the first two years of effective therapy for HIV-1 infection: an observational study 
BMC Infectious Diseases  2014;14:122.
Background
Few studies have compared the impact of different antiretroviral regimens on residual immune activation and inflammation with discordant results. Aim of the study was to investigate the impact of various antiretroviral regimens on markers of immune activation and inflammation during the first two years of effective therapy.
Methods
We studied HIV-infected antiretroviral-naïve patients who began cART with either abacavir/lamivudine or tenofovir/emtricitabine, combined with ritonavir-boosted lopinavir (LPV/r), atazanavir (ATV/r) or efavirenz (EFV). All the patients had a virological response within 6 months, which was maintained for 2 years with no change in their ART regimen. C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), monokine induced by interferon-γ (MIG) and interferon-γ-inducible protein-10 (IP-10) were measured in stored plasma obtained at cART initiation and 24 months later. Mean changes from baseline were analyzed on loge-transformed values and multivariable linear regression models were used to study the effect of the treatment components, after adjusting for factors that might have influenced the choice of ART regimen or biomarker levels. Differences were expressed as the mean fold change percentage difference (Δ).
Results
Seventy-eight patients (91% males) with a median age of 43 years met the inclusion criteria. Their median baseline CD4 cell count was 315/mm3 and HIV-1 RNA level 4.6 log10 copies/ml. During the 2-years study period, IL-6, IP-10 and MIG levels fell significantly, while hs-CRP and sCD14 levels remained stable. IP-10 and MIG levels declined significantly less strongly with ATV/r than with EFV (IP-10Δ -57%, p = 0.011; MIGΔ -136%, p = 0.007), while no difference was noted between LPV/r and EFV. The decline in IL-6 did not differ significantly across the different treatment components.
Conclusions
After the first 2 years of successful cART, IL-6, IP-10 and MIG fell markedly while hs-CRP and sCD14 levels remained stable. The only impact of ART regimen was a smaller fall in markers of immune activation with ATV/r than with EFV. Our results suggest that these markers could be worthwhile when evaluating new antiretroviral drugs.
doi:10.1186/1471-2334-14-122
PMCID: PMC3945800  PMID: 24589015
HIV; cART; Immune activation; Inflammation; Markers
15.  Factors Associated with Remaining on Initial Randomized Efavirenz-containing Regimens in the AIDS Clinical Trials Group 
AIDS (London, England)  2013;27(12):1887-1897.
Objective
Efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral (ARV) regimen. Understanding characteristics related to EFV success is clinically useful.
Design
Data from 2,220 ARV-naïve participants randomized to EFV + 2/3 NRTIs in 4 ACTG trials plus a long-term cohort, were analyzed.
Methods
Logistic regression, using inverse probability of censoring weighting to address selective-followup bias, was used to identify factors associated with EFV success (no treatment interruptions of >30 days, HIV RNA<200 copies/mL) 1 year (yr) post initiation and at yrs 2-5 if successful at yr 1.
Results
Pre-treatment characteristics were: median age 38 yrs, 82% male, 40% white, 10% history of injection drug use (HxIDU), median CD4+ T-lymphocyte 227 cells/uL and 33% HIV RNA>100,000 copies/mL. In a multivariable model, factors associated with yr 1 EFV success were: race (white OR: 1.5; p<0.001; Hispanic OR: 1.5; p=0.003 vs. black), no pre-treatment sign/symptom ≥grade 3 (OR: 1.7; p=0.008) and no HxIDU (OR: 1.7; p=0.001). Predictors of EFV success at yrs 2-5 were: no HxIDU (yrs 2-5; ORs 1.9-2.2); self-reported complete (4-days prior to study visit) adherence during yr 1 (yrs 2-4; ORs 1.6-1.9); fewer missed visits during yr 1 (yrs 2,4,5; ORs 0.92-0.98/1% increase); HIV RNA <50 copies/mL at yr 1 (yrs 2,3; ORs 1.9-2.2); and older age (>50 v. ≤ 30 yrs) (yrs 2,3,4: ORs 2.3-3.7).
Conclusions
Characteristics predictive of EFV success in the short-and longer-term differed except for HxIDU. Behaviors occurring during yr 1 were associated with EFV success over 5 years.
doi:10.1097/QAD.0b013e328361645f
PMCID: PMC4204654  PMID: 23925417
Efavirenz; human immunodeficiency virus; highly active antiretroviral therapy; cohort study; clinical trials
16.  Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring 
Journal of the International AIDS Society  2014;17(4Suppl 3):19524.
Introduction
Wide inter-patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV-positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV-containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)-guided strategy to optimize the EFV dose in HIV-positive Taiwanese patients.
Materials and Methods
The plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV-positive adults who had received EFV-containing cART with viral suppression (plasma HIV RNA load (PVL) <200 copies/mL). For those with EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4–12 weeks after switch using high-performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase-chain-reaction restriction fragment-length polymorphism.
Results
Between April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL <40 copies/ml; 26.4% HBsAg-positive and 7.5% anti-HCV-positive) with plasma C12 efavirenz >2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62–4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53–2.33) for 64 patients who had completed follow-up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9–57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow-up of PVL achieved undetectable PVL (<40 copies/ml) following switch to a reduced dose of EFV after a mean observation of 13 weeks (IQR, 7–15 weeks).
Conclusions
Switch to cART containing a half tablet of EFV (1/2#) in HIV-positive Taiwanese patients with higher plasma EFV concentrations who had achieved viral suppression could maintain successful viral suppression with the guidance of TDM.
doi:10.7448/IAS.17.4.19524
PMCID: PMC4224938  PMID: 25394033
17.  Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1 
PLoS Medicine  2004;1(1):e19.
ABSTRACT
Background
Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV).
Methods and Findings
Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs.
Conclusion
NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.
Comparison of two commonly prescribed non-nucleoside reverse transcriptase inhibitors shows that patients on nevirapine have better blood lipid profiles
doi:10.1371/journal.pmed.0010019
PMCID: PMC523838  PMID: 15526045
18.  Efavirenz and rifampicin in the South African context: is there a need to dose increase efavirenz with concurrent rifampicin therapy? 
Antiviral therapy  2011;16(4):527-534.
Introduction
Increasing EFV dose from 600mg to 800mg daily has been suggested with concomitant RFN, as induction of cytochrome p450 isoenzymes may reduce EFV plasma concentrations
Methods
Individuals from the CIPRA-South Africa cohort taking EFV-based ART with concomitant TB were dosed with either increased-(800mg) or standard-(600mg) dose EFV during TB treatment. After TB therapy all took 600mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and at least 4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed rank test.
Results
Paired-samples were collected from 72 individuals. 45(63%) were women; median weight 59kg (IQR52-67kg). At ART start median CD4 count was114 cells/mm3 (IQR37-165), median viral load 5.5log (IQR5.1–5.9). 38 (53%) took 800mg EFV during TB treatment and 34(47%) took 600mg. EFV concentrations in the 800mg group were higher with RFN [[2.9mg/L (IQR 1.8–5.6)] than without [2.1mg/L (IQR 1.4–3.0)]], p=0.0003. There was no significant difference in EFV concentrations with RFN [2.4mg/L (IQR1.2–5.1)] or without [2.2 mg/L (IQR 1.4 to 3.7)] in the 600mg group. There was no increase in EFV-linked adverse effects in either group. Proportion virologically suppressed at 48 weeks was similar in both groups.
Conclusion
EFV concentrations were significantly increased in the EFV 800mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600mg group. Dose escalation of EFV 600mg to 800mg is not required during concomitant TB therapy in South Africa.
doi:10.3851/IMP1780
PMCID: PMC3145153  PMID: 21685540
antiretroviral therapy; tuberculosis; drug interactions
19.  Efavirenz 400 mg daily remains non-inferior to 600 mg: 96 week data from the double-blind, placebo-controlled ENCORE1 study 
Journal of the International AIDS Society  2014;17(4Suppl 3):19523.
Introduction
ENCORE1 compared the efficacy and safety of reduced versus standard dose efavirenz (EFV) with tenofovir/emtricitabine (TDF/FTC) as first-line HIV therapy. The primary analysis at 48 weeks showed 400 mg EFV was safe and virologically non-inferior to 600 mg. This analysis explores over 96 weeks the durability of efficacy and safety.
Materials and Methods
A multinational, double-blind, placebo-controlled, non-inferiority trial in treatment-naïve HIV-positive adults randomized to TDF/FTC plus reduced (400 mg, EFV400) or standard dose (600 mg, EFV600) EFV. The difference between proportions of participants with plasma HIV RNA (VL) <200 log10 copies/mL by intention-to-treat (ITT missing=failure) was compared using a non-inferiority margin of −10%. Non-inferiority was also examined in per protocol (PP) and non-completer = failure (NC=F) populations. Adverse events (AEs) and serious adverse events (SAEs) were summarized by treatment arm.
Results
The ITT population comprised 630 patients (EFV400 = 321; EFV600 = 309); 32% were female; 37%, 33% and 30% were African, Asian and Caucasian, respectively. A total of 585 (EFV400 = 299; EFV600 = 286) completed 96 weeks on randomized therapy. At 96 weeks, proportions with VL <200 copies/mL were EFV400 (90.0%) and EFV600 (90.6%) (difference −0.6; 95% CI −5.2 to 4.0; p=0.72) demonstrating continued non-inferiority. Non-inferior efficacy was also observed for VL thresholds of <50 and <400 copies/mL irrespective of baseline VL (<100,000 versus ≥100,000 copies/mL). There was no between-arm difference in time to loss of virological response (>200 copies/mL) (p=0.47) or mean change from baseline VL (p=0.74). Mean change from baseline in CD4 T-cell counts at week 96 remained significantly higher for EFV400 than EFV600 (difference 25 cells/µL; 95% CI 2–48; p=0.03). There was no difference in the frequency or severity of AEs (EFV400 = 89.4%, EFV600 = 89.3%; difference 0.09; 95% CI −4.73 to 4.90; p=0.97). The proportions ever reporting an AE definitely or probably EFV-related were EFV400 (37.7%) and EFV600 (47.9%) (difference −10.2%; 95% CI −17.9 to −2.51; p=0.01). SAEs did not differ in frequency (EFV400 = 7.5%, EFV600 = 10.4%; difference −2.9%; 95% CI −7.3 to 1.6; p=0.20).
Conclusions
Non-inferiority of EFV 400 mg to EFV 600 mg when combined with TDF/FTC as initial HIV therapy was confirmed at week 96. Both doses demonstrated similar safety profiles. These results support the use of a lower EFV dose as part of routine HIV management.
doi:10.7448/IAS.17.4.19523
PMCID: PMC4224894  PMID: 25394032
20.  Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy 
Journal of the International AIDS Society  2014;17(4Suppl 3):19544.
Introduction
Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies.
Materials and Methods
Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests.
Results
145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference −16.3 [CI 95%: −31.4, −1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference −21.8 [−38.0, −5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated.
Conclusions
In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.
doi:10.7448/IAS.17.4.19544
PMCID: PMC4224902  PMID: 25394051
21.  Outcomes for Efavirenz versus Nevirapine-Containing Regimens for Treatment of HIV-1 Infection: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(7):e68995.
Introduction
There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz (EFV) and nevirapine (NVP) in first-line antiretroviral therapy (ART).
Methods
We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR) and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I2 statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.
Results
Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73–0.99] I2 = 0%) and observational studies (RR 0.65 [0.59–0.71] I2 = 54%). EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00–1.08] I2 = 0%) and observational studies (RR 1.06 [1.00–1.12] I2 = 68%).
Conclusion
EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.
doi:10.1371/journal.pone.0068995
PMCID: PMC3718822  PMID: 23894391
22.  Single tablet regimens are associated with reduced Efavirenz withdrawal in antiretroviral therapy naïve or switching for simplification HIV-infected patients 
Background
Efavirenz (EFV) administration is still controversial for its high rates of interruption mainly related to central nervous system side effects (CNS-SE). Aim of the study was to define if single tablet regimen (STR) as compared to bis-in-die (BID) or once-daily (OD) with ≥2 pills-a-day EFV formulations reduced the risk of interruption.
Methods
Patients starting any cART regimen including EFV + 2NRTIs or switching to EFV + 2NRTIs for simplification after virological suppression were retrospectively selected. Incidence, probability and prognostic factors of interruption by different causes were assessed by survival analysis and Cox regression model.
Results
Overall, 553 patients starting EFV-containing regimens were included: 38.2% started BID regimen, 44.5% OD regimens ≥2 pills and 17.4% STR. The overall proportion of EFV interruption was 37.4% at 4 years; at the same time point, interruptions for virological failure and toxicity were 8.8% and 16.5% (8% for CNS-SE), respectively. Starting EFV co-formulated in STR was associated with lower proportion of overall interruption at 4 years (17.1% vs. 40.6%, p < 0.01). Only one virological failure was observed with STR up to 4 years (1.1% vs. 10.3% in non-STR, p = 0.051). STR also accounted for lower proportion of interruption by patient decision (1.5% vs. 11.8%, p = 0.01). No differences of interruption by overall toxicity and CNS-SE were observed. In multivariable analysis, STR and male gender were associated with lower risk of EFV interruption, while higher CD4 nadir and IDU with higher risk.
Conclusions
In our experience, starting EFV co-formulated in STR was associated with lower virological failure and higher adherence, despite a similar proportion of CNS toxicity, thus reducing the risk of treatment interruption.
doi:10.1186/1471-2334-14-26
PMCID: PMC3897945  PMID: 24418191
STR; Discontinuation; Combination antiretroviral therapy; Toxicity; Adherence
23.  Treatment modification in HIV-Infected individuals starting antiretroviral therapy between 2011 and 2014 
Journal of the International AIDS Society  2014;17(4Suppl 3):19768.
Introduction
While antiretroviral therapy (ART) has increased the survival of HIV patients and turned HIV infection into a chronic condition, treatment modifications and poor adherence might limit this therapeutic success.
Methods
Patients from the Austrian HIV Cohort Study, who started their first ART after Rilpivirine became available in February 2011, were analyzed for factors associated with treatment modification which could be either a change of drugs or a stop of the regimen. A drug was considered as stopped when the regimen was interrupted for more than eight days. Drugs of particular interest were Darunavir (DRV), Atazanavir (ATV), Raltegravir (RAL), Rilpivirine (RPV) and Efavirenz (EFV). RPV and EFV were analyzed only when taken as single tablet regimen. Other drugs were summarized as “other.” Proportional hazards regression methods were used to identify predictors of discontinuation and Kaplan–Meier estimates were used to calculate probabilities of discontinuation. Patients who died were censored at the date of death.
Results
965 patients started ART, 282 with DRV, 161 with ATV, 96 with RAL, 108 with RPV and 118 with EFV. Median time for taking initial ART is 11.6 months. 322 (33.4%) patients modified their initial ART. The overall probability of modification at one year was 28.7%, at two years 40.0% and at three years 49.8%. In a multivariable proportional hazards regression analysis, AIDS diagnosis at baseline and injecting drug use (IDU) of men compared with men who have sex with men (MSM) have a higher risk of switch/stop. Compared with DRV, RPV showed a much lower and ATV and particularly “other” a higher risk for discontinuation (Table 1).
Availability of more effective/convenient treatment (28.9%) was the main reason for discontinuation, especially in the group “other” (43.5%), RAL (34.6%) and DRV (31.6%). Non-specified patient or physician wish to modify therapy was revealed in 17.4% and 9.3% respectively. EFV was modified in 52.8% due to central nervous system toxicity and ATV in 27.8% for gastrointestinal toxicity including hyperbilirubinemia.
Conclusion
Rates of modification and interruption were still high in recent years, particularly in the first year of ART. The decreased rate of modification found in patients treated with Rilpivirine may be attributed to selection of patients according to guidelines.
doi:10.7448/IAS.17.4.19768
PMCID: PMC4225345  PMID: 25397512
24.  Virological failure of staggered and simultaneous treatment interruption in HIV patients who began Efavirenz-based regimens after allergic reactions to nevirapine 
Objective
The objective of this work was to study the virological outcomes associated with two different types of treatment interruption strategies in patients with allergic reactions to nevirapine (NVP). We compared the virological outcomes of (1) HIV-1-infected patients who discontinued an initial NVP-based regimen because of cutaneous allergic reactions to NVP; different types of interruption strategies were used, and second-line regimen was based on efavirenz (EFV); and (2) HIV-1-infected patients who began an EFV-based regimen as a first-line therapy (controls).
Methods
This retrospective cohort included patients who began an EFV-based regimen, between January 2002 and December 2008, as either an initial regimen or as a subsequent regimen after resolving a cutaneous allergic reaction against an initial NVP-based regimen. The study ended in March 2010. The primary outcome was virological failure, which was defined as either (a) two consecutive plasma HIV-1 RNA levels >400 copies/mL or (b) a plasma HIV-1 RNA level >1,000 copies/mL plus any genotypic resistance mutation.
Results
A total of 559 patients were stratified into three groups: (a) Simultaneous Interruption, in which the subjects simultaneously discontinued all the drugs in an NVP-based regimen following an allergic reaction (n=161); (b) Staggered Interruption, in which the subjects discontinued NVP treatment while continuing nucleoside reverse transcriptase inhibitor (NRTI) backbone therapy for a median of 7 days (n=82); and (c) Control, in which the subjects were naïve to antiretroviral therapy (n=316). The overall median follow-up time was 43 months. Incidence of virological failure in Simultaneous Interruption was 12.9 cases per 1,000 person-years, which trended toward being higher than the incidences in Staggered Interruption (5.4) and Control (6.6). However, differences were not statistically significant.
Conclusions
Among the patients who had an acute allergic reaction to first-line NVP-based therapy and later began an EFV-based regimen, virological outcomes resulting from a staggered interruption of treatment (with a continuation of NRTI backbone therapy for 7 days after discontinuing NVP) did not differ from those of the patients who began an EFV-based regimen as their initial therapy (Control). However, the virological failure of Simultaneous Interruption was possibly higher than those of Control and Staggered Interruption.
doi:10.1186/1742-6405-10-4
PMCID: PMC3576311  PMID: 23347647
Nevirapine hypersensitivity or allergy; Efavirenz; Simultaneous interruption; Staggered interruption; Thai
25.  Effect Modification by Sex and Baseline CD4+ Cell Count Among Adults Receiving Combination Antiretroviral Therapy in Botswana: Results from a Clinical Trial 
Abstract
The Tshepo study was the first clinical trial to evaluate outcomes of adults receiving nevirapine (NVP)-based versus efavirenz (EFV)-based combination antiretroviral therapy (cART) in Botswana. This was a 3 year study (n=650) comparing the efficacy and tolerability of various first-line cART regimens, stratified by baseline CD4+: <200 (low) vs. 201-350 (high). Using targeted maximum likelihood estimation (TMLE), we retrospectively evaluated the causal effect of assigned NNRTI on time to virologic failure or death [intent-to-treat (ITT)] and time to minimum of virologic failure, death, or treatment modifying toxicity [time to loss of virological response (TLOVR)] by sex and baseline CD4+. Sex did significantly modify the effect of EFV versus NVP for both the ITT and TLOVR outcomes with risk differences in the probability of survival of males versus the females of approximately 6% (p=0.015) and 12% (p=0.001), respectively. Baseline CD4+ also modified the effect of EFV versus NVP for the TLOVR outcome, with a mean difference in survival probability of approximately 12% (p=0.023) in the high versus low CD4+ cell count group. TMLE appears to be an efficient technique that allows for the clinically meaningful delineation and interpretation of the causal effect of NNRTI treatment and effect modification by sex and baseline CD4+ cell count strata in this study. EFV-treated women and NVP-treated men had more favorable cART outcomes. In addition, adults initiating EFV-based cART at higher baseline CD4+ cell count values had more favorable outcomes compared to those initiating NVP-based cART.
doi:10.1089/aid.2011.0349
PMCID: PMC3423643  PMID: 22309114

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