Pneumococcal infection is common in children with HIV infection, but osteomyelits is unusual. The best treatment for bone and joint infection due to antibiotic resistant pneumococci is not known, especially in immunocompromised children.Streptococcus pneumoniae 9S resistant to penicillin, with reduced susceptibility to ceftriaxone.A 6 month old girl, infected with HIV by mother to child transmission, had recently started combination antiretroviral therapy (cART). She presented with osteomyelitis of the left radius confirmed on bone scan. Blood cultures grew 6/l).Osteomyelitis was treated with parenteral teicoplanin, oral rifampicin and azithromycin. After two weeks of treatment she developed rash and fever. These were thought to be a drug eruption and resolved when teicoplanin was stopped. She completed a 3 month course of rifampicin and azithromycin and continued on cART. She has normal function of her left wrist 18 months after treatment. She remains on her original cART regimen with an undetectable viral load and normal CD4 count (34%; 1398 × 10The combination of rifampicin and azithromycin was well tolerated, simple to administer and effective. This combination deserves further study in bone and joint infection caused by antibiotic resistant Gram positive bacteria. Streptococcus pneumoniae is the commonest pathogen causing bacteraemia in children infected with the human immunodeficiency virus (HIV). However osteomyelitis is reported infrequently, and osteomyelitis due to penicillin-resistant S. pneumoniae has not been reported previously in this patient group [nt group .We report successful treatment of penicillin and cephalosporin non-susceptible pneumococcal osteomyelitis in a child with HIV, using rifampicin and azithromycin.A 6 month old HIV positive black African girl presented with a two week history of intermittent fever. Her mother had been found to be HIV positive when 30 weeks pregnant. Mother was given combivir and nevirapine and her viral load fell from 20,000 copies/ml to 290 copies/ml at delivery. The infant was given zidovudine for 4 weeks after delivery. However pro-viral DNA for HIV was positive at birth in the infant, implying antenatal infection with HIV. The infant remained well, thrived and had a CD4 count above 35%. She was therefore not started immediately on antiretroviral therapy, but was given prophylactic co-trimoxazole.Streptococcus pneumoniae with reduced sensitivity to penicillin, resistant to trimethoprim but sensitive to cephalosporins and macrolides. She was given intravenous cefotaxime for 3 days then oral erythromycin for 2 weeks.On presenting with fever aged six months there were no physical signs of note. Blood cultures were taken which grew 6/l}).On review one month later she had been intermittently febrile since stopping antibiotics. Repeat blood cultures showed no growth, but she was given 14 days of parenteral ceftriaxone empirically. Following this she was commenced on combination antiretroviral therapy , because of these symptoms and falling CD4 count (17%{221 × 10Streptococcus pneumoniae 9S resistant to penicillin (MIC >2 mg/l) and trimethoprim, with reduced sensitivity to cephalosporins (MIC 1–2 mg/l), but sensitive to vancomycin, rifampicin and macrolides.She re- presented aged 8 months (one month after starting cART) with a swollen left wrist, fever and raised C-reactive protein (86 mg/l). A radio-isotope bone scan was compatible with osteomyelitis of the left radius. Blood cultures grew Aspiration of bone was not done since blood cultures were positive. She was given parenteral teicoplanin (10 mg/kg once daily) with oral rifampicin (10 mg/kg twice daily) and azithromycin (10 mg/kg once daily). After 2 weeks of treatment she developed rash and fever. These were thought to be a drug eruption and resolved when teicoplanin was stopped. She completed a 3 month course of rifampicin and azithromycin and continued on cART. Subsequent blood cultures were negative.6/l).Eighteen months after treatment her left wrist is normal, she remains on her original cART regimen with an undetectable viral load and CD4 count of 34% (1398 × 10S pneumoniae causes 3–6% of bone and joint infections in children with normal immunity [immunity ,3. Penicimmunity .The combination of rifampicin and azithromycin was effective in treating osteomyelitis caused by a penicillin and cephalosporin non-susceptible pneumococcus in a child with HIV. Rifampicin and azithromycin have different sites of action in bacteria. This combination has been shown to be effective in animal models of staphylococcal osteomyelitis . There iBoth azithromycin and rifampicin achieve high levels in bone. However azithromycin monotherapy is ineffective for the treatment of experimental staphylococcal osteomyelitis,  whilst rS pneumoniae, making macrolides in general less useful for treating osteomyelitis. However in this case the isolate was macrolide sensitive, despite penicillin and cephalosporin resistance.In the UK macrolide resistance is more common in penicillin non-susceptible Rifampicin can also interact with anti-retroviral drugs, especially protease inhibitors and nevirapine. Current advice is that low dose ritonavir/protease inhibitors combinations or nevirapine should not be given with rifampicin . In our Other antibiotics may have been effective in this case, but also had potential drawbacks. Ceftriaxone may be effective for non-ceftriaxone susceptible pneumococcal infection outside the central nervous system, as long as the MIC is < 2.0 mg/l . HoweverPreventive strategies against pneumococcal disease may have been useful in this child. Prophylactic co-trimoxazole gives some protection against bacterial infection in HIV positive children, but the organism in this case was trimethoprim resistant. Conjugate pneumococcal vaccine provides some protection, even in HIV positive children . A 7 valThe combination of rifampicin and azithromycin was well tolerated, simple to administer and effective in treating penicillin and cephalosporin insensitive pneumococcal osteomyelitis. This combination deserves further study for treatment of bone and joint infections, especially those due to antibiotic resistant Gram positive bacteria.Written informed consent was obtained from the patient's mother for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interestsAR helped to draft and revised the manuscript. SA drafted the manuscript, CG revised the manuscript. All authors read and approved the final manuscript.


Acute Human Immunodeficiency Virus infection is associated with a range of neurological conditions. Guillain-Barré syndrome is a rare presentation; acute inflammatory demyelinating polyneuropathy is the commonest form of Guillain-Barré syndrome. Acute inflammatory demyelinating polyneuropathy has occasionally been reported in acute Immunodeficiency Virus infection but little data exists on frequency, management and outcome.We describe an episode of Guillain-Barré syndrome presenting as acute inflammatory demyelinating polyneuropathy in a 30-year-old man testing positive for Immunodeficiency Virus, probably during acute seroconversion. Clinical suspicion was confirmed by cerebrospinal fluid analysis and nerve conduction studies. Rapid clinical deterioration prompted intravenous immunoglobulin therapy and early commencement of highly active anti-retroviral therapy. All symptoms resolved within nine weeks.Unusual neurological presentations in previously fit patients are an appropriate indication for Immunodeficiency-Virus testing. Highly active anti-retroviral therapy with adequate penetration of the central nervous system should be considered as an early intervention, alongside conventional therapies such as intravenous immunoglobulin. Human Immunodeficiency Virus (HIV) infection is neurotropic and a wide array of neurological presentations has been described. Alongside common presentations of meningitis, encephalitis and peripheral neuropathies, Guillain-Barré syndrome (GBS) has rarely been reported. Fewer reports exist of the acute inflammatory demyelinating polyneuropathy (AIDP) variant of GBS presenting as an acute HIV seroconversion. Little data exists on patient outcomes or treatment options in HIV-GBS, including intravenous immunoglobulin (IVIg) and highly active anti-retroviral therapy (HAART). We discuss the clinical presentation, outcome and management including the current evidence base.In 2007 a previously well 30-year-old homosexual man presented with a 5 day history of progressive bilateral ascending lower limb weakness, preceded by a flu-like illness lasting for 2 weeks. Examination revealed normal tone but slightly reduced power at Medical Research Council (MRC) grading 4/5 . Sensati3 (95% lymphocytes), a protein level of 0.72 g/l  and a glucose level of 2.3 mmol/l (blood glucose was 5.2 mmol/l). CSF culture and polymerase chain reaction analyses for herpes simplex virus, herpes zoster virus, enterovirus, Epstein Barr Virus and cytomegalovirus (CMV) were negative. The suspected diagnosis was AIDP, part of the heterogeneous GBS grouping.Cerebrospinal fluid (CSF) examination showed 26 leucocytes/mm1 was reduced at 2.7 l (59% of predicted) and oxygen therapy was commenced. Transfer to the Intensive Therapy Unit was planned if the FEV1 fell below 1.5 l. After neurological advice, a 5 day course of daily intravenous immunoglobulin therapy (IVIg) (0.4 g/kg/day) was commenced. Over the next 3 days his condition deteriorated and by day 4 of IVIg therapy, he had lost all lower limb power and was developing sensory abnormalities, upper limb weakness, difficulty swallowing and blunting of speech.He received supportive management and twice daily spirometry was undertaken. Although not dyspnoeic, his FEVHe had been successfully treated for syphilis in 2005. HIV antibody testing at that time was negative but, in view of his established risk factors and new symptoms, a repeat test was now undertaken and was positive. Screening for other blood-borne viruses, opportunistic infections and magnetic resonance imaging of brain and spine were negative.3. He was commenced on highly active antiretroviral therapy (HAART) with zidovudine, lamivudine and efavirenz. Less than 12 hours later his symptoms plateaued and a gradual recovery began.On day 5 of IVIg his speech was barely intelligible and left sided facial nerve palsy developed Figure . BilaterSensory nerve conduction studies were normal. EMG motor studies revealed active denervation in distal lower limb muscles.3. He remains asymptomatic 7 months after withdrawal of HAART.Over the next 9 weeks, he received intensive complex neuro-rehabilitation and at discharge no neurological deficits were present, but he continued to experience mild lower limb neuropathic pain. HAART stopped at 6 months with a CD4 count of 901 cells/mmHIV infection is associated with a range of peripheral neuropathies; distal sensory polyneuropathy, mononeuritis multiplex, polyradiculopathy, demyelination and drug toxicities . A speciGuillain-Barré syndrome has also been described in advanced HIV. CMV polyradiculopathy can be clinically indistinguishable at CD4 counts <50 cells/mm , leadingSeveral pathological variants of GBS are recognised. AIDP represents 75% of cases and classically presents with ascending symmetrical paresis or paraesthesia, loss of deep tendon reflexes and autonomic dysfunction. Other subtypes include a purely motor variant called Acute Motor Axonal Neuropathy (AMAN), and Fisher's syndrome, characterised by acute ophthalmoplegia, ataxia and areflexia, often in association with lower cranial nerve palsies. Overlap syndromes combining the above features occur . Our patDiagnosis is based on clinical features, neurophysiological testing and lumbar puncture. The CSF protein level is raised in 80% of cases. CSF white cells are typically absent in HIV-negative patients but, as in our case, cells are regularly seen in HIV-GBS . This diThe pathogenesis of HIV-GBS is incompletely understood. Possible mechanisms include direct HIV neurotoxicity or autoimmunity. Several features favour an immune mechanism. Typical neural histology supports an antibody-mediated process and high titres of autoantibodies to myelin sheath glycosphingolipids are found in the serum of affected patients . The preIn the initial stages, neurological weakness is rapidly progressive, involving respiratory muscles in 25% of cases. These patients may require mechanical ventilation. After a disease nadir, usually 2–4 weeks after onset of symptoms and a variable plateau phase, recovery occurs over a period of weeks to months. Mortality varies between four and 15%, and 20% remain disabled at one year despite treatment. Outcomes in HIV-positive patients are equivalent to those of HIV-negative patients. Early treatment with plasmapheresis or IVIg therapy have equal efficacy in reducing the proportion of patients requiring ventilation during the first four weeks [Since 1996, HAART has revolutionised the treatment of HIV. Given the proposed role of autoimmunity in HIV-GBS, it seems likely that antiretroviral drugs will alter the course of neurological illness. Individual case reports of patients on pre-established HAART describe GBS as a drug side effect  but ther3) and made a good recovery with long term HAART. Two others, like our case, began therapy at higher CD4 counts and improved. Our patient's apparent treatment response was unusually rapid, raising the possibility that HAART initiation was coincidental with onset of natural recovery but when viewed alongside the other cases it does seem that early introduction of antiretroviral treatment is beneficial, particularly if symptoms are severe and progressive.Three antiretroviral-naïve HIV-GBS patients presented with low CD4 counts (<200 cells/mmBoth previous cases of HIV-GBS at high CD4 counts encountered transient neurological relapses when HAART was stopped. Recurrent GBS or Chronic Inflammatory Demyelinating Polyneuropathy affects 3% of HIV negative patients [Finally, the choice of antiretroviral drug combination requires consideration. Eight drugs from three different antiretroviral classes were used in the five previous cases. The best combination is unclear. As HIV is a neurotropic virus and the nervous system is a sanctuary site for infection, drugs which effectively cross the blood-brain barrier are most appropriate. The nucleoside reverse transcriptase inhibitors zidovudine, lamivudine and abacavir, and non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine penetrate the central nervous system well but protease inhibitors are less reliable. This explains our choice of zidovudine, lamivudine and efavirenz. Nevirapine was avoided as the risk of adverse events with this drug increases at higher CD4 counts.The AIDP variant of GBS is a rare presentation of acute HIV seroconversion, with significant mortality and morbidity. Early neurological diagnosis and consideration of HIV testing are important to improve outcome. Although data are sparse, it appears reasonable to consider early commencement of HAART using drugs with good CNS penetration, particularly if there is continued deterioration on conventional therapy. This case adds to the limited literature on this topic and highlights the need for further study.1: Forced expiratory volume in one second; EMG: Electromyography; AMAN: Acute motor axonal neuropathyHIV: Human immunodeficiency virus; GBS: Guillain-Barré syndrome; AIDP: Acute inflammatory demyelinating polyneuropathy; IVIg: Intravenous immunoglobulin; HAART: Highly active antiretroviral therapy; CNS: central nervous system; CSF: cerebrospinal fluid; MRC: Medical Research Council; CMV: cytomegalovirus; FEVWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.DS and MBJB conceived of and drafted the case presentation. DS reviewed the literature and wrote the discussion and conclusions. AN provided specialist neurological input. AROM and NJB were the consultants responsible for the patient's care and provided general support. All authors read and approved the final manuscript.


Different strategies of ritonavir-boosted lopinavir monotherapy have been explored; however, data regarding salvage therapy among HIV-infected patients who failed nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) is still limited.A prospective study was conducted among HIV-infected patients who failed NNRTI-based antiretroviral therapy with M184V, TAMs, and NNRTI mutations, and were naïve to protease inhibitor. LPV/r at 400/100 mg and lamivudine 150 mg were given twice daily. CD4 and HIV-1 RNA were monitored at week 0, 12, 24, and 48. LPV Cmin was assayed for the first 14 patients using HPLC.3 and median (IQR) HIV-1 RNA was 55,800  copies/mL. By intend-to-treat analysis, 30 (75%) and 24 (60%) patients achieved HIV-1 RNA at <400 and <50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 29 (83%) and 23 (67%), respectively. Low-level viral rebound was found in 6 (15%) patients at week 48. Medians CD4 at week 12, 24, 36 and 48 were 249, 283, 307, and 351 cells/mm3 and significantly changed from baseline . At 6 and 12 weeks, median (min-max) LPV Cmin was 6.52 (1.62-11.64) mg/L and 5.79 (0.75-16.31) mg/L, respectively. There were increments of mean total cholesterol and triglyceride at 48 weeks from baseline (P < 0.05).There were 40 patients with a mean age of 37 years and 70% were male. Median (IQR) baseline CD4 was 123 (37-245) cells/mmLPV/r monotherapy with recycled lamivudine can maintain virological suppression in a substantial proportion of patients failing NNRTI-based regimen and provides adequate plasma concentrations of LPV although the incidence of low-level viremia is relatively high. Currently, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) is widely prescribed as an initial therapy for treatment naïve HIV-infected patients, particularly in many resource-constrained countries . HoweverAmong several previous reports using ritonavir-boosted protease inhibitor, ritonavir-boosted lopinavir monotherapy has been extensively studied so far . DiffereAll patients followed at Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Thailand, between April 2007 and February 2008 were evaluated for antiretroviral therapy failure based on guidelines for antiretroviral therapy of the Thai AIDS Society, which define failure as viral load >1,000 copies/mL after 6 months of receiving treatment or a rebound of viral load to >1,000 copies/mL in any duration after undetectable viral load .P values < 0.05 were considered to be statistically significant. The institutional ethics committees of Bamrasnaradura Infectious Diseases Institute and Ministry of Public Health approved the study. All patients signed the inform consent.All analyses were performed using SPSS, version 14.0. Mean values (± standard deviations) or median values  and frequency were used to describe the patients' characteristics for continuous and categorical data, respectively. The proportion of patients with plasma HIV-1 RNA <50 copies/mL after 48 weeks of ART were analyzed as intend-to-treat and as-treated. Paired t-test was used to compare parameters between time points. Table P values < 0.05). At 6 and 12 weeks of treatment, median (min-max) lopinavir minimum concentrations were 6.52 (1.62-11.64) mg/L and 5.79 (0.75-16.31) mg/L, respectively. All but one patient achieved lopinavir minimum concentrations greater than the recommended minimum concentration that was 1 mg/L. With regard to adverse reactions, 1 patient discontinued ritonavir-boosted lopinavir due to diarrhea after the first 2 weeks of ritonavir-boosted lopinavir treatment. Compared measures at week 48 to baseline values, there were increments of mean total cholesterol  and mean triglyceride . Eight patients and 24 patients had total cholesterol to HDL ratio ≥6.5 and ≥4 at week 48, respectively. Three patients needed to initiate anti-lipid agents during the follow-up period. There was an increment of fasting blood sugar from week 48 to baseline value . Two patients were receiving oral hypoglycemic agents at enrollment and another two patients had started oral hypoglycemic agents during the follow-up period.The proportion of patients who had different stratum of plasma HIV-1 RNA at weeks 48 of treatment by intend-to-treat analysis was displayed in figure As NNRTI-based HAART regimen is extensively prescribed in many resource-limited countries and due to delayed detection of virological failure from lacking the effective monitoring tools and/or inadequate infrastructure in the real-life practice, extensive NRTI and NNRTI-associated mutations could be problematic in those area. To the best of our knowledge, this is the first clinical trial that has shown clinical outcome and pharmacokinetic measures of ritonavir-boosted lopinavir together for the patients experienced with NRTIs and NNRTIs although it was conducted in a small study. Our data indicate that ritonavir-boosted lopinavir monotherapy combined with recycled lamivudine can maintain virological suppression in a substantial proportion of patients who were failing NNRTI-based regimens with M184V, TAMs and NNRTI mutations but were naïve to protease inhibitor. Using intend-to-treat analysis, 60% of patients reached the virological success, i.e., plasma HIV-1 RNA <50 copies/mL, after 48 weeks of treatment. This result is relatively consistent with a recent report that involved antiretroviral-naïve patients by Delfraissy and colleagues . Of 84 pInterestingly, 15% of our patients had low level viremia. This number is considered to be a significant proportion. Of this proportion, 5% achieved undetectable plasma HIV-1 RNA and 10% still had low level viremia at 72 weeks (data not shown). One possible explanation is the lack of viral suppression in some compartments, such as genital secretion and cerebrospinal fluid ,17. TherRegarding adverse reactions, the most commonly reported side effect associated with lopinavir/ritonavir is mild to moderate diarrhea ,19. In aIn treatment-experienced patients failing NNRTI-based regimens with limited NRTI options, switching to at least 2 fully active drugs to an optimized antiretroviral regimen is principally the best strategy so far. In patients with earlier first-line treatment failure and have developed either only M184V or with few TAMs, the option of NRTI backbone is still not limited. In these cases, there is a possibility to include 1 or 2 active NRTI drugs in combination with a new drug class, such as PIs, to assure the effectiveness of the regimen. Thus in settings where other new ARV classes beside PIs cannot be assessable, early detect virological failure is crucial to preserve the NRTI backbone. While waiting for a randomized control trial to prove HIV monotherapy with ritonavir-boosted protease inhibitor in these particular patients, the present data provide support to physicians currently facing choices of salvage regimen options in many resource-constrained countries. Ritonavir-boosted lopinavir combined with recycled lamivudine to decrease viral fitness can maintain virological suppression in a substantial proportion of patients failing NRTI and NNRTI with M184V and provides adequate plasma concentrations of lopinavir although incidence of low-level viremia is relatively high. A further larger study would be required to assess the risk and benefit of this proposed strategic treatment in the resource-constrained settings.The authors declare that they have no competing interests.WM participated in the design of the study, statistical analysis and draft the manuscript. SK, WA, WP, ST, KR and SS participated in the design of the study and draft the manuscript. SN participated in the design of the study. All authors read and approved the final manuscript.This study was supported by research grants from Bamrasnaradura Infectious Diseases Institute, Thailand.


International HIV guidelines have recently shifted from a medium-late to an early-start treatment strategy. As a consequence, more people will be eligible to Highly Active Antiretroviral Therapy (HAART). We estimate mean life years gained using different treatment indications in low income countries.We carried out a systematic search to identify relevant studies on the treatment effect of HAART. Outcome from identified observational studies were combined in a pooled-analyses and we apply these data in a Markov life cycle model based on a hypothetical Tanzanian HIV population. Survival for three different HIV populations with and without any treatment is estimated. The number of patients included in our pooled-analysis is 35 047.Providing HAART early when CD4 is 200-350 cells/μl is likely to be the best outcome strategy with an expected net benefit of 14.5 life years per patient. The model predicts diminishing treatment benefits for patients starting treatment when CD4 counts are lower. Patients starting treatment at CD4 50-199 and <50 cells/μl have expected net health benefits of 7.6 and 7.3 life years. Without treatment, HIV patients with CD4 counts 200-350; 50-199 and < 50 cells/μl can expect to live 4.8; 2.0 and 0.7 life years respectively.This study demonstrates that HIV patients live longer with early start strategies in low income countries. Since low income countries have many constraints to full coverage of HAART, this study provides input to a more transparent debate regarding where to draw explicit eligibility criteria during further scale up of HAART. The optimal time to start treatment for HIV/AIDS has been a contentious issue since the introduction of Highly Active Antiretroviral Treatment (HAART). Initially a "hit hard and early" strategy was promoted . BecauseThe debate regarding optimal timing of treatment start has tremendous implications for HAART demand, and subsequently, on the estimated treatment coverage in different settings. Towards the end of 2008, only 3 million people out of 33 million with HIV were given HAART -15. In cLife years gained by different CD4 starting points is necessary information for making informed choices about early or late start of treatment. Studies in low income countries have found that patients starting HAART early (CD4 <350 cells/μl) have life expectancies from 9.4 to 17.2 life years and that life expectancies are 6.8 - 14.9 with late treatment strategies (CD4 < 200 cells/μl) . Only onOur overall aim is to inform the ethical dilemma of choosing between providing HIV treatment to patients with potential best outcomes and giving fair chances to the more severely ill patients with less potential benefit. The objective of this study is therefore to estimate the life years gained with early and late treatment strategies in low income countries. In the absence of randomized clinical trials, we model life years gained by using best available evidence from observational studies.We did a structured literature review and combined findings in a pooled-analysis to find the best evidence underlying the different treatment strategies. Based on these findings, a Markov life cycle model was constructed to estimate the expected remaining life years with and without HAART stratified in three baseline CD4 strata at the time patients first present for care: CD4 <50 cells/μl or 50-199 cells/μl or 200-350 cells/μl. The model can be applied on any population, and we test it on a Tanzanian HIV population since information on HIV prevalence and life tables were easily available ,25. We eThe set of mutually exclusive health states in the model and the various events that can occur in the history of HIV are illustrated in Figure We assume that patients presenting for care have a mean age of 35 years because this agreed with the characteristics of the underlying HIV demographics in the region and mean age of the studies included in the pooled-analysis tables  and 2. WTo identify evidence used as input in our analysis we carried out searches in the Cochrane Database of Systematic Reviews (inception to first quarter 2009), Ovid Medline (1996 to March 2009), EMBASE (inception to March 2008), ISI Web of Science (1992 to March 2008), conference abstracts from the International AIDS Society (2006 to 2008), the Conference on Retroviruses and Opportunistic Infections (inception to 2009) and the HIV Implementers' Meetings (2006-2008). References from relevant papers were also "hand" searched.Search terms were; "HIV, Africa, low income countries, mortality & survival". Only English language papers were reviewed. Eligible studies were identified by the first author and their relevance confirmed by the other authors. Inclusion criteria for the structured review are: low income countries, randomised controlled trial or observational studies with minimum one year observational period, effect measures that could be converted to one year absolute risk of death, death risks stratified into baseline CD4 strata <50 or 50-199 or 200-350 cells/μl, information on number of participants in the various CD4 strata and participants older than 15 years of age.We found no published randomised controlled trials evaluating the effect of different starting points versus placebo in low income countries. It is considered unethical to conduct such trials today. Analysis must therefore draw on the best available evidence from observational studies. We found no controlled observational studies, that is, studies comparing survival between an intervention and a control group. Effect size in terms of life expectancy can therefore only be evaluated through modelling. We identified six observational studies showing survival before initiation of HAART in low-income settings with accurate information on stratified survival according to baseline CD4 count table ; two frow) and confidence intervals (CI) as follows:The principal outcome measure in the pooled-analysis tables  and 2 isw is the weighted probabilities, ni denote number of individuals in i-th study, and pi represent the probability of death in the i-th study.Where pWe combine mortality rates with a weighted mean rather than a narrative syntheses or simple mean because larger sample size (n) increases the chance the sample is representative and leads to increased precision in estimates. Hence, more weight should be given to large sample size. Weighted probabilities were used as transition probabilities in the Markov model. The effect size measure between studies in the Markov model was net life years gained and total remaining life years.For patients not receiving HAART we assumed constant annual mortality rates of 0.796, 0.355 and 0.109 for the CD4 health states <50, 50-199 and 200-350, respectively  HIV prevalence in Tanzania is 5.7% and it is estimated that 2.2 million people are living with HIV . To our We calculated expected remaining life years without HAART and net life years gained from HAART by different CD4 starting points figure . From fiResults from the one-way sensitivity analyses are shown in table Our study suggests that providing HAART early is likely to yield most life years if everyone receives treatment. This is in concordance with the recommendations in the revised 2009 WHO guidelines. However, few governments in low income countries are capable of providing optimal treatment to all if everyone with CD4 < 350 cells/μl are considered to be eligible. Given the severe budget constraints low income countries face, a policy where fewer patients are considered to be eligible is the more common practice.In terms of stratified net life years gained from HAART, we believe our study to be unique. From international published databases, we were unable to identify any studies which describe stratified net life years gained from HAART with various starting points. Five studies reported life expectancy for HIV patients when starting treatment at CD4 < 200 cells/μl and results ranged from 6.8 life years to 14.9 life years, which is comparable to our total survival (without treatment + HAART) of 9.6 life years in figure The Tanzanian ART guideline from 2005, which is still being used in 2009, recommends treating asymptomatic patients when the CD4 count drops below 200 cells/μl . AsymptoA major strength of our analysis is its' simplicity and use of evidence-based transition probabilities. The disadvantage of this approach is that we were not able to model the dynamic changes in CD4 counts for patients on HAART, which has been done in several recent studies ,19-21. TA second strength is that the analysis includes the death risk from observational studies with more than one year observational period. This enabled us to include variations in death risks during the first two years and to reduce the effect of the high mortality peak often observed during the first 6-12 months after patients have started HAART.Death risk from year two and onwards for patients with CD4 <50 on HAART table  is low aFinally, we applied age-related background mortality in order to provide a more precise estimate of the long term effects of HAART. However, it is uncertain at what extent the pooled HIV-related mortality rates incorporate a long term epidemiological shift for HIV patients.This study demonstrates that HIV patients live longer with early start of antiretroviral treatment in low income countries, and highlights the ethical dilemma of choosing between providing HIV treatment to patients with potential best outcomes and giving fair chances to all the more severely ill patients with less potential benefit. Since low income countries have many constraints to full coverage of HAART and more people will be eligible with an early start strategy, the results of this study is a good starting point for a more transparent and reasoned debate when drawing explicit eligibility criteria during further scale up of HAART.Kjell Arne Johansson has the right to grant on behalf of all authors and does grant on behalf of all authors.The Corresponding Author This study did not involve patients or sensitive information about patients and did not therefore require ethical approval.The authors declare that they have no competing interests.All authors fulfill the criteria of authorship and contributed collaboratively to conception and design, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content and final approval of the version to be published. We assure that there is no one else who fulfils the criteria of authorship that has not been included as an author.KAJ was principal investigator, designed the study, performed the systematic literature search, developed the Markov model, led the analysis, and was lead author for the paper. BR was a co-investigator and participated in the planning, analysis and writing of the paper. OFN sought funding for the study, contributed to design, planning, analysis and writing of the paper. All authors read and approved the final manuscript.


Successful treatment of HIV-positive patients is fundamental to controlling the progression to AIDS. Causes of treatment failure are either related to drug resistance and/or insufficient drug levels in the blood. Severe side effects, coupled with the intense nature of many regimens, can lead to treatment fatigue and consequently to periodic or permanent non-adherence. Although non-adherence is a recognised problem in HIV treatment, it is still poorly detected in both clinical practice and research and often based on unreliable information such as self-reports, or in a research setting, Medication Events Monitoring System caps or prescription refill rates. To meet the need for having objective information on adherence, we propose a method using viral load and HIV genome sequence data to identify non-adherence amongst patients.With non-adherence operationally defined as a sharp increase in viral load in the absence of mutation, it is hypothesised that periods of non-adherence can be identified retrospectively based on the observed relationship between changes in viral load and mutation.Spikes in the viral load (VL) can be identified from time periods over which VL rises above the undetectable level to a point at which the VL decreases by a threshold amount. The presence of mutations can be established by comparing each sequence to a reference sequence and by comparing sequences in pairs taken sequentially in time, in order to identify changes within the sequences at or around 'treatment change events'. Observed spikes in VL measurements without mutation in the corresponding sequence data then serve as a proxy indicator of non-adherence.It is envisaged that the validation of the hypothesised approach will serve as a first step on the road to clinical practice. The information inferred from clinical data on adherence would be a crucially important feature of treatment prediction tools provided for practitioners to aid daily practice. In addition, distinct characteristics of biological markers routinely used to assess the state of the disease may be identified in the adherent and non-adherent groups. This latter approach would directly help clinicians to differentiate between non-responding and non-adherent patients. Whilst the first cases of AIDS were identified in the USA ,2, and sAt present, HIV is treated with a combination of drugs known as highly active anti-retroviral therapy (HAART) or combined anti-retroviral therapy, which works on the principle of using a combination of different classes of drugs to simultaneously impact a range of viral targets. The extent to which patients adhere to their therapy regime is pivotal to treatment success. Although adherence-nonadherence occurs on a continuum, in the case of HIV treatment exceptionally high levels of adherence (> 95%) to HAART are required to suppress viral replication .Treatment change decisions for patients with AIDS who are undergoing HAART are commonly based on clinical treatment history data, ideally including VL, CD4 and genotype information with adherence assumed, based on practical experience or self-declared. Thus designing successful treatment regimes requires an accurate understanding of factors affecting or affected by patients' adherence.The side effects from HAART drugs affect most patients and can be debilitating. Since HIV causes long-term infection, patients often become fatigued by the constant necessity to take medication and from their severe side effects. Whilst these drugs are highly effective when taken correctly, incorrect use can lead to the development of resistance. Contrastingly, adherence levels which are too low to generate resistance do not decrease or delay the progression to AIDS , but a 1vice versa) has been associated with increased mortality, as these patients are thought to be less able to produce complete responses to treatment [Whilst research has shown that 100% adherence is not necessary for viral suppression, accumulation of drug resistance increases with adherence where patients have incomplete viral suppression . It has reatment .The literature provides a wealth of possible methodologies to improve patient adherence. Whilst work in Africa has improved adherence through the instigation of workplace clinics , work elet al. suggests that adherence behaviour can be influenced by a minimal educational effort prior to the commencement of retroviral therapy [Modelling of patient data suggests that patients who feel confident in their ability to adhere to their treatments are more likely to adhere and maintain undetectable VL levels . This no therapy  althoughet al. [The ability of patients to understand both their disease and its treatment has a major effect on adherence; by supplying information in a (primarily) pictographic rather than written form, researchers were able to demonstrate improved understanding and compliance by patients with literacy issues . Patientet al.  and Straet al. .Given its importance, a plethora of literature focuses on assessment of adherence, typically using medical variables , inventory-type indicators , self-reports (patient diaries) or questionnaires on behavior or psychological assessments of factors assumed to predispose the risks for nonadherence . HoweverAs yet there is no 'gold standard' for adherence measurement in HIV patients and recent research  has suggIt is apparent that the use of plasma drug levels to directly measure drug concentrations would be the most accurate and objective way of measuring adherence , howeveret al. [Short-term changes in VL  have been shown to be associated with short term decreases in adherence, associated with the development of resistance and/or subsequent treatment failure . In prevet al.  recentlyet al. .The importance of having accurate information on adherence is underscored by the fact that in order to achieve successful treatments, physicians must have accurate and reliable information on the effectiveness and efficacy of the prescribed treatment regime. To meet the need for having objective information on adherence, a method is proposed using VL and HIV genome sequence data to observe adherence amongst patients.et al. [et al. [et al. have shown that poor responses to treatments may not be related to the development of drug resistance mutations [Previous work has shown that VL is strongly predicted by patient adherence, whereas drug resistance is a weaker predictor of VL. Bangsberg et al.  have sug [et al.  demonstrutations .Many studies have used current data from patients to establish the relationships between VL and adherence  in VL, which would appear as 'spikes' in the VL time series. The 'spikes' could then be classified into the 'likelihood of adherence/non-adherence' groupings based upon the rate of change of VL and the presence of mutation.10 (VL) of greater than 2 log – In keeping with the clinical practice underlying the EuResist modelling work, this magnitude of change is suggested as it would give a large enough change to avoid inclusion of insignificant fluctuations in VL [The preliminary work relating to testing this hypothesis requires longitudinal data that includes VL and sequence data from patients. VL points should be collated to produce pairs of VL measurements relating to the start and end points of an increase in logns in VL . These pResist prediction engine [The HIV pol sequences should be compared to a reference pol sequence and if possible to a previously collected sequence. For information on HIV genomic sequencing that will be used to test the hypothesis, see the background documents of the Eun engine . In orden engine  and FASTn engine  would fan engine .Once the mutation status has been ascertained, rates of change in VL can be compared to a threshold value in order to decide whether the patient is likely to have been adherent during the period shortly before and during the spike. As an example, Fig 10 (VL) is defined as the increase in log10(VL) divided by the time period over which it occurred. For example, for spike 1 the rate would be (5.2–1.8) divided by (number of days between 1 June 1998 and 1 Oct 1998). It is clear from the graph in Fig The rate of change in logWhilst clearly preliminary work to validate this hypothesis needs to be undertaken, if validated the information gained could be used to corroborate and clarify verbal adherence discussions between patients and care-providers, enabling care-providers to recognise adherence problems more accurately and identify opportunities to provide appropriate (re-) education, assistance or regimen change, to minimise disease progression.If established, this approach will clearly allow for the level of adherence to drug therapy regimes to be monitored. Additionally, such an analysis would facilitate a more accurate assessment of the progression of the patient in terms of their disease status relative to treatment stratagem with a known integrity continuum, resulting in improved treatment and better life expectancy of HIV infected patients.In clinical practice, removed from research studies utilising various methods to detail adherence in patients, clinicians routinely rely on verbal discussions to identify periods of non-adherence. With a clear expectation for adherence, it is plausible that some (or many) patients are unwilling to openly admit non-adherence, leading to inadvertently misleading their treating physicians. The utilisation of VL data, with knowledge of the presence (or lack) of drug resistant mutations, should allow clinicians to form a more accurate picture of the adherence levels of their patients. This will allow treatment change events and clinical management alterations to be made that may prevent or reduce the occurrence of patient non-adherence to the therapeutic regime. It should be noted however, that the levels of accuracy in this type of analysis are likely to be dependent on the time periods between VL measurements, which are typically every six months in patients with HIV. The limitations of this hypothesis as applied to clinical practice include the access to and costs of sequencing.Therefore, it is envisaged that the hypothesised approach will serve as a first step on the road to clinical practice. The information on adherence inferred from clinical data is a crucially important feature of treatment prediction models provided for practitioners to aid daily practice. In addition, distinct characteristics of biological markers routinely used to assess the state of the disease may be identified in the adherent and non-adherent groups. This latter approach would directly help clinicians to differentiate between non-responding and non-adherent patients.The authors declare that they have no competing interests.Resist: the consortium supplied the databases upon which the hypothesis was formulated. All authors have read and approved the final manuscript.All authors have contributed to the hypothesis development, drafting and critically reviewing the manuscript. EuResist is a research consortium funded under the EC's FP6 IST programme .IRT is a PhD student, PB is a Principal Lecturer in Statistics, JDP is a Principal Lecturer in Computing, AP is a Reader in Public Health, MDF is a Reader in Medical Microbiology. Eu


In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART .We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 , 8.3 , and 12.4 , respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8  to 1.5  and 1.4  after adjustment for latest levels of IL-6 and D-dimer, respectively.Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls . Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment , James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers. Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells . The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands  without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections  and cancers  that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers  and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy.3 . Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis.Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART , or ART only when their CD4 cell counts were below 250 cells/mmThe researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial  and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month.Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.http://dx.doi.org/10.1371/journal.pmed.0050203.Please access these Web sites via the online version of this summary at HIV infection and AIDS and about the SMART trialInformation is available from the US National Institute of Allergy and Infectious Diseases on HIV InSite has comprehensive information on all aspects of HIV/AIDSHIV/AIDSInformation is also available from Avert, an international AIDS charity, on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of HealthMore information about the SMART trial is available on  The episodic ART strategy was also associated with an 84% (p = 0.007) increased risk of all-cause mortality. Most of the deaths that occurred were not attributable to AIDS-defining conditions [The Strategies for Management of Anti-Retroviral Therapy (SMART) trial compared episodic use of antiretroviral treatment (ART) guided by CD4+ count with the current practice of continuous ART. Risk of opportunistic disease (OD) or death was more than twice as great for those in the episodic compared to the continuous ART group initiated and continued until the CD4+ count rose above 350 cells/mm3. Upon confirmation that the CD4+ count was over 350 cells/mm3, ART was to be stopped and resumed again when CD4+ count was below 250 cells/mm3. During periods of ART use, the goal was to achieve maximal viral suppression.In SMART, patients were randomized to one of two ART strategies. The viral suppression (VS) strategy aimed to maximally suppress viral replication by continuous use of ART. The drug conservation (DC) strategy entailed intermittent use of ART for periods defined by CD4+ count thresholds. Use of ART was stopped (or deferred) until CD4+ count dropped to less than 250 cells/mmUnderlying cause of death was classified using the CoDe system by an Endpoint Review Committee blinded to treatment group . As prevIn SMART, follow-up study visits occurred at month 1, month 2, then every 2 mo for the first year, and every 4 mo thereafter. Of the 5,472 participants in SMART, 1,415 in the United States were asked to consent prior to randomization to have plasma stored at baseline (study entry) and at every follow-up visit beginning with the 1-mo visit; 1,361 of these participants consented. For the remaining 4,057 participants, consent was requested at the time of randomization for storing blood at either 4- or 12-mo intervals; 3,800 of these participants consented. Plasma specimens were collected using EDTA (lavender top) blood collection tubes and were shipped frozen to a central repository.Only specimens obtained prior to 11 January 2006, were used for the analyses described in this paper. As previously reported, on that date investigators and ART-experienced participants were notified of a safety risk in the DC group, enrollment was stopped, and participants in the DC group were advised to restart ART [Four inflammatory markers, high sensitivity C-reactive protein (hsCRP), IL-6, amyloid A, and amyloid P, and two coagulation markers, D-dimer and prothrombin fragment 1+2 (F1.2), were measured by the Laboratory for Clinical Biochemistry Research at the University of Vermont for cases and controls and for a random sample of participants in each treatment group. Biomarkers for the random sample and the case–control study were analyzed in the same batches blinded to treatment group (DC or VS) and case–control status. These six biomarkers were prospectively chosen because they have high laboratory and biological reproducibility  and havePlasma samples collected at baseline and during follow-up were identified for all who died (85 participants) prior to 11 January 2006, and for two matched controls for each death (170 patients) . MatchinThe single follow-up specimen selected for each participant was from the visit before death (latest level). Specimens from the same follow-up visit were used for the matched controls. Follow-up specimens were available for 74 deaths and 141 controls. The median time between measurement of follow-up biomarkers and death was 69 d .Nested case–control studies with the same matching criteria were also carried out for all cases of AIDS and for cases of CVD, renal disease, and liver disease. These studies will be reported separately. In selected analyses, controls from these studies were used to supplement the controls chosen for deaths . SpecifiSpecimens collected at study entry and 1 mo after randomization were identified for a random sample of 250 participants from each treatment group who reported no history of CVD at entry . One parp-values. In addition to models that categorized biomarkers according to quartiles, models with log10 transformed biomarker levels were considered, and estimated parameters were used to determine the increase in risk associated with a difference in the biomarker corresponding to its interquartile range (IQR). The IQR was determined from the random sample of 499 study participants. Separate models were fit for each biomarker. The following covariates assessed at study entry were used for the adjusted analyses cited: age, self-reported race , use of ART and HIV-RNA level , CD4+ cell count, smoking status, body mass index (BMI), prior CVD, diabetes, use of blood pressure (BP) medication, use of lipid-lowering medication, total/HDL cholesterol, co-infection with hepatitis B or C, and treatment group.Summary statistics and illustrations appropriate for matched case–control studies were used to summarize key findings . ConditiFor some biomarkers very large ORs for the associations with mortality were observed. To investigate the possibility that these large ORs were due to sparse data , the num10 transformed biomarker and treatment group) was included in the logistic models. Similar methods were used for studying subgroups defined by prior disease history, co-infection with hepatitis, and baseline CD4+ cell count.The associations between baseline biomarker levels and mortality were considered for DC and VS participants separately. To assess whether associations between biomarker levels and mortality varied by treatment group, an interaction term  was used because there was a chance difference in the number of DC and VS controls with latest biomarker levels in the case–control study with 1:2 matching. This resulted in an unadjusted DC versus VS difference in mortality that was not as great as previously reported [For analyses of latest biomarker levels and mortality, log10 transformation) and HIV-RNA change at 1 mo for DC participants with an HIV-RNA level ≤400 copies/ml at study entry was studied using linear regression analysis.The association between each biomarker and other covariates at study entry was studied using linear regression analysis. Biomarker changes after 1 mo were compared for DC and VS participants using analysis of covariance. The association of biomarker change  . All repp = 0.007), baseline CD4+ count (p = 0.03), co-infection with hepatitis B or C (p = 0.0008), smoking status (p = 0.0001), diabetes (p = 0.03), use of BP-lowering treatment (p = 0.02), and prior CVD (p = 0.04) (p = 0.02), smoking (p = 0.01), prior CVD (p = 0.04), co-infection with hepatitis B or C (p = 0.03), and baseline CD4+ cell count (p = 0.10) were associated (p = 0.10 or lower) with mortality.Most of the deaths (79 of 85) occurred in the US. Sites in the US began enrollment 2 to 3 y before most sites in other countries and accounted for 55% of the randomized participants. In univariate analyses, cases and controls differed with respect to age ( = 0.04) . In multp < 0.0001); hsCRP was also significantly higher among deaths than controls (p = 0.005).With the exception of amyloid P, levels of the inflammatory markers were higher in deaths than matched controls  and upper quartile (>75th percentile) was striking. For D-dimer, there were 23 controls with levels in the lowest quartile (<0.18 μg/ml) that were matched with deaths that had levels in the upper quartile. In contrast, there were only two controls with D-dimer levels in the upper quartile matched with deaths in the lowest quartile. For IL-6, there were 25 controls with levels in the lowest quartile (<1.6 pg/ml) matched with deaths that had levels in the upper quartile, and three controls with IL-6 in the upper quartile matched with deaths in the lowest quartile.10 transformation, a difference corresponding to the IQR was associated with an OR of 3.4  for IL-6 and 3.9  for D-dimer. Covariate adjustment tended to strengthen these associations  was 2.0 . Higher levels of amyloid P were associated with a lower risk of death in analyses based on the continuous biomarker level, but no apparent trend by quartile was evident. This association was only of borderline significance after covariate adjustment and may be due in part to outliers. After excluding outliers (ten deaths and seven controls), the OR associated with a one IQR higher level of amyloid P was 1.1  .p = 0.002) for IL-6 and 6.1  for D-dimer. ORs for a difference corresponding to the IQR were 2.7  for IL-6 and 2.6  for D-dimer.When IL-6 and D-dimer were considered together in the same model they each remained significantly associated with all-cause mortality. Unadjusted ORs for the highest versus lowest quartile were 4.7 ; for those co-infected with hepatitis or not ; and for those with a baseline CD4+ cell less than 600 cells/mm3 (approximate median) and 600 cells/mm3 or more.Likewise, associations were similar for those with prior cancer, CVD, renal or liver disease (31% of deaths and 16% of controls), and those with no history of these conditions (p = 0.16), 2.5 , and 3.9 , respectively. For deaths occurring after the first year, ORs for hsCRP, IL-6, and D-dimer were 1.9 , 5.0 , and 3.9 .Associations with hsCRP, Il-6, and D-dimer were also similar for deaths in the first year (38 deaths) and after the first year (47 deaths). During the first year, the OR corresponding to the IQR for hsCRP, IL-6, and D-dimer were 1.5  for hsCRP, 3.2  for IL-6, and 3.2  for D-dimer.Deaths due to substance abuse (eight deaths) or to accidents, violence, or suicide (seven deaths) could attenuate the associations between the biomarkers and mortality. Thus, analyses were carried out excluding these 15 deaths. Unadjusted ORs corresponding to a difference equal to the IQR were 1.9  for hsCRP, 3.7  for IL-6, and 4.0  for D-dimer. Each of these ORs is larger by a small amount compared to the corresponding estimates in p = 0.0008 for IL-6 and p = 0.003 for D-dimer). After considering latest level of hsCRP, the study entry level was not significant (p = 0.07). In models that also included latest levels of HIV-RNA and CD4+ cell count, neither of which were significantly associated with all-cause mortality, these associations were diminished slightly but remained significant. For latest levels of hsCRP, IL-6, and D-dimer, the ORs were 2.2 (p = 0.009), 1.7 (p = 0.04), and 2.0 (p = 0.04).As previously reported, the majority of patients in SMART were using ART at entry . In the 10 transformation) on baseline covariates were performed. The covariates used in the regression analyses were the same as those used in the adjusted case–control analysis. An exception was history of CVD since no one in the random sample had a history of CVD  and for those on ART with an HIV-RNA over 400 copies/ml . Other biomarkers did not vary significantly according to use of ART and HIV-RNA level at study entry.Multiple regression analyses of each biomarker (after logy of CVD . D-dimerp = 0.19 for smoking and p = 0.16 for co-infection) or D-dimer (p = 0.64 for smoking and p = 0.39 for co-infection) at baseline. Smoking was not significantly associated with any of the biomarkers. hsCRP was lower by 0.217 μg/ml after log10 transformation (p = 0.0001) and amyloid P was lower by 0.068 (p = 0.0005) for those who were co-infected with hepatitis; co-infection was not associated with the other biomarkers.Smoking and co-infection with hepatitis B or C, which were both significantly related to mortality, were not significantly associated with either IL-6  and BMI . For log10 D-dimer, in addition to ART and HIV-RNA level, levels were greater among older participants , for black participants , for participants with diabetes , and for those with greater BMI . D-dimer levels were lower for men  and for those with higher CD4+ cell counts . To put these changes in perspective, the IQRs on the log10 scale for IL-6 and D-dimer were 0.39 pg/ml and 0.58 μg/ml, respectively. Differences as large as the IQR for each marker were associated with 3- to 4-fold greater risks of all-cause mortality.Significant predictors of log10 transformed biomarker levels 1 mo after randomization. IL-6 and D-dimer increased significantly  from study entry to 1 mo in the DC group compared to the VS group (p < 0.0001). Considering the non-transformed levels, the median increase in D-dimer for DC patients was 0.05 μg/ml (a 16% increase); IL-6 increased by 0.60 pg/ml in the DC group (a 30% increase). For VS patients, the median increases were 0.0 μg/ml and 0.12 pg/ml (a 5% increase) for D-dimer and IL-6, respectively. Changes in hsCRP and amyloid A were in the same direction—greater increases for DC compared to VS patients—but did not differ significantly between treatment groups.p < 0.0001 for treatment difference). Similarly, for IL-6, the median increases for DC and VS patients were 0.98 (a 43% increase) and 0.08 pg/ml, respectively (p < 0.0001 for difference).For both IL-6 and D-dimer, treatment differences were greater for patients who were on ART at entry and had HIV-RNA levels 400 copies/ml or below. For this subgroup (52% of patients), D-dimer increased in the DC group by 0.07 μg/ml (a 27% increase) and declined in the VS group by −0.02 μg/ml  increased risk of death.Results in Matched logistic models were used to assess the effect of adjusting for latest levels of IL-6 and D-dimer on the DC/VS OR for death. In the model with two controls per case, the unadjusted OR for the DC versus the VS group was 1.3 . Because this OR was considerably lower than the hazard ratio previously reported for all-cause mortality [We also considered the effect of adjusting for both study entry and latest levels of IL-6 and D-dimer and of adjusting for HIV- RNA and CD4+ cell count on the DC/VS OR . SimilarElevated levels of either IL-6 or D-dimer at study entry were strongly related to all-cause mortality in the case–control study. In the random sample, both D-dimer and IL-6 increased in the DC group compared to the VS group, particularly in the large subgroup on ART at entry with a suppressed HIV-RNA level. Increases in both markers in the DC group were related to the level of HIV-RNA after 1 mo. Finally, increases in these markers following randomization were associated with mortality. Taken together, these findings suggest that HIV-induced activation of inflammatory and coagulation pathways has an adverse effect on all-cause mortality among patients with relatively preserved CD4+ counts, and that interrupting ART may further increase this risk by raising IL-6 and D-dimer levels. Further research on the relationship of these biomarkers with mortality and morbidity in treated and untreated HIV-infected individuals is warranted.The associations between IL-6 and D-dimer levels at study entry with all-cause mortality were much stronger than in previous studies of non-HIV-infected populations that usually focused on CVD morbidity and mortality ,20–22,313 at entry  require validation, as mortality rates were low. However, if substantiated, and because most patients in the VS group had HIV-RNA levels of 400 copies/ml or less at study entry, ongoing activation of these pathways may exist even in the presence of effective ART, consistent with data demonstrating ongoing viral replication, even in patients with HIV-RNA of less than 50 copies/ml . ConsideIncreases in hsCRP, IL-6, and D-dimer from study entry to the visit preceding the death were associated with an increased risk of death. Whether the activation of tissue factors secondary to inflammation is the key event is likely but unproven in this study. Several alternative hypotheses are possible. One study showed that tissue factor, an initiator of coagulation, is generated by HIV-related proteins and could have pathologic effects . AnotherART interruption resulted in increases in IL-6 and D-dimer, therefore the effect of these treatment differences on the DC/VS OR for mortality was explored. Adjustment for follow-up (latest) levels of IL-6 and D-dimer resulted in a modest reduction of the DC/VS OR for mortality, supporting the hypothesis that the excess risk of death in the ART interruption group may be explained by biological mechanisms for which IL-6 and D-dimer are markers.There are some limitations in our work. Confidence intervals for ORs were wide due to the small number of deaths. While we selected six biomarkers from a large number of possible markers based on previous work in non-HIV-infected populations, some associations may have resulted from chance. This is less likely for the associations of IL-6 and D-dimer levels at study entry with all-cause mortality, which were highly significant. Cost considerations limited the number of controls for each death for which we could assess biomarkers. This reduced the statistical power to detect associations with mortality. The limited matching carried out, particularly for the expanded case–control study with four controls, may have resulted in incomplete control of confounding factors. However, regression adjustment for a number of covariates did not alter our overall conclusions. We measured latest levels at the visit immediately prior to the event of interest. For biomarker levels proximal to death, it is possible that reverse causality  may explain these findings. In addition, follow-up specimens were not available for 11 deaths and 29 controls, and this limited our ability to assess the prognostic importance of biomarker changes on mortality. Finally, while we did not find evidence for different associations with mortality for DC compared to VS patients, the number of events experienced by VS patients was small, limiting the power for those comparisons. Similarly, power for other subgroup analyses considered was also low.In summary, elevated levels of D-dimer and IL-6 identify HIV-infected patients at high risk of death. The magnitude of the association is clinically relevant and reasons for it require further study.Figure S1Matching was on date of randomization to ensure latest levels for deaths, and controls were determined at similar time point following randomizations.Click here for additional data file.Figure S2Solid lines give median levels at baseline for deaths (4.3 μg/ml) and controls (2.1 μg/ml). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Figure S3Solid lines give median levels at baseline for deaths (4.75 mg/l) and controls (3.65 mg/l). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Figure S4Solid lines give median levels at baseline for deaths (58.8 μg/l) and controls (67.8 μg/l). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Figure S5IL-6 level was missing for one death. Solid lines give median levels at baseline for deaths (3.8 pg/ml) and controls (2.3 pg/ml). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Figure S6Solid lines give median levels at baseline for deaths (0.49 μg/ml) and controls (0.26 μg/ml). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Figure S7F1.2 level was missing for one death. Solid lines give median levels at baseline for deaths (344.0 pmol/l) and controls (351.4 pmol/l). Red circles and lines are for deaths, and blue circles and lines are for controls.Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.Table S4Click here for additional data file.Table S5Click here for additional data file.Text S1Click here for additional data file.Text S2Click here for additional data file.


P < 0.0001), alanine aminotransferase >3 × ULN , non-cirrhotic status , age ≤ 40 years , white non-Latino ethnicity  and individual study (P < 0.0001). These factors plus body mass index ≤ 27 kg/m2 were predictive of cEVR. After adjusting for these factors, mean on-treatment ribavirin dose >13 mg/kg/day was predictive of RVR  and cEVR , whereas peginterferon alfa-2a dose reduction was not. Greater decreases in haematologic parameters were observed in patients who achieved cEVR compared with patients who did not. In conclusion, several baseline and on-treatment factors were associated with RVR and cEVR to peginterferon alfa-2a plus ribavirin in difficult-to-treat HCV genotype-1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population.Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on-treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR . The analysis comprised 1550 HCV genotype-1 patients from five clinical trials, including three enriched with difficult-to-treat populations, randomized to peginterferon alfa-2a 180 μg/week plus ribavirin 1000–1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA ≤ 400 000 IU/mL (OR: 7.34;  The recommended treatment for chronic hepatitis C (CHC) patients is combination therapy with pegylated interferon plus ribavirin. The goal of this treatment is a sustained virologic response (SVR), defined as the absence of detectable viral ribonucleic acid (RNA) at 6 months after the end of treatment. Despite improvements that have increased SVR rates, treating CHC remains a challenge in certain populations such as those patients infected with hepatitis C virus (HCV) genotype 1, with high viral load, cirrhosis or of African American race/ethnicity .10 decrease from baseline in HCV RNA after 12 weeks of treatment) had a lower likelihood of achieving SVR with an additional 36 weeks of treatment ) in the intent-to-treat (ITT) efficacy analyses of virologic end-points. There were small variations between studies in the detection limits for HCV RNA. Undetectable levels were defined as HCV RNA <28 IU/mL in one study (Roche High Pure System/COBAS® TaqMan® HCV Monitor Test) , <60 IU/vs >40 years), sex, race/ethnicity (white non-Latino vs other), body mass index , baseline alanine aminotransferase (ALT) quotient , serum HCV RNA concentration (≤400 000 vs >400 000 IU/mL), cirrhosis classification (cirrhotic vs non-cirrhotic) and individual study. The final model was based on the stepwise multiple variable logistic regression. Factors that had a P < 0.1 from the univariate analysis were allowed to enter the multiple regression model and factors with an adjusted P < 0.2 were kept in the model. Wald chi-square confidence intervals (CI) and P-values were used for testing the effects; P ≤ 0.2 indicated significant factors that remained in the final model. To account for differences between the studies, each individual study was forced into the model as a stratification factor regardless of its significance level. Odds ratios (OR) and 95% CI were calculated for the independent predictive factors.Baseline and demographic factors used in stepwise multiple logistic regression analyses included age (≤40 vs >13 mg/kg) and peginterferon alfa-2a dose reductions (yes vs no).Additional multiple variable logistic regression analyses included adjusting for all individually identified significant baseline prognostic factors and investigating the association of two on-treatment characteristics with RVR and cEVR: average daily exposure to ribavirin  measures of host responses to interferons and may also reflect drug exposure and adherence.Neutrophil counts, platelet counts and hemoglobin concentrations were assessed to determine if there were any associations between virologic and haematologic responses in these patients. Changes from baseline in these haematologic parameters were compared at weeks 4 and 12 in the RVR P-values from the univariate analyses are presented in Patient demographics and characteristics at baseline are shown in Overall, a total of 16 patients (1%) and 40 patients (2.6%) withdrew from the study due to safety reasons by weeks 4 and 12, respectively. Seventeen patients (1.1%) and 44 patients (2.8%) withdrew due to non-safety reasons by weeks 4 and 12, respectively. Adverse events leading to withdrawal by week 4 included anaemia, chest pain, fatigue, rash, tongue oedema, headache, gastrointestinal events such as nausea and abdominal pain, and psychiatric effects such as aggression, suicide ideation and emotional instability.P < 0.0001), ALT quotient >3 × ULN , non-cirrhotic status , age ≤40 years , white non-Latino race  and individual study (P < 0.0001). The same independent factors were associated with a cEVR in this analysis: baseline serum HCV RNA ≤400 000 IU/mL , non-cirrhotic status at baseline , age ≤40 years , baseline ALT quotient >3 × ULN , white non-Latino race  and individual study (P < 0.0001). In addition, BMI (≤27 vs >27 kg/m2) was associated with a cEVR in this analysis . In this report we defined HCV RNA <400 000 IU/mL as low viral load. However, similar results were obtained when the analysis was repeated with higher HCV RNA cut-off levels (≤600 000 vs >60 000 IU/mL and ≤800 000 vs >800 000 IU/mL). Also, similar results were also obtained when the analysis was repeated using different BMI cut-off levels (>25 vs≤25 kg/m2 and >30 vs≤30 kg/m2) .The results of the multiple logistic regression analyses demonstrated that baseline factors independently associated with a RVR included serum HCV RNA ≤400 000 IU/mL  and cEVR . BMI was associated with cEVR before, but was not after, adjusting for ribavirin exposure. BMI was not associated with RVR (vs no) was not a predictor of RVR or cEVR.After adjusting for significant risk factors in the baseline characteristics model , multiplwith RVR . In contP = 0.0003). Platelet counts decreased from baseline at weeks 4 and 12 in all groups although the changes were not significant. Mean haemoglobin concentrations also decreased between weeks 4 and 12 in all groups. The decrease from baseline to week 12 in the cEVR group was greater than that in the non-cEVR group (P = 0.0160). In the univariate analysis, body weight and on-treatment drug exposure were both associated with RVR and cEVR. The influence of these factors on the observed decreases in haematologic parameters between the response and non-response groups was analysed. After adjusting for body weight and on-treatment drug exposure, the decrease from baseline to week 12 in neutrophil counts and haemoglobin concentrations in the cEVR group compared with the non-cEVR group remained significant ; the decrease in platelet counts remained non-significant (P = 0.2093) . The results in the RVR and non-RVR groups also remained unchanged. This suggests that body weight and on-treatment drug exposure were not confounding factors in the observed haematologic changes between the response and non-response groups.The association of other host pharmacodynamic effects of peginterferon and ribavirin with antiviral activity was investigated . In the The response to antiviral therapy in HCV-infected patients is heterogeneous and, despite increases in SVR rates, treatment outcomes with peginterferon alfa-2a plus ribavirin are not optimal in certain patient populations and might still be improved ,2. MonitBoth RVR and cEVR are associated with the achievement of SVR in patients with CHC . Identifvs≤13 mg/kg/day was associated with a greater proportion of patients achieving RVR and cEVR . Further analysis to determine the effect of average on-treatment daily ribavirin dose on the likelihood of RVR and cEVR suggested that a linear relationship existed up to ∼12 and 10 mg/kg/day, respectively, after which the effect remained relatively constant (data not shown). However, cut-off points could not be identified since no clear inflection points were obtained. Individual study was also found to be predictive of RVR and cEVR even after adjusting for the effects of known factors such as Latino ethnicity which accounted for ∼50% of the LATINO study population [The analysis presented here demonstrated that several patient characteristics, including lower serum HCV RNA, higher ALT quotient, absence of cirrhosis, younger age and white non-Latino race/ethnicity were associated with successful achievement of RVR and cEVR in patients infected with HCV genotype 1. In addition, lower BMI was associated with achieving cEVR. The effects of peginterferon-alfa 2a dose and ribavirin dose on RVR and cEVR were also analysed. Ribavirin dose was a predictor of RVR and cEVR, whereas peginterferon-alfa 2a dose or dose reduction was not. This finding is in agreement with previous studies that evaluated the effect of ribavirin dose reductions on virologic response rates in HCV genotype 1-infected patients . Our anaet al. [post hoc analysis of 216 HCV genotype 1-infected patients randomized to 24 weeks of treatment with peginterferon alfa-2a 180 μg/week plus ribavirin either 800 mg/day (low dose) or 1000/1200 mg/day (standard dose), and showed that baseline viral load was a significant predictor of RVR. Although the overall RVR rate was 23.6%, patients with baseline HCV RNA <200 000 IU/mL, 200 000–600 000 IU/mL and >600 000 IU/mL had RVR rates of 49.1%, 26.0% and 9.2%, respectively. Statistical analysis showed that, relative to patients with baseline HCV RNA >600 000 IU/mL, those patients with HCV RNA <200 000 IU/mL  or 200 000–600 000 IU/mL  were significantly more likely to achieve RVR. Overall, SVR rates were considerably higher in patients who achieved RVR than in those patients who did not (89%vs 19%), and RVR was a significant predictor of SVR . In addition, patients infected with HCV subtype 1b were more likely to achieve RVR than those patients infected with HCV subtype 1a . A lack of RVR was also associated with liver fibrosis or cirrhosis. More recently, in a multicenter study conducted in the south of Italy, 696 HCV genotype 1-infected patients were randomized to treatment with peginterferon alfa-2a or alfa-2b, each plus ribavirin, for either 48 weeks or for an individualized duration based on the time at which HCV RNA undetectability was first achieved [P = 0.004), low baseline viral load (P = 0.0001) and fibrosis stage ≤2 (P = 0.0001) were associated with RVR. In multivariate analysis, HCV RNA levels <400 000 IU/mL  and absence of advanced fibrosis  were independently associated with achieving a RVR. Lower baseline viral load (<400 000 IU/mL) was also the only significant factor associated with a RVR  in 200 previously untreated Taiwanese patients infected with HCV genotype 1 who were randomized to treatment with peginterferon alfa-2a plus ribavirin for either 24 or 48 weeks [Limited data have been published regarding the factors associated with RVR and cEVR. A few studies have shown that in patients receiving peginterferon alfa plus ribavirin, lower viral load, younger age, lower body weight and absence of advanced fibrosis may be associated with a RVR ,19–21. Jet al.  conducteHaematologic adverse effects are relatively common when interferons are combined with ribavirin  and can In the current analysis, 16% of patients achieved RVR. This rate is lower than the rates reported in other studies ,20,21 anIn this retrospective analysis, we demonstrated that baseline and on-treatment factors, including lower serum HCV RNA concentration, higher ALT quotient, absence of cirrhosis, younger age, white non-Latino ethnicity and daily on-treatment ribavirin dose >13 mg/kg, were independently associated with achieving RVR and cEVR in patients infected with HCV genotype 1 and treated with peginterferon alfa-2a plus ribavirin for 48 weeks. There is a need to improve further the efficacy of combination therapy, as well as limit the associated side-effects and healthcare costs, especially in those patient populations considered difficult to treat. Optimizing the antiviral response is crucial for accomplishing these goals. Since ribavirin dose is one of the only modifiable factors identified in this analysis that is associated with an increase in RVR and cEVR, physicians may be advised to maintain a higher ribavirin dose to increase the likelihood of achieving SVR. Thus, identifying the predictors of response to peginterferon alfa-2a plus ribavirin therapy and tailoring treatment regimens for individual patients based on their risk profile may be one approach for achieving maximum antiviral response. These findings will need to be supported by large, prospective clinical studies that are designed to evaluate whether SVR rates can be increased by modifying baseline or on-treatment factors.


Anti-epileptic drugs (AEDs) are frequently prescribed to persons with HIV/AIDS receiving combination antiretroviral therapy (cART) although the extent of AED use and their interactions with cART are uncertain. Herein, AED usage, associated toxicities and immune consequences were investigated.HIV replication was analysed in proliferating human T cells during AED exposure. Patients receiving AEDs in a geographically-based HIV care program were assessed using clinical and laboratory variables in addition to assessing AED indication, type, and cumulative exposures.in vitro of both HIV-infected and uninfected T cells (p <0.05) but AED exposures did not affect HIV production in vitro. Among 1345 HIV/AIDS persons in active care between 2001 and 2007, 169 individuals were exposed to AEDs for the following indications: peripheral neuropathy/neuropathic pain (60%), seizure/epilepsy (24%), mood disorder (13%) and movement disorder (2%). The most frequently prescribed AEDs were calcium channel blockers , followed by sodium channel blockers  and valproate. In a nested cohort of 55 AED-treated patients receiving cART and aviremic, chronic exposure to sodium and calcium channel blocking AEDs was associated with increased CD4+ T cell levels (p <0.05) with no change in CD8+ T cell levels over 12 months from the beginning of AED therapy.Valproate suppressed proliferation AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved. The i certain .in vitro effects of frequently used AEDs on T cell proliferation and HIV replication.Given these complex circumstances, the working hypothesis was: as AEDs are frequently prescribed for protracted periods for a variety of conditions in HIV/AIDS patients, AEDs might exert substantial effects on virologic, immunologic and clinical outcomes. Viremic status provides a robust indicator of control of HIV infection, which can be used to monitor potentially adverse effects of other interventions such as AEDs initiation, as assessed in the present studies. Herein, we investigated the extent and impact of AED use among aviremic and viremic persons with HIV/AIDS attending a regional HIV program as well as the Primary human peripheral blood lymphocytes (PBLs) were purified from healthy HIV seronegative subjects' blood with Histopaque (Sigma) and maintained in RPMI 1640 medium with 15% FBS with phytohemagglutinin-P (PHA-P) stimulation for 3 days, followed by hIL-2 stimulation and/or an anti-hCD3 monoclonal antibody  for the duration of the experiment [10 copies/ml). SAC has access to all contemporary antiretroviral drugs approved in Canada.The Southern Alberta Clinic (SAC) is a multidisciplinary, geographically-based clinical program, which provides care to all HIV seropositive patients in southern Alberta, Canada . ParticiAll adult patients receiving AEDs were identified within the clinic database (Jan 01/2001-May 01/2007), an in-house computerized database containing all relevant patient characteristics dating back to 1985, which is updated with each patient visit to the clinic. Clinical aspects, laboratory findings, demographic features and AED usage were analyzed. Liver function tests (LFTs) , aspartate aminotransferase (AST), total bilirubin) were recorded for every AED-treated patient during AED therapy. The severity of hepatotoxicity was graded based on the guideline of AIDS clinical trial group (ACTG)  and the 10 copies/ml) prior to the introduction of an AED and remained on the same cART regimen for the full duration of AED exposure/therapy and had no episodic of protracted virologic failure (>2 log10 copies/ml) during the period of concomitant exposure to cART and AED; patients were defined as "viremic" if they had detectable viral loads, because they were unable to maintain sustained adherence to drug therapies or had not received antiretroviral therapy prior to AED treatment. The viral load, CD4+ and CD8+ T cell levels prior to initiating AED therapy (baseline) were compared with corresponding values at 6 and 12 month follow-up visits. Patients were not included in this sub-analysis if they did not have viral loads or CD4+ T cell levels prior to the initiation of AED therapy or received AED therapy less than 6 months.AED-treated patients were stratified into two groups based on virologic status: AED-receiving patients were defined as "aviremic" if they had been receiving cART for at least one month with an undetectable plasma viral (aviremic) load  were exposed to AED therapy among all HIV/AIDS patients (n = 1345) actively receiving care at SAC during the study period in the current cohort. Comparison of demographic and clinical features of AED-treated viremic and aviremic (stable cART regimen) patients disclosed no differences in age, mortality, AIDS status, gender, ethnicity, HIV risk factor, duration of HIV infection and CD4+ T cell nadir and viral burden at the time of first diagnosis although CD4+ T cell levels were significantly higher at the time of HIV diagnosis in the viremic group  Figure . The AEDThe potential for metabolic interactions between AEDs and different cART regimens is substantial, particularly in terms of ensuing hepatic dysfunction . To addrin vivo, AEDs were classified based on their putative mechanisms of action within the cART and AED-exposed aviremic group including calcium channel blockers  (55.4%), sodium channel blockers  (21.5%), valproate (13.9%), and Others  (9.2%). Among the 55 patients in this group, 8 were treated with more than one AED at different times during the study period. Viremic patients or ARV-naïve patients had detectable viral loads (>2 log10 copies/ml)  loads were maintained at or near detection levels in aviremic group during the 12 months of treatment irrespective of whatever AED prescribed to the patients  Figure . Mean pls Figure . Aviremis Figure . Over ths Figure . In conts Figure . Mean bls Figure . These fThe present study provides the first longitudinal analysis of cumulative AED use in patients with serious systemic comorbidities and at high risk of drug interactions. Indeed, AEDs were prescribed for multiple indications with limited side-effects in this broadly representative regional population of HIV-infected persons. Despite frequent use and high cumulative doses of AEDs, no events of virologic or organ failure, attributable to AED use were recorded. Drugs within all of the AED classes were prescribed herein but sodium and calcium channel blocking AEDs were the most commonly observed with associated benefits in terms of a rise in CD4+ T cell levels over time while valproate was not associated with improvement in systemic immunity. The frequent use (>10%) of AEDs in HIV/AIDS patients also underscored the burden of neuropsychiatric diseases within this patient population yet provides assurance that AEDs can be used safely among patients receiving cART without serious adverse consequences.Due to the numerous potential interactions between AEDs and cART in terms of hepatic metabolism, neuropsychiatric and renal side-effects, the relative paucity of adverse events herein was encouraging. In fact, minimal changes in AEDs regimens were required, as dictated by measured AED blood levels. In some instances, the AED dosages were increased to compensate for increased metabolism to achieve therapeutic AED blood levels. Although 1/3 of patients exhibited one abnormal LFT, the severities of abnormal LFTs were mild. This relative lack of undesirable interactions might have been due to regular clinical monitoring of patients with repeated AED blood levels when available  together with the frequent use of gabapentin/pregabalin, which are excreted renally. Importantly, previous studies suggest that AEDs including gabapentin and lamotrigine were well tolerated when prescribed to patients with HIV/AIDS ,25,26. Nin vitro although the mechanism remains uncertain but this effect was thought to enhance clinical clearance of the virus from tissue reservoirs, eventually improving clinical outcomes [in vitro regardless of the presence or absence of concomitant HIV infection, suggesting that valproate influenced the ability of T cells to divide efficiently and further analysis on the effects of antiepileptic drugs on T cell subpopulation is of interest. Indeed, valproate has recently been shown to affect proliferation of malignant cells [in vivo effects on viral replication or CD4+ T cell levels [In the present study, several patients were receiving valproate; of interest, earlier studies suggested that valproate increased HIV replication outcomes . Howeveroutcomes . Conversnt cells ,28 but hl levels ,29-31. HThis report is the first to assess cumulative exposure of multiple AEDs in any population over time. Despite high cumulative doses of different AEDs, our study showed that the use of several AEDs in HIV-infected patients receiving cART was comparatively safe and might be beneficial to immune status. These findings are clinically relevant because AEDs are widely prescribed in HIV-infected patients with various neuropsychiatric syndromes, as well as in the general population. In summary, this is the first analysis of AED use and effects in HIV/AIDS patients closely monitored in a clinical setting, but also raised interesting questions to be explored in the future regarding immune benefits of AEDs and their underlying mechanisms.ACTG: AIDS clinical trial group; AED: anti-epileptic drug; AIDS: acquired immune deficiency syndrome; ALT: alanine aminotransferase; ARV: antiretroviral drug; AST: aspartate aminotransferase; cART: combination antiretroviral therapy; CCB: calcium channel blocker; CFSE: carboxyfluorescein succinimidyl ester; LFT: liver function test; HIV: human immunodeficiency virus; IQR: interquartile range; PBL: peripheral blood lymphocyte; PHA-P: phytohemagglutinin-P; SAC: Southern Alberta Clinic; SCB: sodium channel blockerThe authors declare that they have no competing interests.in vitro studies, performed statistical analysis and data interpretation together with drafted and revised the manuscript content. RS and HBK took part in acquisition and analysis of clinical data. FM participated in the in vitro studies and data analysis. MJG was involved in study concept and design, data analysis and manuscript drafting. CP participated in study concept and design, obtained funding, as well as drafted and revised the manuscript. All the authors have read and approved the final version of the manuscript.KL participated in the development of study concept, acquired and performed analysis of clinical data. PV carried out the The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/44/prepubFigure S1. Liver toxicity of AEDs. (A) and (B) Based on ACTG guidelines, aviremic patients with concurrent AED use had similar aspartate aminotransferase (AST) and alkaline phosphatise abnormalities to viremic patients (3A and 3B). In contrast, aviremic patients showed a trend toward lower hyperbilirubinemia (3E). Both aviremic and viremic patients displayed similar profile of additional LFT abnormalities after the initiation of AEDs (Figure s Figure .Click here for file


Sir,I thank Dr. Gonzalez for replying. I want tThe goal of initial HAART in the naïve patient should be to devise a regimen that will achieve maximal durable viral suppression (<50 copies/mL) and be tolerated for an indefinite period of time.3For ARV therapy-naïve patients, the initial HAART regimen should include a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a ritonavir-boosted protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Unfortunately, there is no clear data available at present on which to base distinction between these two approaches.3The use of NNRTI-based regimen for initial therapy may preserve PIs for later use. For NNRT3 or men with CD4 counts >400 cells/mm3. However, it can be used in men and women with CD4 counts <400 and <250 cells/mm3, respectively.[We agree with you that clinicians should not use nevirapine as part of the initial regimen in women with CD4 counts >250 cells/mmThe nevirapine as initial treatment is contraindicated only in cases of moderate to severe hepatic impairment (Child-Pugh score B or C). This patWhen nevirapine or efavirenz were used as initial treatment, no significant difference was noted in efficacy between these two drugs in combination with stavudine and lamivudine and toxicity was only slightly higher with nevirapine.Lamivudine/stavudine/nevirapine is one of the prescribed regimens for treatment of HIV in African countries as approved by the World Health Organization. It is used as a first-line combination in eight African countries. This is also the most cost-effective initial drug regimen.I agree with the author that measuring serum antiretroviral drug levels after transplant might help with drug dosing.