Low-level drug resistance is not detected by routine consensus sequence genotype analysis (CSA) but low levels of specific mutations, such as the non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutation K103N, can be quantitated by allele-specific PCR (ASP). This study has applied an ASP to quantitate low-level K103N in patients presenting for clinical HIV genotyping and assess the correlation with antiretroviral treatment history and outcomes. HIV RNA was extracted from patient plasma and subjected to PCR amplification of the reverse transcriptase (RT) region followed by genotyping by CSA and real-time ASP for K103N. When applied to samples from patients presenting for genotyping, the ASP detects K103N, not K103 nor K103R, but cross-reacts with K103S. ASP identified all samples that were K103N by CSA (10.5%) and an additional 14% by ASP only, representing patients who were therapy naïve and with NNRTI treatment history. ASP detected therapy-acquired K103N at low levels up to 6 years after cessation of NNRTI therapy. In three patients with new HIV diagnosis and K103N detected by ASP only, K103N virus declined rapidly from the circulation but persisted in PBMC DNA at >12 months post-diagnosis. Efavirenz (EFV) combination therapy in three patients with low-level K103N suppressed successfully viral load, although one patient developed failure and CSA-detectable K103N after 15 months of therapy. Thus, analysis of K103N by ASP in conjunction with CSA genotyping provides additional information that reflects K103N transmission and persistence but detection of low-level K103N does not preclude successful EFV-containing combination therapy.
At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/μl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ± 189 vs. 259 ± 191 cells/μl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014).
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To compare the response to protease inhibitor (PI) and efavirenz-containing combination therapy among treatment-naive HIV-infected persons.
Fluconazole is a triazole antifungal used to treat mycotic infections. Fluconazole is reported to act as a teratogen when used continuously at a dosage of 400-800 mg daily. Fluconazole embryopathy was previously reported in 4 cases. The common features that were also seen in the current case include multiple synostosis (including craniosynostosis and digital synostosis), congenital heart defects, skeletal anomalies, and recognizable dysmorphic facial features.
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Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed.
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Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.
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The use of the first generation non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) as a component of first-line antiretroviral therapy has been accepted worldwide. EFV is the only antiretroviral agent currently on the market that has been combined with emtricitabine and tenofovir disoproxil fumarate in a single tablet and administered once daily.
212 patients (77.4% males) of mean age 45.8 years were enrolled; 202 completed the study. One month post switch to FDR the adherence rate increased significantly to 96.1% from a baseline value of 93.8% (P < 0.01). The increase was steadily maintained throughout the study (96.2% at 6 months). QoL improved over time from 68.8% to 72.7% (P = 0.042) as well, and was significantly associated with the perception of health status, presence of adverse events (AEs) and number of reported AEs (P < 0.0001). QoL significantly influenced adherence (P < 0.0001). During FDR use the mean CD4 count increased from 556 to 605 cells/muL (P < 0.0001). At the end of follow-up 98% of patients maintained HIV-RNA level < 50 copies/mL and 100% <400 copies/mL. Four patients stopped therapy because they were lost to follow-up and 6 because of AEs (insomnia/nervousness 4, allergy 1, difficulties swallowing pills 1).
Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.
Dupont Pharmaceutical studies have demonstrated the efficacy of efavirenz with AZT and 3TC in treatment-naive patients. When compared to a protease inhibitor regimen, 95 percent of the patients taking the efavirenz combination achieved a viral load of less than 400 copies/ml at 24 weeks. Abacavir is also attracting attention due to its potency and dosing convenience. Abacavir has contributed to lower viral loads in treatment naive patients when combined with ZDV and 3TC. Both efavirenz and abacavir should be available in the Fall.
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Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0-128·0] in patients with TAMS vs 95·0 cells per μL [37·0-177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13-1·47; p<0·0001) INTERPRETATION: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains.
Only one trial has shown beneficial effects and safety of TDF+ FTC + EFV as first-line treatment for patients with HIV. The effects and safety of TDF + FTC + EFV as first-line treatment for patients with HIV cannot be assessed on the basis of only one trial. Further studies evaluating the effects and safety of TDF + FTC + EFV as first-line treatment for patients with HIV are needed.
These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs.
We explored the mean differences in routinely measured lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) according to exposure to different combination antiretroviral regimens in Asian (n = 2051) and Australian (predominantly Caucasian, n = 794) cohorts. The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs) and either of at least one protease inhibitor (PI) or non-nucleoside-reverse transcriptases (NNRTIs). We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both); and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol (P for interaction between regimen and cohort: <0.001) but not in case of other lipids (P for interaction: >0.05). The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations.
TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 x 10 cells/l and viral load > 100,000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence.
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/mm(3), 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.
We present the first case report in the UK of acute liver failure caused by efavirenz therapy culminating in liver transplantation. A 26-year-old Zimbabwean woman commenced emtricitabine, tenofovir and efavirenz (Atripla) in December 2011. Her liver function tests at baseline and at 20 days after initiating antiretroviral therapy were normal. At three months of therapy her blood tests haemolysed and were not processed. She had previously missed follow-up appointments and on this occasion failed to return for repeat tests. She was not seen again until after six months of antiretroviral therapy when she presented to her general practitioner with acute liver failure. Her condition deteriorated and she required liver transplantation. She recovered well and re-started antiretroviral therapy to good effect. The case illustrates the value of routine monitoring after initiating antiretroviral therapy and the fundamental importance of engaging patients in long-term management to ensure safe treatment.
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The neurologic events related to antiretroviral therapy (ART) in HIV-infected ART-naive patients are relatively common. Side effects of ART and complications of HIV infection may overlap significantly. Establishing etiology of neurologic (neuropathy and neuropathic pain, changes in cognition, dementia, and myelopathy) and psychiatric (neurocognitive disorders, depression, anxiety, substance abuse and dependence, and others) complications can present a significant challenge. It has long been documented that neurologic and psychological side effects can occur with many of the agents used to treat HIV infection. Particularly, efavirenz from the non-nucleoside reverse transcriptase inhibitor (NNRTI) has been associated with neurologic and psychological complaints that may be difficult to differentiate from pre-existing mental illness, substance abuse, and HIV-related neuropsychiatric symptoms. Peripheral neuropathy (PN) of at least 6 different types is a well-known adverse effect of treatment with nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-infected patients. Lack of dealing with early stages of neurologic and psychological side effects of HIV infection and Highly Active Anti-retroviral Therapy (HAART) are observed in daily practice. The purpose of this article is to identify the neurologic, neuropsychiatric and psychiatric complications related to HIV and anti-retroviral therapy, to discuss current knowledge about these disorders, and to suggest strategies for their diagnosis and management.
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When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.
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We identified treatment-naive human immunodeficiency virus (HIV-1)-infected individuals who had commenced HAART since 1996 and who had a starting CD4 count of <200 cells/mm(3). Immunological success was defined as achieving a CD4 count of >200 cells/mm(3) and treatments were compared using univariate and multivariate Cox's proportional hazards models in order to establish whether protease inhibitor (PI)-based regimens were significantly different to regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs). Both regimens utilize a nucleoside analogue (NA) backbone.
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The objective of this study was to determine the incidence and prevalence of chronic alanine ALT elevation among patients infected with HIV who are negative for hepatitis B or C infection.
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Over 144 weeks, this 600 patient, multicentre randomized, placebo-controlled, double-blind trial compared stavudine (301 patients) and TDF (299 patients), both administered in combination with lamivudine and efavirenz, in antiretroviral-naive patients. TDF or placebo and stavudine or placebo were administered in an open-label fashion. All medications were taken orally. At screening, all patients had serum creatinines <1.5 mg/dl, calculated creatinine clearances > or =60 ml/min and a serum phosphorus > or =2.2 mg/dl.
The studies reviewed demonstrate that dose reduction of antiretroviral therapy provides adequate plasma concentrations and effective immunological and virological responses in, mainly, a Thai population compared with whites. The differences in these pharmacokinetic parameters could possibly be due to differences in body weight and composition, drug-food interactions, metabolism, environmental factors and genetic background. Moreover, dose reduction can possibly decrease toxicity and save costs for patients in low- and middle-income countries.